The diagnostic value of conventional radiography and musculoskeletal ultrasonography in calcium pyrophosphate deposition disease: a systematic literature review and meta-analysis.

OBJECTIVE: To examine and compare the accuracy of conventional radiography (CR) and musculoskeletal ultrasonography (US) in the diagnosis of calcium pyrophosphate (CPP) crystals deposition disease (CPPD). DESIGN: A systematic search of electronic databases (PubMed, Embase, and Cochrane), conference abstracts and reference lists was undertaken. Studies which evaluated the accuracy of CR and/or US in the diagnosis of CPPD, using synovial fluid analysis (SFA), histology or classification criteria as reference tests were included. Subgroup analyses by anatomic site and by reference test were performed. RESULTS: Twenty-six studies were included. Using SFA/histology as reference test, CR and US showed an excellent (CR AUC = 0.889, 95%CI = 0.811-0.967) and an outstanding (US AUC = 0.954, 95%CI = 0.907-1.0) diagnostic accuracy (p < 0.01), respectively. Furthermore, US showed a higher sensitivity (0.85, 95%CI = 0.79-0.90 vs 0.47, 95%CI = 0.40-0.55) and only a little lower specificity (0.87, 95%CI = 0.83-0.91 vs 0.95, 95%CI = 0.92-0.97) than CR. A considerable heterogeneity between the studies was found, with adopted reference test being the main source of heterogeneity. In fact, subgroup analysis showed a significant change in the diagnostic accuracy of CR, but not of US, using Ryan and McCarty criteria or SFA/histology as reference test (CR: AUC = 0.956, 95%CI = 0.925-1.0 vs AUC = 0.889, 95%CI = 0.828-0.950, respectively, p < 0.01) (US: AUC = 0.922, 95%CI = 0.842-1.0 vs AUC = 0.957, 95%CI = 0.865-1.0, respectively, p = 0.08) CONCLUSIONS: Although US is more sensitive and a little less specific than CR for identifying CPP crystals, both these two techniques showed a great diagnostic accuracy and should be regarded as complementary to each other in the diagnostic work-up of patients with CPPD.

Ultrasound in the assessment of musculoskeletal involvement in systemic lupus erythematosus: state of the art and perspectives.

Musculoskeletal manifestations are extremely common in patients with systemic lupus erythematosus. Transient and migratory arthralgia is frequently reported even without clinical signs of joint or tendon inflammation. In less than 15% of patients, joints may be more severely affected by deforming (Jaccoud's arthropathy) and/or erosive arthropathy (Rhupus syndrome). In recent years, ultrasound has emerged as a promising imaging technique for the assessment of musculoskeletal involvement in systemic lupus erythematosus, having demonstrated the ability to detect inflammation and structural damage both at articular and periarticular level. Recent ultrasound studies have also revealed new insights into musculoskeletal involvement in patients with systemic lupus erythematosus, some of them questioning the traditional concepts of systemic lupus erythematosus arthropathy, with potential clinical, prognostic and therapeutic implications. In daily clinical practice, the use of ultrasound in the assessment of joint and tendon involvement in patients with systemic lupus erythematosus is still limited. Several methodological issues encountered in ultrasound studies evaluating musculoskeletal involvement in systemic lupus erythematosus patients need to be addressed in order to improve both the reliability and clinical usefulness of ultrasound findings. This paper reviews ultrasound studies assessing musculoskeletal involvement in patients with systemic lupus erythematosus, highlighting certainty, limits, potential applications and future perspectives of ultrasound use in systemic lupus erythematosus patients.

Systemic lupus erythematosus arthropathy: the sonographic perspective.

Background Despite being promising, the use of ultrasound (US) in the assessment of musculoskeletal manifestations of systemic lupus erythematosus (SLE) is still limited. Literature on this topic is scarce and the spectrum and clinical relevance of US abnormalities has not yet been outlined. With this paper, we aim to explore the panel of joint and tendon US findings in a group of SLE patients. Methods Twenty-five consecutive SLE patients, with current or medical history of musculoskeletal symptoms, were studied. All patients underwent routine clinical examination and US evaluation. The US examination targeted sites clinically involved in the physical examination and/or indicated as painful in the patient's medical history. Results One or more US changes were found in all the patients. US abnormalities were detected in 85 out of the 243 scanned joints (35%), in 70 out of the 215 scanned tendons (32.6%) and in 10 out of the 41 scanned entheses (24.4%). Synovial effusion, synovial hypertrophy, "mixed" synovitis (coexistence of synovial effusion and synovial hypertrophy), joint dislocation, bone erosion, and cartilage damage were found in 9.5%, 11.5%, 14%, 3.7%, 2.1%, and 4.5% of the scanned joints, respectively. Tenosynovitis, tendon dislocation, tendon tear, tendon thinning, and tendinitis/peritendinitis were detected in 17.7%, 8.4%, 0.9%, 4.2%, and 4.7% of the scanned tendons, respectively. Power Doppler signal, hypoechogenicity, thickening, enthesophytes, calcifications, and bone erosions were detected at the entheseal level in 12.2%, 9.8%, 12.2%, 7.3%, 7.3%, and in 0% of the scanned entheses, respectively. Conclusions This study revealed an unexpectedly wide heterogeneity of US pathologic findings in the joints and tendons of patients with SLE. A broad spectrum of US changes also involving anatomic structures not considered in previous investigations, including entheses and tendons with no synovial sheath, was detected. These preliminary results suggest that US is able to identify several US "patterns" whose clinical, prognostic, and pathogenetic significance is still to be defined.

Opposite effects of ß2-adrenoceptor gene deletion on insulin signaling in liver and skeletal muscle.

BACKGROUND AND AIM: ß2-Adrenoceptors (ß2-ARs) are G protein-coupled receptors (GPCRs) expressed in the major insulin target tissues. The interplay between ß2-AR and insulin pathways is involved in the maintenance of glucose homeostasis. The aim of this study was to explore the consequences of ß2-ARs deletion on insulin sensitivity and insulin signaling cascade in metabolically active tissues. METHODS AND RESULTS: We evaluated glucose homeostasis in skeletal muscle and liver of ß2-AR-null mice (ß2-AR-/-) by performing in vivo (glucose tolerance test and insulin tolerance test) and ex vivo (glucose uptake and glycogen determination) experiments. ß2-AR gene deletion is associated with hepatic insulin resistance and preserved skeletal muscle insulin sensitivity. Importantly, we demonstrate that hepatic ß2-AR regulates insulin-induced AKT activation via Grb2-mediated SRC recruitment through a Gi-independent mechanism. CONCLUSIONS: ß-AR stimulation contributes to the development of early stages of insulin resistance progression in the liver. Our findings indicate that the cross-talk between ß2-AR and insulin signaling represents a fundamental target towards the development of novel therapeutic approaches to treat type 2 diabetes and metabolic syndrome.

Dual role of GRK5 in cancer development and progression.

GRK5 is a multifunctional protein that is able to move within the cell in response to various stimuli to regulate key intracellular signaling from receptor activation, on plasmamembrane, to gene transcription, in the nucleus. Thus, GRK5 is involved in the development and progression of several pathological conditions including cancer. Several reports underline the involvement of GRK5 in the regulation of tumor growth even if they appear controversial. Indeed, depending on its subcellular localization and on the type of cancer, GRK5 is able to both inhibit cancer progression, through the desensitization of GPCR and non GPCR-receptors (TSH, PGE2R, PDGFR), and induce tumor growth, acting on non-receptor substrates (p53, AUKA and NPM1). All these findings suggest that targeting GRK5 could be an useful anti-cancer strategy, for specific tumor types. In this review, we will discuss the different effects of this kinase in the induction and progression of tumorigenesis, the molecular mechanisms by which GRK5 exerts its effects, and the potential therapeutic strategies to modulate them.

[An unusual pneumomediastinum case in a child caused by spontaneous bronchial rupture]. / Un insolito caso di pneumomediastino in un bambino da rottura spontanea di bronco.

We report a case of spontaneous pneumomediastinum (SPM) in a 3 year-old child, admitted to the emergency department because he presented dyspnea for a few hours, after a paroxysm of cough. The SPM is rare in children; the term "spontaneous" is reserved for cases of pneumomediastinum that haven't a traumatic cause. SPM is seen most commonly in asthmatics and in any patient who induces a Valsalva maneuver. The clinical diagnosis is confirmed by chest radiograph. When the diagnosis is uncertain, the chest CT scan is considered the gold standard of imaging tests, capable of detecting pneumomediastinum even in patients with small amounts of mediastinal air. In this case CT images showed the cause: spontaneous bronchial rupture. The direct sign of bronchial injury is the contiguity of the luminal air with that in the mediastinum. In the literature SPM cases are very rare, at least in health patients without tracheobronchial anomalies. The SPM is generally a benign entity that requires supportive care, and resolution occurs spontaneously, such as in our patient. In this article we want to explain the main clinical, diagnostic and therapeutic aspects of SPM, because, even if it's rare in children, it must be considered in the differential diagnosis of dyspnea; then we want to demonstrate as, in this case, a TC scan was important to identifying the SPM cause: a bronchial rupture.

Calmodulin-dependent kinase II mediates vascular smooth muscle cell proliferation and is potentiated by extracellular signal regulated kinase.

Vascular smooth muscle cell (VSMC) proliferation contributes to vascular remodeling in atherosclerosis and hypertension. Calcium-dependent signaling through calcium/calmodulin-dependent kinase II (CaMKII) and ERK1/2 activation plays an important role in the regulation of VSMC proliferation by agents such as alpha-adrenergic receptor agonists. Nevertheless, how the CaMKII and ERK pathways interact in VSMCs has yet to be characterized. The aim of the present study was to clarify this interaction in response to alpha(1)-adrenergic receptor-mediated VSMC proliferation. We discovered that phenylephrine stimulation resulted in complex formation between CaMKII and ERK in a manner that facilitated phosphorylation of both protein kinases. To assess the effects of CaMKII/ERK association on VSMC proliferation, we inhibited endogenous CaMKII either pharmacologically or by adenoviral-mediated gene transfer of a kinase-inactive CaMKII mutant. Inhibition of CaMKII activation but not CaMKII autonomous activity significantly decreased formation of the CaMKII/ERK complex. On the contrary, the expression of constitutively active CaMKII enhanced VSMC growth and CaMKII/ERK association. In addressing the mechanism of this effect, we found that CaMKII could not directly phosphorylate ERK but instead enhanced Raf1 activation. By contrast, ERK interaction with CaMKII facilitated CaMKII phosphorylation and promoted its nuclear localization. Our results reveal a critical role for CaMKII in VSMC proliferation and imply that CaMKII facilitates assembly of the Raf/MEK/ERK complex and that ERK enhances CaMKII activation and influences its subcellular localization.

beta-Blockade and increased dyslipidemia in patients bearing Glu27 variant of beta2 adrenergic receptor gene.

In this study, the effects of polymorphisms of the beta(2) and beta(3) adrenergic receptor genes on the occurrence of dyslipidemia and diabetes mellitus in hypertensive patients treated with beta-blockers (atenolol or metoprolol) were evaluated. Patients who gave written informed consent were asked to return for blood sampling for estimation of serum glucose, total cholesterol, HDL, triglycerides and for genotype determination. Genotyping analysis was performed by PCR-RFLP assay. In patients bearing beta(2)AR Glu27 or the beta(3)AR Arg64 variant there was a larger occurrence of hypertriglyceridemia, alone or in combination with elevated cholesterol levels. Furthermore, the beta(2)AR Glu27 variant significantly associates with hypetriglyceridemia in a cumulative fashion. The risk to develop this side effect after beta-blockade was four-fold higher in patients homozygous for the beta(2)AR Glu27 variant as compared to beta(2)AR27Gln allele. This result allows the identification of patients at high risk to develop metabolic complications to chronic beta-blockade treatment.

Radioimmunoassay to detect antitransglutaminase autoantibodies is the most sensitive and specific screening method for celiac disease.

OBJECTIVE: The aim of this study was to establish the most sensitive and specific screening method for celiac disease. We tested three methods based on different principles, which all detect autoantibodies against the same antigen (tissue transglutaminase). METHODS: Sixty-two celiac children at the first biopsy (group 1), 78 celiac children on a gluten-free diet (group 2), 14 celiac children on a gluten-challenge (group 3), and 56 controls with a normal duodenal mucosa (group 4) were studied. The methods used were: 1) radioimmunoprecipitation assay using recombinant tissue transglutaminase (RIA); 2) commercial enzyme immunoassay using guinea pig tissue transglutaminase (ELISA); and 3) indirect immunofluorescence method for detection of antiendomysium antibodies (IF-EMA). RESULTS: RIA antitransglutaminase autoantibodies were detected in 100% of group 1, 43.6% of group 2, 100% of group 3, and none of the control subjects. ELISA antitransglutaminase autoantibodies were detected in 90.3% of group 1, 9% of group 2, 78.6% of group 3, and in none of the control subjects. IF-EMA were detected in 95.2% of group 1, 11.5% of group 2, 92.3% of group 3, and 1.8% of the controls. CONCLUSIONS: Our results demonstrate a very high sensitivity and specificity of the RIA method to detect antitransglutaminase autoantibodies in comparison to ELISA and IF-EMA assays. We can explain this finding with the use of human recombinant antigen and the increased capacity of the RIA method to detect low titers of autoantibodies. If our data are confirmed by studies on larger series, tissue transglutaminase RIA could be proposed as the best screening method for celiac patients.

Importance of gluten in the induction of endocrine autoantibodies and organ dysfunction in adolescent celiac patients.

OBJECTIVE: It is well known that a high number of celiac patients may develop autoantibodies against endocrine glands, but it has not yet been clarified if this increased autoimmune response and the impaired organ function that can develop may be related to the presence or absence of gluten in the diet. The aim of the present study was to evaluate the effect of gluten on the autoimmunity and function of the endocrine glands in adolescent celiac patients. METHODS: To clarify this aspect we investigated 44 patients (28 females), aged 11-20 yr (15.21+/-2.7 yr): 25 (mean age, 15.1+/-2.2 yr) on a gluten-free diet (treated patients) and 19 (mean age 15.4+/-2.9 yr) with a diet containing gluten (untreated patients). Forty adolescent subjects, aged 14-19 yr (mean age, 14.9+/-2.7 yr), of whom 20 were females, were studied as controls. Antibodies against the thyroid, adrenal, and pancreas were evaluated. Thyroid-stimulating hormone FT3, FT4, T3, T4, dehydroepiandrosterone sulphate, 17-OH progesterone, and cortisol, analyzed basally and 60 min after intravenous ACTH stimulation, were assayed to evaluate thyroid and adrenal function. The fasting glycemia level was used to evaluate the endocrine pancreas function. An ultrasonogram of the thyroid gland was performed on all patients. HLA class II typing for DR3 and DQB1 was performed in 32 of 44 patients. RESULTS: Seven of 44 (15.9%) patients were positive for antibodies against peroxidase. Six of 44 (13.6%) were positive for antibodies against thyreoglobulin and four of them also showed positive antibodies against peroxidase. Therefore, in nine of 44 at least one antibody directed against thyroid tissue was positive. Seven of 44 (15.9%) were positive for antibodies against islet cell, one of 44 (2.3%) positive for antibodies against glutamic acid decarboxilase, one of 44 (2.3%) positive for antibodies against insulin, and none for antibodies against islet cell- 512bdc. In 15 of 44 (34%) at least one antibody against an endocrine tissue was positive. The genotype DR3 was found in 21 of 32 (65.6%) celiac patients (10 in the untreated and 11 in the treated group, respectively) and the genotype DQB1*02 (DQ2) was found in 30 of 32 (93.8%) patients (16 in the treated and 14 in the untreated group, respectively). DHA-S values were significantly lower in the untreated (30.5+/-28.5 microg/dl) than in the treated group (61.3+/-59.4 microg/dl, p < 0.05), and both showing significantly (p < 0.01) lower levels with respect to the controls (161+/-52 microg/dl). One patient showed diabetes, another one clinical hypothyroidism (thyroid-stimulating hormone > 6), and two patients showed preclinical hypothyroidism. Interestingly, at least one antibody was positive in 10 of 19 untreated patients (52.6%) but only in five of 25 treated patients (20%), with a significantly different distribution (p < 0.001) between the two groups and without differences in the HLA genotype. The ultrasonographic evaluation of the thyroid resulted in a pathological score in six patients of the 44 examined (13.6%), suggesting the presence of thyropathy. CONCLUSIONS: The main results of this study are the high incidence of thyroid and pancreatic antibodies, and the possible role of gluten in the induction of the antibodies as well as, in few cases, the consequent organ dysfunction.

The circulating insulin-like growth factor system in children with coeliac disease: an additional marker for disease activity.

BACKGROUND: Chronic undernutrition resulting from coeliac disease (CD) could be associated with changes in the circulating insulin-like growth factor (IGF) system, which may participate in the pathogenesis of growth retardation occurring in these patients. METHODS: We performed a cross-sectional study in CD subjects attempting to (1) document the pattern of serum IGF-I and IGF binding protein (IGFBP) 1 and 3 at diagnosis and (2) assess the response of circulating IGF system to dietary treatments, in comparison with the response of clinical and laboratory findings utilized for the diagnosis of CD. Thirty-two prepubertal CD children were divided into three groups based on the dietetic treatment: at diagnosis (D, n=18); on gluten-free diet for at least 6 months (GFD, n=7); and on gluten challenge for at least 3 months (CH, n=7). Six postpubertal CD patients were also studied at diagnosis. RESULTS: In prepubertal children IGF-I levels were significantly reduced (by 29%) in D vs sex- and age-matched normal control (NC) subjects, with reductions being more pronounced before 3 years of age. Likewise, serum IGFBP-3 concentrations were decreased by 22%, whereas circulating IGFBP-1 levels were increased by 60%, compared with NC, with more marked IGFBP changes in older children. Similar alterations were observed in postpubertal patients. Changes in the circulating IGF system disappeared in GFD subjects and reappeared in CH children, as positivity of disease-specific antibodies. Body mass index (BMI) also improved in GFD subjects, but did not decrease in CH children. Changes in IGF-I and IGFBPs did not correlate with each other. Levels of IGF-I, but not of IGFBPs, maintained the relation with age and correlated significantly with BMI and positivity of antibodies. CONCLUSIONS: These results demonstrate that CD patients show significant changes in serum IGF-I, in younger children, and IGFBPs (particularly IGFBP-1), in older children and adolescents, correlating with clinical course and response to dietary treatments. The alteration in the circulating IGF system could be implicated in the pathogenesis of growth retardation occurring in CD and may provide an additional tool in monitoring of the disease.

The gluten-free diet: a nutritional risk factor for adolescents with celiac disease?

BACKGROUND: The gluten-free diet is the standard therapy for patients affected by celiac disease, although compliance with the diet is not optimal in adolescents or adults. Moreover, the gluten-free diet may induce nutritional imbalances. METHODS: Alimentary habits and diet composition were examined in 47 adolescents with celiac disease and 47 healthy aged-matched control subjects. All subjects compiled a 3-day alimentary record that allowed determination of their energy intakes: the macronutrient composition of their diets; and their iron, calcium, and fiber intakes. To evaluate compliance with the gluten-free diet, immunoglobulin A antigliadin and antiendomysium antibodies were assessed in all with celiac disease. RESULTS: The analysis of the records and the results of antibody levels showed that 25 subjects strictly followed dietetic prescriptions (group 1A), whereas 22 patients consumed gluten-containing food (group 1B). Those with celiac disease and control subjects (group 2) consumed a normocaloric diet. Lipid and protein consumption was high, however, and the consumption of carbohydrates low. Moreover, dietary levels of calcium, fiber, and especially in girls, iron, were low. These nutritional imbalances were significantly more evident in group 1A than in group 1B, as a consequence of poor alimentary choices. Moreover, in group 1A overweight and obesity were more frequent (72%) than in group 1B (51%) and in the control subjects (47%). CONCLUSIONS: In people with celiac disease, adherence to a strict gluten-free diet worsens the already nutritionally unbalanced diet of adolescents, increasing elevated protein and lipid consumption. In the follow-up of patients with celiac disease, considerable effort has yet to be made to improve compliance with a gluten-free diet, and especially to control the nutritional balance of the diet in compliant patients.

Helicobacter pylori infection in families of Helicobacter pylori-positive children.

Relatives of Helicobacter pylori positive patients show a higher incidence of Helicobacter pylori infection than the general population, probably due to relapses and/or reinfections between members of the family. Aim of this study was to evaluate the prevalence of the infection in 121 relatives of 41 children with Helicobacter pylori positive gastritis. Specific IgG antibodies (ELISA) were evaluated, and bacteria on gastric biopsy specimens were investigated by urease-rapid test, culture test and GIEMSA or acridine orange staining. Of the eighty-two relatives, 68% were antibody positive. Thirty-five agreed to undergo endoscopy. With the exception of one brother, all subjects (97%) were found to be infected by Helicobacter pylori. Two symptomatic relatives, with normal antibody titres, were submitted to endoscopy and found to be colonized by Helicobacter pylori. The present data confirm the high prevalence of infection within families and appear to demonstrate the usefulness of endoscopy for all subjects showing positive antibody titres as well as for symptomatic relatives, even if serologically negative, to confirm the presence of any pathological conditions and reduce the risk of relapses within families.

[Ascaridiasis: a rare cause of recurrent abdominal pain. Report of a clinical case documented by ultrastructural study of the intestinal mucosa]. / L'ascaridiasi: una rara causa di dolori addominali ricorrenti. Presentazione di un caso clinico corredato dallo studio ultrastrutturale della mucosa intestinale.

The case of a six-year-old girl suffering from recurrent abdominal pain is reported. On the basis of the laboratory tests and a number of other clinical investigations, the diagnosis of ascaridiasis was made. At scanning electron microscopy the ultrastructural study of the bioptic fragments obtained during endoscopy showed peculiar lesions of the gastric and duodenal mucosa. We speculate that this unusual picture may be due to the ascaris. These lesions, described for the first time in the literature to our knowledge, were represented by the loss of the apical portion of some cells. Differential diagnosis of recurrent abdominal pain is discussed.