Reumatismo. 2012; 63(4): 263-75
Paparo F, Fabbro E, Ferrero G, Piccazzo R, Revelli M, Camellino D, Garlaschi G, Cimmino MA

Gout, calcium pyrophosphate dihydrate (CPPD) deposition disease, and calcium hydroxyapatite deposition disease (HADD) are the three most common crystal-induced arthropathies. Multimodality imaging may help in their diagnosis, and is useful for a precise and comprehensive assessment and grading of the related osteoarticular damage. Plain film radiography, due to its low cost and wide availability, is the first imaging technique to be used in crystal deposition diseases, providing well-known and specific findings for CPPD deposition disease and HADD, while it may undergrade the early osteoarticular lesions in gouty patients. Ultrasonography (US) is a radiation-free approach that accurately depicts crystal deposits in cartilage, peri- and intra-articular soft tissues, but it does not give a panoramic view of the affected joints. Cross-sectional imaging techniques can examine crystal deposits in the spine and axial joints. CT has the potential to distinguish monosodium urate (MSU) crystals from calcium containing crystals, due to their different attenuation values. MRI may demonstrate synovitis, erosions and bone marrow edema in gouty patients and it may differentiate tophi from other soft tissue nodules due to its high contrast resolution and power of tissue characterization.

Reumatismo. 2012; 63(4): 246-52
Ferrone C, Andracco R, Cimmino MA

Calcium pyrophosphate deposition (CPPD) disease is an arthropathy caused by calcium pyrophosphate dihydrate (CPP) crystal deposits in articular tissues, most commonly fibrocartilage and hyaline cartilage. According to EULAR, four different clinical presentations can be observed: 1) asymptomatic CPPD; 2) osteoarthritis (OA) with CPPD; 3) acute CPP crystal arthritis; 4) chronic CPP inflammatory crystal arthritis. Acute CPP crystal arthritis is characterized by sudden onset of pain, swelling and tenderness with overlying erythema, usually in a large joint, most often the knee, wrist, shoulder, and hip. Occasionally, ligaments, tendons, bursae, bone and the spine can be involved. CPPD of the atlanto-occipital joint (crowned dens syndrome) can cause periodic acute cervico-occipital pain with fever, neck stiffness and laboratory inflammatory syndrome. Chronic inflammatory arthritis is characterized by joint swelling, morning stiffness, pain, and high ESR and CRP. The relationship between OA and CPPD is still unclear. The main problem is whether such crystals are directly involved in the pathogenesis of OA or if they are the result of joint degeneration. Diagnosis is based on evaluation of history and clinical features, conventional radiology, and synovial fluid examination. Non-polarized light microscopy should be used initially to screen for CPPD crystals based upon their characteristic morphology, and compensated polarized light microscopy, showing the crystals to be weakly positive birefringent, is recommended for definitive identification, although this last pattern only occurs in about 20% of samples. The main goals of CPPD therapy are control of the acute or chronic inflammatory reaction and prevention of further episodes.

Reumatismo. 2012; 63(4): 238-45
Grassi W, De Angelis R

Gout is a metabolic disease characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals in the joints and soft tissues, consisting of a self-limited acute phase characterized by recurrent attacks of synovitis and a chronic phase in which inflammatory and structural changes of the joints and periarticular tissues may lead to persistent symptoms. Acute gout is characterized by a sudden monoarthritis of rapid onset, with intense pain, mostly affecting the big toe (50% of initial attacks), the foot, ankle, midtarsal, knee, wrist, finger, and elbow. Acute flares also occur in periarticular structures, including bursae and tendons. The presence of characteristic MSU crystals in the joint fluid, appearing needle-like and showing strong negative birefringence by polarized microscopy, is pivotal to confirm the diagnosis of gout. The time interval separating the first attack from subsequent episodes of acute synovitis may be widely variable, ranging from a few days to several years. During the period between acute attacks the patient is asymptomatic even if MSU deposition may continue to increase silently. The factors that control the rate, location, and degree of ongoing deposition in gouty patients are not well defined. Chronic gout is the natural evolution of untreated hyperuricemia in patients with gouty attacks followed by pain-free intercritical periods. It is characterized by the deposition of solid MSU crystal aggregates in a variety of tissues including joints, bursae and tendons. Tophi can occur in a variety of locations including the helix of the ear, olecranon bursa, and over the interphalangeal joints. Their development is usually related with both the degree and the duration of hyperuricemia. About 20% of patients with gout have urinary tract stones and can develop an interstitial urate nephropathy. There is a strong association between hyperuricaemia and the metabolic syndrome (the constellation of insulin resistance, hypertension, obesity and dyslipidaemia), and gouty patients often have a medical history of kidney disease, diabetes mellitus and signs of vascular illness such as coronary artery disease, heart failure and stroke, resulting with a poor overall quality of life.

Ann Clin Psychiatry. 2012 Feb; 24(1): 82-90
Ramasubbu R, Beaulieu S, Taylor VH, Schaffer A, McIntyre RS

Medical comorbidity is commonly encountered in individuals with major depressive disorder (MDD) and bipolar disorder (BD). The presence of medical comorbidity has diagnostic, prognostic, treatment, and etiologic implications underscoring the importance of timely detection and treatment.A selective review of relevant articles and reviews published in English-language databases (1968 to April 2011) was conducted. Studies describing epidemiology, temporality of onset, treatment implications, and prognosis were selected for review.A growing body of evidence from epidemiologic, clinical, and biologic studies suggests that the relationship between medical illness and mood disorder is bidirectional in nature. It provides support for the multiplay of shared and specific etiologic factors interlinking these conditions.This article describes the complex interactions between medical illness and mood disorders and provides a meaningful approach to their comorbid clinical diagnosis and management.

Ann Clin Psychiatry. 2012 Feb; 24(1): 23-37
Bond DJ, Hadjipavlou G, Lam RW, McIntyre RS, Beaulieu S, Schaffer A, Weiss M

Patients with bipolar disorder (BD) and major depressive disorder (MDD) experience adult attention-deficit/hyperactivity disorder (ADHD) at rates substantially greater than the general population. Nonetheless, ADHD frequently goes untreated in this population.We reviewed the literature regarding the management of adult ADHD in patients with mood disorders. Because a limited number of studies have been conducted in adults, our treatment recommendations also are partly informed by research in children and adolescents with BD+ADHD or MDD+ADHD, adults with ADHD, and our clinical experience.In individuals with mood disorders, ADHD is best diagnosed when typical symptoms persist during periods of sustained euthymia. Individuals with BD+ADHD, particularly those with bipolar I disorder (BD I), are at risk for mood destabilization with many ADHD treatments, and should be prescribed mood-stabilizing medications before initiating ADHD therapies. Bupropion is a reasonable first-line treatment for BD+ADHD, while mixed amphetamine salts and methylphenidate also may be considered in patients determined to be at low risk for manic switch. Modafinil and cognitive-behavioral therapy (CBT) are second-line choices. In patients with MDD+ADHD and moderate to severe depression, MDD should be the treatment priority, whereas in mildly depressed or euthymic patients the order may be reversed. First-line treatments for MDD+ADHD include bupropion, an antidepressant plus a long-acting stimulant, or an antidepressant plus CBT. Desipramine, nortriptyline, and venlafaxine are second-line options.Clinicians should be vigilant in screening for comorbid ADHD in mood disorder patients. ADHD symptoms can respond to appropriately chosen treatments.

Ann Clin Psychiatry. 2012 Feb; 24(1): 6-22
Schaffer A, McIntosh D, Goldstein BI, Rector NA, McIntyre RS, Beaulieu S, Swinson R, Yatham LN

Comorbid mood and anxiety disorders are commonly seen in clinical practice. The goal of this article is to review the available literature on the epidemiologic, etiologic, clinical, and management aspects of this comorbidity and formulate a set of evidence- and consensus-based recommendations. This article is part of a set of Canadian Network for Mood and Anxiety Treatments (CANMAT) Comorbidity Task Force papers.We conducted a PubMed search of all English-language articles published between January 1966 and November 2010. The search terms were bipolar disorder and major depressive disorder, cross-referenced with anxiety disorders/symptoms, panic disorder, agoraphobia, generalized anxiety disorder, social phobia, obsessive-compulsive disorder, and posttraumatic stress disorder. Levels of evidence for specific interventions were assigned based on a priori determined criteria, and recommendations were developed by integrating the level of evidence and clinical opinion of the authors.Comorbid anxiety symptoms and disorders have a significant impact on the clinical presentation and treatment approach for patients with mood disorders. A set of recommendations are provided for the management of bipolar disorder (BD) with comorbid anxiety and major depressive disorder (MDD) with comorbid anxiety with a focus on comorbid posttraumatic stress disorder, use of cognitive-behavioral therapy across mood and anxiety disorders, and youth with mood and anxiety disorders.Careful attention should be given to correctly identifying anxiety comorbidities in patients with BD or MDD. Consideration of evidence- or consensus-based treatment recommendations for the management of both mood and anxiety symptoms is warranted.

PLoS Negl Trop Dis. 2012 Jan; 6(1): e1484
Maia Z, Lírio M, Mistro S, Mendes CM, Mehta SR, Badaro R

The rK39 recombinant protein is derived from a specific antigen produced by the Leishmania donovani complex, and has been used in the last two decades for the serodiagnosis of visceral leishmaniasis. We present here a systematic review and meta-analysis of studies evaluating serologic assays to diagnose visceral leishmaniasis to determine the accuracy of rK39 antigen in comparison to the use of other antigen preparations.A systematic review with meta-analysis of the literature was performed to compare the rK39 strip-test and ELISA formats against serological tests using promastigote antigens derived from whole or soluble parasites for Direct Aglutination Test (DAT), Indirect Immunofluorescence test (IFAT) and ELISA with a promastigote antigen preparation (p-ELISA). Gold standard diagnosis was defined by the demonstration of amastigotes on hematological specimens. A database search was performed on Medline, Lilacs, Scopus, Isi Web of Science, and Cochrane Library. Quality of data was assessed using the QUADAS questionnaire. A search of the electronic databases found 352 papers of which only 14 fulfilled the selection criteria. Three evaluated the rK39 ELISA, while 13 evaluated the rK39 immunochromatographic strip test. The summarized sensitivity for the rK39-ELISA was 92% followed by IFAT 88% and p-ELISA 87%. The summarized specificity for the three diagnostic tests was 81%, 90%, and 77%. Studies comparing the rK39 strip test with DAT found a similar sensitivity of 94%, although the DAT had a slightly higher specificity. The rK39 strip test was more sensitive and specific than the IFAT and p-ELISA. We did not detect any difference in the sensitivity and specificity between strips produced by different manufacturers.The rK39 protein used either in a strip test or in an ELISA, and the DAT are the best choices for implementation of rapid, easy and efficient test for serodiagnosis of VL.

PLoS One. 2012; 7(1): e31131
Hisamatsu T, Okamoto S, Hashimoto M, Muramatsu T, Andou A, Uo M, Kitazume MT, Matsuoka K, Yajima T, Inoue N, Kanai T, Ogata H, Iwao Y, Yamakado M, Sakai R, Ono N, Ando T, Suzuki M, Hibi T

Inflammatory bowel disease (IBD) is a chronic intestinal disorder that is associated with a limited number of clinical biomarkers. In order to facilitate the diagnosis of IBD and assess its disease activity, we investigated the potential of novel multivariate indexes using statistical modeling of plasma amino acid concentrations (aminogram).We measured fasting plasma aminograms in 387 IBD patients (Crohn's disease (CD), n = 165; ulcerative colitis (UC), n = 222) and 210 healthy controls. Based on Fisher linear classifiers, multivariate indexes were developed from the aminogram in discovery samples (CD, n = 102; UC, n = 102; age and sex-matched healthy controls, n = 102) and internally validated. The indexes were used to discriminate between CD or UC patients and healthy controls, as well as between patients with active disease and those in remission. We assessed index performances using the area under the curve of the receiver operating characteristic (ROC AUC). We observed significant alterations to the plasma aminogram, including histidine and tryptophan. The multivariate indexes established from plasma aminograms were able to distinguish CD or UC patients from healthy controls with ROC AUCs of 0.940 (95% confidence interval (CI): 0.898-0.983) and 0.894 (95%CI: 0.853-0.935), respectively in validation samples (CD, n = 63; UC, n = 120; healthy controls, n = 108). In addition, other indexes appeared to be a measure of disease activity. These indexes distinguished active CD or UC patients from each remission patients with ROC AUCs of 0.894 (95%CI: 0.853-0.935) and 0.849 (95%CI: 0.770-0.928), and correlated with clinical disease activity indexes for CD (r(s) = 0.592, 95%CI: 0.385-0.742, p<0.001) or UC (r(s) = 0.598, 95%CI: 0.452-0.713, p<0.001), respectively.In this study, we demonstrated that established multivariate indexes composed of plasma amino acid profiles can serve as novel, non-invasive, objective biomarkers for the diagnosis and monitoring of IBD, providing us with new insights into the pathophysiology of the disease.

PLoS One. 2012; 7(1): e31069
Casaca VI, Illi S, Suttner K, Schleich I, Ballenberger N, Klucker E, Turan E, von Mutius E, Kabesch M, Schaub B

TBX21 (T cell specific T-box transcription factor) and HLX1 (H.20-like homeobox 1) are crucial transcription factors of T(H)1-cells, inducing their differentiation and suppressing T(H)2 commitment, particularly important for early life immune development. This study investigated the influence of TBX21 and HLX1 single nucleotide polymorphisms (SNPs), which have previously been shown to be associated with asthma, on T(H)1/T(H)2 lineage cytokines at birth.Cord blood mononuclear cells (CBMCs) of 200 neonates were genotyped for two TBX21 and three HLX1 SNPs. CBMCs were stimulated with innate (Lipid A, LpA; Peptidoglycan, Ppg), adaptive stimuli (house dust mite Dermatophagoides pteronyssinus 1, Derp1) or mitogen (phytohemagglutinin, PHA). Cytokines, T-cells and mRNA expression of T(H)1/T(H)2-related genes were assessed. Atopic diseases during the first 3 years of life were assessed by questionnaire answered by the parents. Carriers of TBX21 promoter SNP rs17250932 and HLX1 promoter SNP rs2738751 showed reduced or trendwise reduced (p≤0.07) IL-5, IL-13 and TNF-α secretion after LpA-stimulation. Carriers of HLX1 SNP rs2738751 had lower IL-13 levels following Ppg-stimulation (p = 0.08). Carriers of HLX1 exon 1 SNP rs12141189 showed increased IL-5 (LpA, p = 0.007; Ppg, p = 0.10), trendwise increased IL-13 (LpA), higher GM-CSF (LpA/Ppg, p≤0.05) and trendwise decreased IFN-γ secretion (Derp1+LpA-stimulation, p = 0.1). Homozygous carriers of HLX1 promoter SNP rs3806325 showed increased IL-13 and IL-6 (unstimulated, p≤0.03). In carriers of TBX21 intron 3 SNP rs11079788 no differences in cytokine secretion were observed. mRNA expression of T(H)1/T(H)2-related genes partly correlated with cytokines at protein level. TBX21 SNP rs11079788 carriers developed less symptoms of atopic dermatitis at 3 years of age (p = 0.03).Polymorphisms in TBX21 and HLX1 influenced primarily IL-5 and IL-13 secretion after LpA-stimulation in cord blood suggesting that genetic variations in the transcription factors essential for the T(H)1-pathway may contribute to modified T(H)2-immune responses already early in life. Further follow-up of the cohort is required to study the polymorphisms' relevance for immune-mediated diseases such as childhood asthma.

PLoS One. 2012; 7(1): e30955
Brown JC, Huedo-Medina TB, Pescatello LS, Ryan SM, Pescatello SM, Moker E, Lacroix JM, Ferrer RA, Johnson BT

The purpose of this meta-analysis was to examine the efficacy of exercise to reduce depressive symptoms among cancer survivors. In addition, we examined the extent to which exercise dose and clinical characteristics of cancer survivors influence the relationship between exercise and reductions in depressive symptoms.We conducted a systematic search identifying randomized controlled trials of exercise interventions among adult cancer survivors, examining depressive symptoms as an outcome. We calculated effect sizes for each study and performed weighted multiple regression moderator analysis.We identified 40 exercise interventions including 2,929 cancer survivors. Diverse groups of cancer survivors were examined in seven exercise interventions; breast cancer survivors were examined in 26; prostate cancer, leukemia, and lymphoma were examined in two; and colorectal cancer in one. Cancer survivors who completed an exercise intervention reduced depression more than controls, d(+) = -0.13 (95% CI: -0.26, -0.01). Increases in weekly volume of aerobic exercise reduced depressive symptoms in dose-response fashion (β = -0.24, p = 0.03), a pattern evident only in higher quality trials. Exercise reduced depressive symptoms most when exercise sessions were supervised (β = -0.26, p = 0.01) and when cancer survivors were between 47-62 yr (β = 0.27, p = 0.01).Exercise training provides a small overall reduction in depressive symptoms among cancer survivors but one that increased in dose-response fashion with weekly volume of aerobic exercise in high quality trials. Depressive symptoms were reduced to the greatest degree among breast cancer survivors, among cancer survivors aged between 47-62 yr, or when exercise sessions were supervised.

PLoS One. 2012; 7(1): e30936
Joling KJ, van Marwijk HW, Smit F, van der Horst HE, Scheltens P, van de Ven PM, Mittelman MS, van Hout HP

Family caregivers of dementia patients are at increased risk of developing depression or anxiety. A multi-component program designed to mobilize support of family networks demonstrated effectiveness in decreasing depressive symptoms in caregivers. However, the impact of an intervention consisting solely of family meetings on depression and anxiety has not yet been evaluated. This study examines the preventive effects of family meetings for primary caregivers of community-dwelling dementia patients.A randomized multicenter trial was conducted among 192 primary caregivers of community dwelling dementia patients. Caregivers did not meet the diagnostic criteria for depressive or anxiety disorder at baseline. Participants were randomized to the family meetings intervention (n = 96) or usual care (n = 96) condition. The intervention consisted of two individual sessions and four family meetings which occurred once every 2 to 3 months for a year. Outcome measures after 12 months were the incidence of a clinical depressive or anxiety disorder and change in depressive and anxiety symptoms (primary outcomes), caregiver burden and quality of life (secondary outcomes). Intention-to-treat as well as per protocol analyses were performed.A substantial number of caregivers (72/192) developed a depressive or anxiety disorder within 12 months. The intervention was not superior to usual care either in reducing the risk of disorder onset (adjusted IRR 0.98; 95% CI 0.69 to 1.38) or in reducing depressive (randomization-by-time interaction coefficient = -1.40; 95% CI -3.91 to 1.10) or anxiety symptoms (randomization-by-time interaction coefficient = -0.55; 95% CI -1.59 to 0.49). The intervention did not reduce caregiver burden or their health related quality of life.This study did not demonstrate preventive effects of family meetings on the mental health of family caregivers. Further research should determine whether this intervention might be more beneficial if provided in a more concentrated dose, when applied for therapeutic purposes or targeted towards subgroups of caregivers.Controlled-Trials.com ISRCTN90163486.

PLoS One. 2012; 7(1): e30887
Lue N, Kang JW, Yu CC, Barman I, Dingari NC, Feld MS, Dasari RR, Fitzmaurice M

There continues to be a significant clinical need for rapid and reliable intraoperative margin assessment during cancer surgery. Here we describe a portable, quantitative, optical fiber probe-based, spectroscopic tissue scanner designed for intraoperative diagnostic imaging of surgical margins, which we tested in a proof of concept study in human tissue for breast cancer diagnosis. The tissue scanner combines both diffuse reflectance spectroscopy (DRS) and intrinsic fluorescence spectroscopy (IFS), and has hyperspectral imaging capability, acquiring full DRS and IFS spectra for each scanned image pixel. Modeling of the DRS and IFS spectra yields quantitative parameters that reflect the metabolic, biochemical and morphological state of tissue, which are translated into disease diagnosis. The tissue scanner has high spatial resolution (0.25 mm) over a wide field of view (10 cm×10 cm), and both high spectral resolution (2 nm) and high spectral contrast, readily distinguishing tissues with widely varying optical properties (bone, skeletal muscle, fat and connective tissue). Tissue-simulating phantom experiments confirm that the tissue scanner can quantitatively measure spectral parameters, such as hemoglobin concentration, in a physiologically relevant range with a high degree of accuracy (<5% error). Finally, studies using human breast tissues showed that the tissue scanner can detect small foci of breast cancer in a background of normal breast tissue. This tissue scanner is simpler in design, images a larger field of view at higher resolution and provides a more physically meaningful tissue diagnosis than other spectroscopic imaging systems currently reported in literatures. We believe this spectroscopic tissue scanner can provide real-time, comprehensive diagnostic imaging of surgical margins in excised tissues, overcoming the sampling limitation in current histopathology margin assessment. As such it is a significant step in the development of a platform technology for intraoperative management of cancer, a clinical problem that has been inadequately addressed to date.