The immunomodulatory effects of social isolation in mice are linked to temperature control.

Living in isolation is considered an emerging societal problem that negatively affects the physical wellbeing of its sufferers in ways that we are just starting to appreciate. This study investigates the immunomodulatory effects of social isolation in mice, utilising a two-week program of sole cage occupancy followed by the testing of immune-inflammatory resilience to bacterial sepsis. Our results revealed that mice housed in social isolation showed an increased ability to clear bacterial infection compared to control socially housed animals. These effects were associated with specific changes in whole blood gene expression profile and an increased production of classical pro-inflammatory cytokines. Interestingly, equipping socially isolated mice with artificial nests as a substitute for their natural huddling behaviour reversed the increased resistance to bacterial sepsis. Together these results suggest that the control of body temperature through social housing and huddling behaviour are important factors in the regulation of the host immune response to infection in mice and might provide another example of the many ways by which living conditions influence immunity.

Effect of rituximab on malignancy risk in patients with ANCA-associated vasculitis.

OBJECTIVES: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with cyclophosphamide have an increased malignancy risk compared with the general population. We investigated whether treatment with rituximab instead of cyclophosphamide has decreased the malignancy risk in patients with AAV. METHODS: The study included patients with AAV treated at a tertiary vasculitis referral centre between 2000 and 2014. The malignancy incidence in these patients was compared with the incidence in the general population by calculating standardised incidence ratios (SIRs), adjusted for sex, age and calendar year. Malignancy incidence was compared between rituximab-treated and cyclophosphamide-treated patients. RESULTS: Of the 323 included patients, 33 developed a total of 45 malignancies during a mean follow-up of 5.6 years. This represented a 1.89-fold increased (95% CI 1.38 to 2.53) malignancy risk, and a non-significantly increased risk if non-melanoma skin cancer was excluded (SIR, 1.09; 95% CI 0.67 to 1.69). The risk of non-melanoma skin cancer was 4.58-fold increased (95% CI 2.96 to 6.76). Cyclophosphamide-treated patients had an increased malignancy risk compared with the general population (SIR, 3.10; 95% CI 2.06 to 4.48). In contrast, rituximab-treated patients had a malignancy risk similar to the general population (SIR, 0.67; 95% CI 0.08 to 2.43). The malignancy risk in cyclophosphamide-treated patients was 4.61-fold higher (95% CI 1.16 to 39.98) than in rituximab-treated patients. CONCLUSIONS: The malignancy risk in patients with AAV was lower in rituximab-treated patients than in cyclophosphamide-treated patients. Notably, rituximab treatment was not associated with an increased malignancy risk compared with the general population. Rituximab could therefore be a safe alternative to cyclophosphamide in the treatment of AAV.

Bortezomib-based therapy combined with high cut-off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment.

Multiple myeloma (MM) is often associated with renal insufficiency (RI) which adversely influences the prognosis. Several studies demonstrated that bortezomib can improve both renal function and outcome. We prospectively evaluated 21 newly diagnosed MM patients with severe renal impairment secondary to tubular-interstitial damage, most of them due to myeloma kidney, who were primarily treated with bortezomib-based therapy combined with high cut-off hemodialysis (HCOD). The median serum creatinine level at baseline was 6.44 mg dL(-1) and calculated median estimated glomerular filtration rate (eGFR), according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was 8 mL/min/1.73 m(2) . Serum free light chain (sFLC) median concentration was 6,040 mg L(-1) . Post induction and best stringent complete response rates were 19 and 38%, respectively. Responses were fast, occurring within a median of 1.4 months. The combination of bortezomib and HCOD led to a prompt and remarkable (>90%) decrease in sFLC levels. Sixteen patients (76%) became dialysis independent within a median of 32 days. With a median follow up of 17.2 months, the 3-year PFS and OS were 76 and 67%, respectively. No early deaths were observed. This study demonstrates that incorporation of bortezomib into induction therapy combined with HCOD is a highly effective strategy in rescuing renal function and improving outcomes in patients with MM and RI.

The identification of depression and the coverage of antidepressant drug prescriptions in Italian general practice.

BACKGROUND: Studies on antidepressant prescriptions in general practice need to assess the level of prescriptions relative to the need for them ('coverage'), and the variability among doctors. METHODS: Two different cut-off scores on a screening test for depression (the Personal Health Questionnaire, PHQ) are used to predict rates for depression, and rates for depressive patients thought likely to benefit from antidepressants (according to a severity criterion) in primary care patients. These two rates are compared with assessments by 11 GPs of recognised depression, as well as with rates of drug prescribed. RESULTS: The rate for depression thought likely to be treated with antidepressants estimated with the PHQ is broadly comparable with the rate for conspicuous depressive illness, and much lower than that predicted by the PHQ for depression. There was great variability between GPs in their ability to detect depression, and their preparedness to prescribe antidepressants. Antidepressants were only prescribed for 3.5% of the patients, compared to the 8.9% thought to need them. However, antidepressants, mostly SSRIs, are much more likely to be prescribed than tranquillisers. LIMITATIONS: The limitations of the study are that the PHQ is able to estimate 'coverage' but not 'focusing' (the proportion of those receiving antidepressants who needed them). CONCLUSIONS: Although the rate for conspicuous depression is similar to that for depressions thought to be treated with antidepressants, the 'coverage' of antidepressants was only 39.3%. The variability between physicians confirm the need of good practice guidelines and training packages for the identification and management of depression. Large epidemiological studies are needed to overcome the current lack of clinically relevant data on the quality of antidepressant prescriptions in general practice.

[Skin and chronic kidney disease]. / Il coinvolgimento cutaneo nelle patologie metaboliche associate a malattia renale cronica.

Kidneys and skin are seldom considered associated, but their relationship is more closer than generally believed. In some immunological diseases (SLE...) and genetic syndromes (tuberous sclerosis, Fabrys disease...) the cutaneous manifestations are integral parts of the clinical picture. In advanced uremia, besides the well-known itching skin lesions, calciphylaxis may appear, a typical example of cutaneous involvement secondary to the metabolic complications (calcium-phosphate imbalance) of the renal disease. Nephrogenic systemic fibrosis appears only in patients with renal failure and it has a very severe prognosis due to the systemic organ involvement. Moreover, there is a heterogeneous group of metabolic diseases, with renal involvement, that may be accompanied by skin lesions, either related to the disease itself or to its complications (diabetes mellitus, porphyrias). In systemic amyloidosis, fibrils may deposit even in dermis leading to different skin lesions. In some heroin abusers, in the presence of suppurative lesions in the sites of needle insertion, renal amyloidosis should be suspected, secondary to the chronic inflammation. Atheroembolic disease is nowadays frequently observed, as a consequence of the increasing number of invasive intravascular manoeuvres. Skin manifestations like livedo reticularis or the blue toe syndrome are the most typical signs, but often renal dysfunction is also present. In all these conditions, the skin lesion may be a first sign, a warning, that should arouse the suspicion of a more complex pathology, even with renal involvement. Being aware of this relationship is fundamental to accelerate the diagnostic process.

Making the use of psychotropic drugs more rational through the development of GRADE recommendations in specialist mental healthcare.

INTRODUCTION: In recent years the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology has often been used by international or national health authorities, or scientific societies, for developing evidence-based treatment recommendations. However, the GRADE approach has never been used by practicing physicians who aim at harmonizing their prescribing behaviours paying due attention to the best available evidence. This paper describes the experience of a working group of psychiatrists who adopted the GRADE approach to develop clinical recommendations on the use of psychotropic drugs in specialist mental healthcare. CASE DESCRIPTION: The project was conducted in the Department of Mental Health of Verona, Italy, a city located in the north of Italy. At the beginning of 2012, psychiatrists with a specific interest in the rational use of psychotropic drugs were identified and appointed as members of a Guideline Development Group (GDG). The first task of the GDG was the identification of controversial areas in the use of psychotropic drugs, the definition of scoping questions, and the identification of outcomes of interest. The GDG was supported by a scientific secretariat, who searched the evidence, identified one or more systematic reviews matching the scoping questions, and drafted GRADE tables. DISCUSSION AND EVALUATION: On the basis of efficacy, acceptability, tolerability and safety data, considering the risk of bias and confidence in estimates, and taking also into consideration preferences, values and practical aspects in favour and against the intervention under scrutiny, a draft recommendation with its strength was formulated and agreed by GDG members. Recommendations were submitted for consideration to all specialists of the Department, discussed in two plenary sessions open to the whole staff, and finally approved at the end of 2012. CONCLUSION: The present project of guideline development raised several challenging and innovating aspects, including a "bottom-up" approach, as it was motivated by reasons that found agreement among specialists, those who developed the recommendations were those who were supposed to follow them, and values, preferences and feasibility issues were considered paying due attention to local context variables.