Demographic histories and genetic diversity across pinnipeds are shaped by human exploitation, ecology and life-history.

A central paradigm in conservation biology is that population bottlenecks reduce genetic diversity and population viability. In an era of biodiversity loss and climate change, understanding the determinants and consequences of bottlenecks is therefore an important challenge. However, as most studies focus on single species, the multitude of potential drivers and the consequences of bottlenecks remain elusive. Here, we combined genetic data from over 11,000 individuals of 30 pinniped species with demographic, ecological and life history data to evaluate the consequences of commercial exploitation by 18th and 19th century sealers. We show that around one third of these species exhibit strong signatures of recent population declines. Bottleneck strength is associated with breeding habitat and mating system variation, and together with global abundance explains much of the variation in genetic diversity across species. Overall, bottleneck intensity is unrelated to IUCN status, although the three most heavily bottlenecked species are endangered. Our study reveals an unforeseen interplay between human exploitation, animal biology, demographic declines and genetic diversity.

Intravenous immunoglobulin is an effective treatment for refractory cutaneous dermatomyositis.

BACKGROUND: Cutaneous dermatomyositis (DM) is often refractory to multiple systemic medications, suggesting a need for effective alternative treatments. AIM: To investigate the effects of intravenous immunoglobulin (IVIG) on patients with refractory cutaneous DM. METHODS: This was a retrospective review of 42 patients treated with IVIG for refractory cutaneous DM at our institution with clinical data available at DM diagnosis. IVIG was initiated for refractory cutaneous DM alone (n = 15) or refractory cutaneous and muscle/lung disease (n = 27) in patients with various DM subtypes. RESULTS: Overall, 83% of patients had cutaneous DM improvement, including 87% treated for refractory skin disease alone and 81% treated for refractory skin/muscle/lung disease. Cutaneous DM improvement occurred regardless of DM subtype, and was observed after a mean of 1.82 ± 1.38 IVIG cycles. No statistically significant clinical predictors of IVIG response or lack of response were detected. IVIG use resulted in decreased systemic glucocorticoid exposure with or without a decrease in steroid-sparing immunosuppressive medications in 80% of patients. This study is limited by its retrospective nature and lack of objective cutaneous DM activity assessment. CONCLUSION: Use of IVIG resulted in improvement of refractory cutaneous DM in the vast majority of patients relatively soon after initiation and regardless of DM subtype or clinical manifestations. Additionally, IVIG allowed decrease or discontinuation of immunosuppressive medications in 80% of patients. These findings suggest that IVIG can be a clinically efficacious and cost-effective treatment for refractory cutaneous DM and warrants prospective study.

Sarcoidosis following successful treatment of pemphigus vulgaris with rituximab: a rituximab-induced reaction further supporting B-cell contribution to sarcoidosis pathogenesis?

The anti-CD20 peripheral B-cell depleting monoclonal antibody, rituximab, has been shown to be a safe and effective treatment for refractory pemphigus vulgaris (PV), a potentially fatal autoimmune blistering disease. We report a patient who developed skin nodules and arthralgias following successful treatment of refractory PV with rituximab. Clinical, serological and histological findings were consistent with a diagnosis of sarcoidosis. The nodules promptly responded to treatment with corticosteroids, and resolved without recurrence when the medication was tapered several months later. The temporal onset of sarcoidosis following treatment with rituximab and the eventual resolution, coupled with the remarkable similarities between the B-cell immunological environment expected in our patient during the post-rituximab period and the immunological environment described in patients with idiopathic sarcoidosis, strongly implicates exposure to rituximab as the trigger for sarcoidosis development in our patient. We propose that rituximab-induced sarcoidal granulomas may be a rare adverse effect of treatment with this medication, providing further support for an important role of B cells in the pathogenesis of sarcoidosis. With better understanding of the circumstances surrounding sarcoidosis development following rituximab administration, this medication could potentially be used to induce sarcoidosis in animal research models to study the immunopathogenesis of this disease.

Clinically amyopathic dermatomyositis: clinical features, response to medications and malignancy-associated risk factors in a specific tertiary-care-centre cohort.

BACKGROUND: Clinically amyopathic dermatomyositis (CADM) is a subset of dermatomyositis (DM) characterized by the typical DM cutaneous manifestations but without myositis. There is a relative paucity of characterized cases of CADM in the peer-reviewed medical literature. OBJECTIVES: To characterize the clinical features, response to medications and malignancy-associated risk factors of patients with CADM with available baseline data seen at a single tertiary-care centre. METHODS: A retrospective review was undertaken of 44 patients with CADM with available clinical and serological data prior to onset of treatment. RESULTS: Patients with CADM comprised 18% of all patients with DM with baseline data available at our institution. Although the majority of patients showed improvement with the first prescribed treatment, most required additional medications to control their CADM. Six of 44 patients had an associated malignancy. Photosensitivity and periungual erythema were found to be associated with absence of malignancy (P = 0·03 and P = 0·02, respectively). Patients with malignancy-associated CADM were found to be more likely to have a cutaneous response with the first prescribed treatment than patients without malignancy (P = 0·04). CONCLUSIONS: CADM represents a significant subset of the DM population. As with classic DM, the cutaneous manifestations of CADM often represent a therapeutic challenge. A subset of patients with CADM has underlying malignancies, and these may differ from those typically associated with classic DM. Differences in serological abnormalities, cutaneous manifestations and response to first treatment among patients with CADM with and without malignancy were found, and suggest distinct pathophysiologies among CADM subsets. Characterization of this cohort expands the knowledge about this unique DM subset.

Comparison of the effect of propofol and sevoflurane anaesthesia on acute and chronic postoperative pain after hysterectomy.

There is some evidence that propofol may reduce acute postoperative pain; however, the results are inconsistent. Furthermore, there is a paucity of information about the type of anaesthesia and chronic pain. This study was designed to evaluate the hypothesis that propofol reduces acute and chronic postoperative pain compared with sevoflurane. In a randomised, prospective, double-blind trial, we assigned 80 patients having open total abdominal hysterectomy surgery to anaesthesia with either sevoflurane or propofol. Anaesthesia was titrated to clinical needs and bispectral index values to between 40 and 60. Postoperative pain was managed with pethidine and diclofenac. Acute postoperative pain for 24 hours and chronic postoperative pain at one and three months after surgery were evaluated. The Hospital Anxiety and Depression Scale was used to evaluate patient anxiety and depression after one and three months. There were no significant differences between the groups for opioid consumption or opioid-induced side-effects. Pain scores in the first four hours were significantly higher in the sevoflurane group. Persistent surgical pain was observed less frequently (7 out of 40 patients in the propofol group and 21 out of 40 in the sevoflurane group at three months post-surgery, P <0.01) and pain scores were lower at one and three months in the propofol group (0.78±0.55 versus 2.23±0.73 for the sevoflurane group at three months post-surgery, P <0.01). Anxiety and depression scores were significantly lower in the propofol group at three months. In this study, general anaesthesia with propofol was associated with reduced early acute postoperative and persistent pain, compared to sevoflurane-based anaesthesia, among patients undergoing open abdominal hysterectomy.

The hedgehog processing pathway is required for NSCLC growth and survival.

Considerable interest has been generated from the results of recent clinical trials using smoothened (SMO) antagonists to inhibit the growth of hedgehog (HH) signaling-dependent tumors. This interest is tempered by the discovery of SMO mutations mediating resistance, underscoring the rationale for developing therapeutic strategies that interrupt HH signaling at levels distinct from those inhibiting SMO function. Here, we demonstrate that HH-dependent non-small cell lung carcinoma (NSCLC) growth is sensitive to blockade of the HH pathway upstream of SMO, at the level of HH ligand processing. Individually, the use of different lentivirally delivered shRNA constructs targeting two functionally distinct HH-processing proteins, skinny hedgehog (SKN) or dispatched-1 (DISP-1), in NSCLC cell lines produced similar decreases in cell proliferation and increased cell death. Further, providing either an exogenous source of processed HH or a SMO agonist reverses these effects. The attenuation of HH processing, by knocking down either of these gene products, also abrogated tumor growth in mouse xenografts. Finally, we extended these findings to primary clinical specimens, showing that SKN is frequently overexpressed in NSCLC and that higher DISP-1 expression is associated with an unfavorable clinical outcome. Our results show a critical role for HH processing in HH-dependent tumors, identifies two potential druggable targets in the HH pathway, and suggest that similar therapeutic strategies could be explored to treat patients harboring HH ligand-dependent cancers.

[Gallbladder calculi: what therapy of choice?]. / Calcolosi della colecisti: quale terapia in elezione?

The Authors have analyzed all different methods for the treatment of gallbladder stones which are performed today: the non invasive treatment of the gallstones (oral dissolution therapy and the extracorporeal shockwave lithotripsy), the minimally invasive procedures (contact dissolution therapy and the cholecystolithotomy) and at the end the new surgical techniques (the "minicholecystectomy" and the laparoscopic cholecystectomy). From this study and their experience, based upon 1346 standard cholecystectomy, the Authors have reached the following conclusions: 1) the cholecystectomy remains the only definitive therapy for the gallbladder stones and it is the gold standard to which must be compared the other alternative therapies; 2) the laparoscopic cholecystectomy, even though introduced recently, would become the only method used for cholecystectomy.