The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis.

The human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.

Thioalbamide inhibits FoF1-ATPase in breast cancer cells and reduces tumor proliferation and invasiveness in breast cancer in vivo models.

OBJECTIVE: Thioalbamide is a ribosomally synthesized and post-translationally modified peptide (RiPP) belonging to the family of thioamitides, a rare class of microbial specialized metabolites with unusual post-translational modifications and promising biological activities. Recent studies have demonstrated the ability of thioalbamide to exert highly selective cytotoxic effects on tumor cells by affecting their energy metabolism, thus causing abnormal ROS production and triggering apoptosis. This study is aimed to investigate the molecular mechanisms underlying the antitumor activity of thioalbamide in order to identify its exact molecular target. METHODS: Wild type MCF-7 and MDA-MB-231 breast cancer cell lines as well as cancer cells deprived of mitochondrial DNA (ρ0 cells) were employed in order to assess thioalbamide effects on tumor bioenergetics. In this regard, metabolic profile was evaluated by a Seahorse XFe96 analyzer, and the activity of the enzyme complexes involved in oxidative phosphorylation was quantified by spectrophotometric assays. Thioalbamide effects on tumor invasiveness were assessed by gelatin zymography experiments and invasion assays. In vivo experiments were carried out on breast cancer xenograft and "experimental metastasis" mouse models. RESULTS: Experiments carried out on ρ0 breast cancer cells, together with Seahorse analysis and the application of spectrophotometric enzymatic assays, highlighted the ability of thioalbamide to affect the mitochondrial respiration process, and allowed to propose the FoF1-ATPase complex as its main molecular target in breast cancer cells. Additionally, thioalbamide-mediated OXPHOS inhibition was shown, for the first time, to reduce tumor invasiveness by inhibiting metalloproteinase-9 secretion. Furthermore, this study has confirmed the antitumor potential of thioalbamide in two different in vivo models. In particular, experiments on MCF-7 and MDA-MB-231 xenograft mouse models have confirmed in vivo its high anti-proliferative and pro-apoptotic activity, while experiments on MDA-MB-231 ″experimental metastasis" mouse models have highlighted its ability to inhibit breast cancer cell invasiveness. CONCLUSIONS: Overall, our results shed more light on the molecular mechanisms underlying the pharmacological potential of thioamidated peptides, thus reducing the gap that separates this rare class of microbial metabolites from clinical studies, which could validate them as effective tools for cancer treatment.

Susceptibility to ankylosing spondylitis but not disease outcome is influenced by the level of HLA-B27 expression, which shows moderate variability over time.

OBJECTIVE: Previous reports have highlighted the relevance of HLA-B27 expression in the pathogenesis of ankylosing spondylitis (AS). The aim of the current study was to estimate the level of HLA-B27 expression on the cell surface of ex vivo monocytes and lymphocytes by a quantitative method and to correlate this with AS disease susceptibility, disease clinical indexes, and the occurrence of acute anterior uveitis (AAU). METHOD: We recruited 32 B27-positive patients with AS and 32 B27-positive healthy normal controls (NCs) for evaluation at different time points. The expression of HLA-B27 molecules was quantified by flow cytometry on ex vivo peripheral blood mononuclear cells (PBMCs). Patients were also evaluated by scores on the Bath AS disease activity (BASDAI), functional (BASFI), and metrology (BASMI) indexes. RESULTS: The expression of HLA-B27 molecules was significantly higher in patients with AS than in B27-matched controls in the case of both monocytes [219K (IQR 174K-308K) vs. 137K (IQR 96K-170K), p < 0.0001] and lymphocytes [82K (IQR 58K-118K) vs. 54K (IQR 44K-61K), p < 0.0001]; AS only vs. AS with AAU: p = 0.744 in monocytes and p = 0.701 in lymphocytes. Comparisons with metrology and functional indexes were also not significant (BASMI: r = 0.05, p = 0.77; BASFI: r = -0.09, p = 0.67). The overexpression of HLA-B27 molecules was stable after 1 week of follow-up. At 3 years follow-up, the variability was moderate and did not correlate with variations in disease activity (BASDAI: r = -0.01, p = 0.92 ns). CONCLUSIONS: The level of HLA-B27 expression in PBMCs correlates with the susceptibility to AS but not with the disease outcome, nor with the occurrence of extra-articular manifestations such as AAU.

Chronic migraine: current concepts and ongoing treatments.

Migraine is an episodic painful disorder occasionally developing into a chronic form. Such disorder represents one of the most common neurological diseases in clinical practice. Chronicization is often accompanied by the appearance of acute drugs overuse. Chronic migraine (CM) constitutes migraine's natural evolution in its chronic form and involves headache frequency of 15 days/month, with features similar to those of migraine attacks. Medication Overuse Headache (MOH) has been defined as a headache present on > or = 15 days/month, with regular overuse for > 3 months of one or more drugs used for acute and/or symptomatic headache management. Subtypes of MOH attributed to different medications were delineated. Misuse of ergots, triptans, opioids or combination analgesics on > or = 10 days/month was required to make the diagnosis of MOH, while > or = 15 days/month were needed for simple analgesic-overuse headache. CM's low prevalence produces an extremely high disability grade. Therefore, special attention should be paid to both control and reduction of risk factors which might favour the migraine chronicization process and/or the outbreak of MOH. In MOH sufferers, the only treatment of choice is represented by drug withdrawal. Successful detoxification is necessary to ensure improvement in the headache status when treating patients who overuse acute medications. Different procedures have been suggested for withdrawal namely at home, at the hospital, with or without the use of steroids, with re-prophylaxis performed immediately or at the end of the washout period. At the moment we have not a total agreement whether prophylactic treatment should be started before, during, or after discontinuation of the overuse drug. Both drugs have been approved for CM treatment in view of their well-defined resistance to previous prophylaxis drugs. Recently, the PREEMPT clinical program has confirmed onabotulinumtoxinA as an effective, safe, and well-tolerated prophylactic treatment for adults with CM.

Rare malignant tumors of the scalp: a report of four cases, their treatment and a review of the literature.

BACKGROUND AND OBJECTIVES: Malignant tumors occurring in the scalp are not common and when asymptomatic or small in size, may be covered by hair and neglected by the patient, leading to a potential risk of delay in detection and resulting in poorer outcomes. MATERIALS AND METHODS: In our Departments in the last five years more than 200 malignant tumors of the scalp have been operated on. In this article we take into consideration four rare malignant tumours of the scalp taken from this study: a giant recurrent sebaceous carcinoma, a lung cancer metastatic lesion, a malignant melanoma and a breast cancer metastasis. RESULTS: The four patients with rare malignant tumours have been operated with good results. DISCUSSION: These four cases represent an important lesson for the plastic surgeon to learn: in the case of the presence of unusual, ulcerated/pigmented lesion of the scalp or in the case of alopecia we must consider the possibility of a tumour.

Melkersson-Rosenthal syndrome associated with Down syndrome.

We present a clinical case of Melkersson-Rosenthal (M-R) syndrome associated with Down syndrome. No evidence of this association is described in the literature. We also present a technique for the macrocheilia treatment of lower lip caused by M-R syndrome in a patient with Down syndrome. This patient during pediatric age had many events of facial nerve paralysis and edematous episodes of lower lip with unknown etiology. This technique is based on a wedge full thickness central excision of the lower lip and on a transversal lozenge excision in the vermilion portion with orbicular muscle to reverse the chin-labial corner. The results are an agreeable aspect of the lip and physiological digestive and phonetic processes. The technique is safe and simple and the aesthetic functional result is very good. In our case, the postoperative complication is caused by an insufficient collaboration of the patient and it is solved in three weeks.

A functional polymorphism of the vasoactive intestinal peptide receptor 1 gene correlates with the presence of HLA-B*2705 in Sardinia.

The association of HLA-B27 with ankylosing spondylitis (AS) is the strongest among all inflammatory diseases. However, the exact role of these molecules in disease pathogenesis is still unknown. The existence of HLA-B27 variants rarely found in patients introduces a further level of complexity. It is now accepted that other genes of minor impact contribute to modify disease susceptibility and these genes might be diverse in different populations depending on the genetic background. We report here a study performed in Sardinia, an outlier population in which two major HLA-B27 subtypes are present, B (*)2705 strongly associated with AS and B (*)2709 which is not, and show the co-occurrence of the B (*)2705 allele with a single nucleotide polymorphism (SNP) mapping at 3'-UTR of the receptor 1 (VIPR1) for the vasoactive intestinal peptide (VIP), a neuropeptide with anti-inflammatory properties. This same SNP is associated with a different kinetics of down-modulation of the VIPR1 mRNA in monocytes after exposure to lipopolysaccharide (P=0.004). This particular setting, HLA-B (*)2705 and a functional polymorphism in VIPR1 gene, might be due to a founder effect or might be the result of a selective pressure. Irrespectively, the consequent downregulation of this receptor in the presence of a 'danger' signal might influence susceptibility to AS.

HLA-B*2709 and lack of susceptibility to sacroiliitis: further support from the clinic.

Interferons (IFN) are well known triggers of immunomediated diseases in genetically predisposed subjects. We describe the unique case of a HLA-B*2709 positive subject who underwent IFN-alpha treatment for essential thrombocythemia and developed arthritis of the proximal interphalangeal joints of the hands but not sacroiliitis. The possible mechanisms of IFN-induced arthritis are discussed.

Association of MICA alleles with psoriatic arthritis and its clinical forms. A multicenter Italian study.

OBJECTIVE: Analysis of the association between psoriatic arthritis (PsA) clinical forms and MICA gene transmembrane polymorphisms. METHODS: Patients were classified as having peripheral asymmetric oligoarthritis (AO), peripheral symmetric poly-arthritis (PA) and spondylitis (SP), or disease combinations (PA/SP, OA/SP). Two hundred and twenty-six patients with PsA were typed for MICA exon 5 microsatellite (TM) by heteroduplex analysis and compared with 225 normal controls. RESULTS: MICA-TM microsatellite typing revealed that, among the different clinical forms of PsA, only the combined PA/SP subset shows a significant positive association with MICA-A9 and a lower frequency of MICA-A4, A5 genotype in PsA patients with a decrease, only in the PA/SP cohort, of all MICA-A5 combinations except MICA-A5, -A9. CONCLUSION: These results suggest a role for genes within the HLA region in the pathogenesis of PsA, and reinforce the idea that the different forms of PsA may have heterogeneous genetic basis.

Acceptability of potential interventions to increase firearm safety among patients in VA mental health treatment.

OBJECTIVE: Veterans in mental health care have high rates of firearm-related suicide; reducing firearm access during high-risk periods could save lives. We assessed veteran patients' attitudes towards voluntary interventions to reduce access. METHODS: Descriptive data came from surveys mailed to random samples of veterans receiving mental health care in five geographically diverse VA facilities. Survey items inquired about the acceptability of seven voluntary health system interventions to address firearm access, ranging from lower-intensity interventions that addressed safety but might not reduce access (i.e., clinician screening; distribution of gunlocks) to interventions substantially limiting access (i.e., storage of firearms offsite; gun disposal). Mailings occurred between 5/11/15 and 10/19/15; 677 of 1354 veterans (50%) returned the surveys. RESULTS: 93.2% of respondents endorsed one or more health system interventions addressing firearm access; 75.0% endorsed interventions substantially limiting access. Although veterans with household firearms were less likely to endorse interventions, fully 50.4% would personally participate in at least one intervention that substantially limited access. DISCUSSION: A majority of veterans in VA mental health care endorse voluntary health system interventions addressing firearm access during high-risk periods for suicide. Approximately half of veterans with firearms would personally participate in an intervention that substantially limited firearm access.

CD8(+) T-cell autoreactivity to an HLA-B27-restricted self-epitope correlates with ankylosing spondylitis.

HLA-B27 is highly associated with ankylosing spondylitis (AS), but the mechanism is unknown. Among the HLA-B27 alleles, B*2709, which differs by one amino acid from the susceptible B*2705, is not associated with the disease. Here, we analyze the reactivity, in patients with AS and in healthy controls carrying the B*2709 or B*2705 alleles, to an EBV epitope derived from LMP2 (236-244) and to a sequence-related self-peptide from vasoactive intestinal peptide receptor 1 (VIP1R 400-408). We found that both B*2705(+) and B*2709(+) subjects possess LMP2 236-244-specific, HLA-B27-restricted T cells, whereas only the B*2705(+) individuals respond significantly to VIP1R 400-408. These results prompted us to compare, by IFN-gamma ELISPOT analysis, the T-cell response to VIP1R 400-408 in patients with AS versus B*2705 healthy controls. The data show that VIP1R 400-408-specific reactivity is a major feature of the patients with AS. These findings show, for the first time to our knowledge, a widespread reactivity in patients with AS against a self-epitope that exhibits some features of a putative "arthritogenic" peptide.

Impact of symptomatic skeletal events on health-care resource utilization and quality of life among patients with castration-resistant prostate cancer and bone metastases.

BACKGROUND: Data regarding the impact of symptomatic skeletal events (SSEs) on health economics and patient-reported outcomes in men with castration-resistant prostate cancer (CRPC) and bone metastases from a clinical setting are lacking. Hence, this study aimed to quantify the effects of SSEs on health-care resource utilization (HRU), health-related quality of life (HRQoL) and pain in men with CRPC metastasized to bone. METHODS: This cohort study included men with CRPC and bone metastasis treated at a tertiary center during December 1996-July 2015. SSEs, including pathological fracture, radiation to bone, spinal cord compression and bone surgery, as well as HRU were identified retrospectively through medical records and clinical database. A subset of surviving patients completed Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain Inventory-Short Form (BPI-SF) questionnaires. The incremental effect of SSEs on HRU was evaluated using multivariable generalized linear regression. Questionnaire scores were compared using effect sizes (ES); ES⩾0.33 indicated meaningful differences between SSE and non-SSE cohorts. Lower scores suggest lower HRQoL and pain. RESULTS: Of the 832 patients, 207 developed ⩾1 SSE (mean 1.5±0.8) during follow-up (median 2.1 years). Radiation to bone was the most common SSE (84.1%). SSE cohort had significantly higher emergency room (incidence rate ratio (IRR)=1.48; P=0.006), outpatient (IRR=1.17; P=0.005) and inpatient (IRR=1.74; P<0.001) visits. Of the 107 eligible survey patients, 103 (96.3%) responded. SSE cohort had lower mean FACT-P functional well-being (17.5 vs 19.8; P=0.158; ES=0.36), higher mean pain severity (2.5 vs 1.6; P=0.048; ES=0.47) and worst pain scores (3.6 vs 2.3; P=0.033; ES=0.50) compared with the non-SSE cohort, indicating meaningful differences between cohorts. CONCLUSIONS: This study demonstrated high economic and HRQoL burden of SSEs. The findings underscore the need for better supportive and disease-modifying treatments for these patients.

Evaluation of chromogranin A expression in patients with non-neuroendocrine tumours.

BACKGROUND: Chromogranin A (CgA) is well established as a serum marker for neuroendocrine tumours and has also been associated with some non-neuroendocrine tumours, suggesting a possible role for somatostatin analogues such as octreotide in the treatment of these tumours. OBJECTIVE: The aim of this study was to measure plasma CgA levels in patients with various non-neuroendocrine tumours in order to identify those patients who might benefit from octreotide therapy. METHODS: Plasma CgA levels were tested in 151 patients with metastatic non-neuroendocrine tumours. Patients with highly elevated levels were assessed by OctreoScan scintigraphy to determine their somatostatin receptor status, and those with positive results were offered treatment with the somatostatin analogue octreotide, 20 mg every 4 weeks, and followed up every 3 months. RESULTS: CgA levels were elevated (>18 U/L) in 34/72 patients with breast cancer, 11/21 with lung cancer, 10/28 with gastrointestinal cancer, 7/12 with gynaecological cancer, 6/9 with genitourinary cancer, 5/5 with haematological cancer, and 3/4 with head and neck cancer. Eight patients with CgA levels >150 U/L underwent scintigraphy, five of whom (two colorectal, two prostate, one non-small cell lung cancer [NSCLC]) showed positive results and received treatment with octreotide. Follow-up for a mean 12-16 months showed improvements in biochemical parameters, cenesthesis and quality of life. CONCLUSION: CgA levels were found to be elevated in approximately 50% of patients with non-neuroendocrine tumours. Further studies are required to determine the value of CgA as a marker for non-neuroendocrine tumours and the role of somatostatin analogues as a treatment for these tumour types.

Bergamot (Citrus bergamia Risso) Flavonoids and Their Potential Benefits in Human Hyperlipidemia and Atherosclerosis: an Overview.

Elevated serum cholesterol, triglycerides and LDL levels are often associated with an increased incidence of atherosclerosis and coronary artery disease. The most effective therapeutic strategy against these diseases is based on statins administration, nevertheless some patients, especially those with metabolic syndrome fail to achieve their recommended LDL targets with statin therapy, moreover, it may induce many serious side effects. Several scientific studies have highlighted a strong correlation between diets rich in flavonoids and cardiovascular risk reduction. In particular, Citrus bergamia Risso, also known as bergamot, has shown a significant degree of hypocholesterolemic and antioxidant/radical scavenging activities. In addition, this fruit has attracted considerable attention due to its peculiar flavonoid composition, since it contains some flavanones that can act as natural statins. Hence, the study of bergamot flavonoids as metabolic regulators offers a great opportunity for screening and discovery of new therapeutic agents. Cholesterol metabolism, flavonoid composition and potential therapeutic use of C. bergamia Risso will be discussed in the following review.

Predictors of duration of abiraterone acetate in men with castration-resistant prostate cancer.

BACKGROUND: Androgen receptor signaling remains important in castration-resistant prostate cancer (CRPC) as demonstrated by the efficacy of abiraterone acetate (henceforth abiraterone) in phase III trials. Given that heterogeneous patient responses are observed, we sought to identify clinical factors associated with duration of abiraterone. METHODS: We retrospectively identified patients with CRPC treated with abiraterone in our database. Patient characteristics and types and duration of prostate cancer (PC) therapies were analyzed. These parameters were analyzed with duration of abiraterone in univariate and multivariable analyses. RESULTS: We identified 161 patients who had received abiraterone. All had received primary androgen-deprivation therapy (ADT), 86% prior secondary hormone therapy (SHT) and 33% prior chemotherapy. The median duration of primary ADT was 23 months, duration of SHT (excluding abiraterone) was 17 months and duration of chemotherapy was 8 months. We demonstrated that lower PSA at abiraterone initiation, longer primary ADT duration, no prior ketoconazole, no prior chemotherapy and longer chemotherapy duration were associated with a longer duration on abiraterone in univariate analysis. In multivariable analysis, duration of primary ADT (duration of abiraterone 9 versus 13 months for ⩽12 versus >12 months, P=0.03) and no use of prior chemotherapy (duration of abiraterone 16 versus 7 months for no versus yes prior chemotherapy, P<0.01) were associated with duration of abiraterone. CONCLUSIONS: Several clinical parameters, including type and duration of prior therapy, are predictive of responsiveness to abiraterone. These parameters are logical and correlate with smaller disease burden or less exposure to PC therapies. This information can help physicians counsel patients about the potential durability of efficacy of abiraterone. Identifying predictive biomarkers that inform patient selection for therapy is critical to optimizing treatment outcomes.

Sodium retention in preascitic stage of cirrhosis.

Renal Na+ handling abnormalities have been shown in preascitic cirrhosis. To investigate the underlying pathophysiology, the effects of different sodium intakes on Na(+) balance and renal hemodynamics were assessed at 100 mEq Na+/day (low-sodium diet [LSD]) and after 6 days of 250 mEq Na+/day (high-sodium diet [HSD]). Eight asymptomatic patients with cirrhosis (Pugh-Child A class) (PAC) and 10 healthy controls (CON) were studied. At HSD, although CON readjusted Na+ excretion within the fourth day, PAC did not reach the new balance and developed a final greater Na+ retention (+437 mEq in PAC v +228 mEq in CON, P<.001). In PAC, fractional Na+ excretion (FENa) was significantly lower than in CON at LSD (P<.05), and, after HSD, increased in both groups (P<.05). In PAC, renal vascular resistances (RVR) at LSD resulted lower than in CON (P<.05) and failed to decrease after HSD. As a consequence, after HSD, glomerular filtration rate and renal plasma flow failed to increase in PAC. PRA and plasma aldosterone were significantly lower in PAC, than in CON at LSD (P<.05), and decreased in both groups after HSD (P<.05). Proximal Na+ reabsorption (RProx) [as indicated by fractional free water clearance measured in a state of maximal water diuresis] at LSD was lower in PAC than in CON (P<.05) and decreased in both groups after HSD (P<.05). In summary, early stages of cirrhosis are characterized by: (1) a reduction of RVR, probably associated with splanchnic vasodilation; (2) a Na+ retention already at LSD, as indicated by the lower FENa observed in PAC, that produces extracellular volume (ECV) expansion, with a consequent RProx and renin-angiotensin-aldosterone axis (RAS) suppression; (3) a greater Na+ retention after HSD, associated with an abnormal adaptation of renal hemodynamic, a greater ECV expansion and a consequent Rprox and RAS suppression. These data show the presence of early renal hemodynamic dysfunction in PAC. Our findings also show in this phase of the disease a preserved adaptation of RProx and RAS, thus suggesting that the observed tubular Na+ reabsorption derangement is probably related to abnormal ANP behavior.

The importance of peritoneal imaging in the workup of genital edema in patients on continuous ambulatory peritoneal dialysis.

BACKGROUND: Genital edema is a well-reported complication of peritoneal dialysis. This phenomenon has been associated with extravasation of dialysate from the peritoneal cavity through a defect in the abdominal wall or through an wall or through an inguinal hernia (or patent processus vaginalis, persistent sac). In the first case, fluid tracks through the soft tissues of the abdominal wall and settles in the dependent genitalia. In the second, fluid tracks through the inguinal hernial defect and infiltrates into the tissues distal to the defect. It is difficult to precisely diagnose the etiology of many of these cases but it is obviously important. METHOD: We report a case of a patient who presented with penile and scrotal edema and was eventually found to have bilateral patent processus vaginalae. We used computed tomography and peritoneal scintigraphy in order to ascertain the diagnosis. RESULTS/CONCLUSIONS: We believe that computed tomography and peritoneal scintigraphy are extremely helpful in the workup of genital edema in patients on continuous ambulatory peritoneal dialysis.

Complications of subcutaneous injection ports.

Subcutaneous injection ports have become widely used for patients who require prolonged central venous access. Complications of their placement and use are well documented in the existing literature. We report two previously undocumented complications occurring in Port-a-Cath units, and suggest methods to lessen the likelihood of recurrence of these problems.

Photographic standards in plastic surgery.

Standard photographic technique in plastic surgery is an important topic that has been stressed in the discipline over the past several years. Clinical photographs should always be taken with the same camera lens, lens setting, lighting, film, and patient position to ensure reproducibility and to enable valid pre- and postoperative comparisons. A 35-mm single lens reflex camera is highly recommended for this type of photography. Two lenses are suggested, one with a focal length range of 50 to 60 mm and one with a focal length range of 90 to 105 mm. Both should have macro capability. Two or more flash units are recommended, either camera-mounted or a studio system set-up in the office. Using the patient preparation method and technique outlined in the text, the Standards in Clinical Photography achieve consistency from patient to patient and also in the same patient in pre- and postoperative photographs. Henceforth, the information discussed in the article forms the basis for standard views, regardless of the image-capture medium.