Sexual Function in Women With Differences of Sex Development or Premature Loss of Gonadal Function.

BACKGROUND: Previous studies have suggested that sexual function may be compromised in women born with differences of sex development (DSD) or early loss of gonadal function. AIM: To describe sexual function and sexual wellbeing in women with complete androgen insensitivity syndrome (CAIS), complete gonadal dysgenesis (GD) and premature ovarian insufficiency (POI) in relation to gynecological measures and in comparison with unaffected women. METHODS: A cross sectional study including 20 women with CAIS, 8 women with 46,XY GD, 8 women with 46,XX GD, 21 women with POI, and 62 population-derived controls. Study participants underwent gynecological examination for anatomical measurements and evaluation of tactile sensitivity. They responded to the validated Sexual Activity Log (SAL), Profile of Female Sexual Function (PFSF), and the Personal Distress Scale (PDS). RESULTS: The women with CAIS, XY GD, XX GD and POI showed overall satisfying sexual function in comparison to unaffected age-matched population female controls with a median of 1 to 2 satisfying sexual episodes per week among both the patients and the controls depending on available partner. Women with CAIS had shorter vagina and smaller clitoris and women with XY GD had a significantly shallower vagina in comparison to controls. Clitoral width was also significantly smaller among women with XX GD compared to controls. However, results showed overall good genital touch sensitivity with no significant differences between groups. CLINICAL IMPLICATIONS: Women with DSD or POI can be informed on overall satisfactory sexual function and normal genital touch sensitivity. STRENGTHS & LIMITATIONS: The strength is the use of age-matched population-based controls to these rare conditions of DSD and POI. Limitations are the nonresponder rate of recruited controls, as well as the small groups of women with DSD. CONCLUSION: Women with differences of sex development or early loss of gonadal function show overall good sexual well-being, however clinicians have to make efforts to optimize caretaking and treatment to ensure good sexual quality of life for all patients. Engberg H, Strandqvist A, Berg E, et al., Sexual Function in Women With Differences of Sex Development or Premature Loss of Gonadal Function. J Sex Med 2022;19:249-256.

A Randomized Controlled Trial of Intranasal Neuropeptide Y in Patients With Major Depressive Disorder.

BACKGROUND: Since about one-third of patients with major depressive disorder (MDD) do not respond adequately to available antidepressants, there is a need for treatments based on novel mechanisms of action. Neuropeptide Y (NPY), a normal brain constituent, is reduced in cerebrospinal fluid of patients with MDD and post-traumatic stress disorder and in corresponding rodent models. Moreover, NPY administered centrally or intranasally rescues pathophysiology in these models. Consequently, we conducted the first, to our knowledge, controlled trial of NPY as a treatment for MDD. METHODS: Thirty MDD patients on a stable dose of a conventional antidepressant insufflated 6.8 mg NPY (n = 12) or placebo (n = 18) in a double blind randomized fashion. Effects were assessed at baseline, +1 hour, +5 hours, +24 hours, and +48 hours. The primary outcome was change in depression severity measured with the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: NPY was superior to placebo at +24 hours (change -10.3 [95% CI: -13.8; -6.8]) vs -5.6 (95% CI: -8.4; -2.7); group*time F = 3.26, DF = (1,28), P = .04; Cohen's d = 0.67). At +5 hours MADRS decreased -7.1 ([95% CI: -10.0; -4.2] vs -3.5 [95% CI: -5.8; -1.2]; group*time F = 2.69, DF = (1,28), P = .05; Cohen's d = 0.61). MADRS reduction at +48 hours was not significant. CONCLUSIONS: Since no results regarding the trajectory of NPY effects existed prior to this study we extrapolated from the known NPY biology and predicted the effects will occur 5-48 hours post insufflation. We chose +48 hours as the primary endpoint and +1, +5, and +24 hours as secondary endpoints. The results, the first of their kind, indicate that insufflated NPY is antidepressant, despite not meeting the primary outcome, and call for dose ranging and repeated NPY insufflation trials. CLINICAL TRIAL REGISTRATION: EudraCT Number: 2014-000129-19.

Objective evaluation by reflectance spectrophotometry can be of clinical value for the verification of blanching/non blanching erythema in the sacral area.

Early detection of non blanching erythema (pressure ulcer category I) is necessary to prevent any further skin damage. An objective method to discriminate between blanching/non blanching erythema is presently not available. The purpose of this investigation was to explore if a non invasive objective method could differentiate between blanching/non blanching erythema in the sacral area of patients undergoing hip fracture surgery. Seventy-eight patients were included. The sacral area of all patients was assessed using (i) conventional finger-press test and (ii) digital reading of the erythema index assessed with reflectance spectrophotometry. The patients were examined at admission and during 5 days postsurgery. Reflectance spectrophotometry measurements proved able to discriminate between blanching/non blanching erythema. The reliability, quantified by the intra-class correlation coefficient, was excellent between repeated measurements over the measurement period, varying between 0·82 and 0·96, and a significant change was recorded in the areas from day 1 to day 5 (P < 0·0001). The value from the reference point did not show any significant changes over the same period (P = 0·32). An objective method proven to identify early pressure damage to tissue can be a valuable tool in clinical practice.

What Everybody is Doing but No One is Talking About: Use of Complementary and Alternative Medicine in the ANCA Associated Vasculitis Population.

The use and impact of complementary and alternative medicine (CAM) for anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) has not been reported. AAV patients seeking care at our center inquired about CAM, prompting a formal study. Study objectives were to discern how many AAV patients used CAM and its perceived helpfulness in disease management. METHODS: AAV patients completed a CAM questionnaire between July 2011 and May 2012. Patients were 18 years or older and had biopsy proven and/or clinical evidence of AAV. Medical record abstraction supplemented data. Classification detailed CAM type including "Mind" or "Mind-Body". Perceived helpfulness of CAM was assessed as "very", "somewhat" or "not at all/don't know". RESULTS: A total of 107 patients participated and were a mean age of 53 (range: 18-85), 62% female; 48% proteinase 3 (PR3)-ANCA, 44% myeloperoxidase (MPO)-ANCA and 8% ANCA-negative. Top organs involved included kidney (87%), joints (55%), lung (53%) and upper respiratory (53%). At least one type of CAM treatment or self-help practice was reported by 81% of study participants, with the most frequent being prayer (64%), exercise (27%) and massage therapy (19%). Mind-based practices were used by 28% (excluding prayer) and Mind-Body practices by 14%. Most practices were used to improve wellbeing, and Mind and Mind-Body were deemed very helpful by 83% and 87% respectively. Only 24% of study participants discussed CAM with their physician. CONCLUSION: CAM practices were commonly used to improve well-being and found to be beneficial among AAV patients, but more open discussion is needed about CAM between physicians and patients.

Psychometric properties of the Hospital Survey on Patient Safety Culture, HSOPSC, applied on a large Swedish health care sample.

BACKGROUND: A Swedish version of the USA Agency for Healthcare Research and Quality "Hospital Survey on Patient Safety Culture" (S-HSOPSC) was developed to be used in both hospitals and primary care. Two new dimensions with two and four questions each were added as well as one outcome measure. This paper describes this Swedish version and an assessment of its psychometric properties which were tested on a large sample of responses from personnel in both hospital and primary care. METHODS: The questionnaire was mainly administered in web form and 84215 forms were returned (response rate 60%) between 2009 and 2011. Eleven per cent of the responses came from primary care workers and 46% from hospital care workers. The psychometric properties were analyzed using both the total sample and the hospital and primary care subsamples by assessment of construct validity and internal consistency. Construct validity was assessed by confirmatory (CFA) and exploratory factor (EFA) analyses and internal consistency was established by Cronbachs's α. RESULTS: CFA of the total, hospital and primary care samples generally showed a good fit while the EFA pointed towards a 9-factor model in all samples instead of the 14-dimension S-HSOPSC instrument. Internal consistency was acceptable with Cronbach's α values above 0.7 in a major part of the dimensions. CONCLUSIONS: The S-HSOPSC, consisting of 14 dimensions, 48 items and 3 single-item outcome measures, is used both in hospitals and in primary care settings in Sweden for different purposes. This version of the original American instrument has acceptable construct validity and internal consistency when tested on large datasets of first-time responders from both hospitals and primary care centres. One common instrument for measurements of patient safety culture in both hospitals and primary care settings is an advantage since it enables comparisons between sectors and assessments of national patient safety improvement programs. Future research into this version of the instrument includes comparing results from patient safety culture measurements with other outcomes in relation to safety improvement strategies.

Clinicopathological analysis of colorectal cancer: a comparison between emergency and elective surgical cases.

BACKGROUND: Approximately 15 to 30% of colorectal cancers present as an emergency, most often as obstruction or perforation. Studies report poorer outcome for patients who undergo emergency compared with elective surgery, both for their initial hospital stay and their long-term survival. Advanced tumor pathology and tumors with unfavorable histologic features may provide the basis for the difference in outcome. The aim of this study was to compare the clinical and pathologic profiles of emergency and elective surgical cases for colorectal cancer, and relate these to gender, age group, tumor location, and family history of the disease. The main outcome measure was the difference in morphology between elective and emergency surgical cases. METHODS: In total, 976 tumors from patients treated surgically for colorectal cancer between 2004 and 2006 in Stockholm County, Sweden (8 hospitals) were analyzed in the study. Seventeen morphological features were examined and compared with type of operation (elective or emergency), gender, age, tumor location, and family history of colorectal cancer by re-evaluating the histopathologic features of the tumors. RESULTS: In a univariate analysis, the following characteristics were found more frequently in emergency compared with elective cases: multiple tumors, higher American Joint Committee on Cancer (AJCC), tumor (T) and node (N) stage, peri-tumor lymphocytic reaction, high number of tumor-infiltrating lymphocytes, signet-ring cell mucinous carcinoma, desmoplastic stromal reaction, vascular and perineural invasion, and infiltrative tumor margin (P<0.0001 for AJCC stage III to IV, N stage 1 to 2/3, and vascular invasion). In a multivariate analysis, all these differences, with the exception of peri-tumor lymphocytic reaction, remained significant (P<0.0001 for multiple tumors, perineural invasion, infiltrative tumor margin, AJCC stage III, and N stage 1 to 2/3). CONCLUSIONS: Colorectal cancers that need surgery as an emergency case generally show a more aggressive histopathologic profile and a more advanced stage than do elective cases. Essentially, no difference was seen in location, and therefore it is likely there would be no differences in macro-environment either. Our results could indicate that colorectal cancers needing emergency surgery belong to an inherently specific group with a different etiologic or genetic background.

Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis.

Anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCA-negative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.

Patients with antineutrophil cytoplasmic antibody-associated vasculitis have defective Treg cell function exacerbated by the presence of a suppression-resistant effector cell population.

OBJECTIVE: The development of pathogenic antineutrophil cytoplasmic antibodies (ANCAs) can result in systemic small vessel vasculitis. However, the breakdown in immune tolerance that results in the induction and persistence of ANCAs is not well understood. We undertook this study to test our hypothesis that abnormal T cell regulation is central to disease pathogenesis in patients with ANCA-associated vasculitis (AAV). METHODS: Peripheral blood samples were obtained from 62 patients with AAV and 19 healthy controls for flow cytometric analysis of CD4+ T cell populations. Functional T cell studies were performed with fluorescence-activated cell sorted CD4+ T cell populations stimulated with anti-CD3/anti-CD28. RESULTS: We demonstrated two separate abnormalities in T cell regulation in patients with AAV. First, we showed that the Treg cell frequency was increased in the peripheral blood of patients with active disease, but Treg cells from patients with AAV had decreased suppressive function. Treg cells from patients with active disease disproportionately used a FoxP3 isoform lacking exon 2, which might alter Treg cell function. Second, we identified a CD4+ T cell population with increased frequency that was resistant to Treg cell suppression, produced proinflammatory cytokines, and was antigen experienced. CONCLUSION: AAV is associated with disruption of the suppressive Treg cell network and with increased frequency of a distinct proinflammatory effector T cell subset that comprises the majority of peripheral CD4+ T cells.

Decreased CD5⁺ B cells in active ANCA vasculitis and relapse after rituximab.

BACKGROUND AND OBJECTIVES: B cell significance in ANCA disease pathogenesis is underscored by the finding that ANCA alone can cause disease in mouse models and by the effectiveness of rituximab as therapy in ANCA-small vessel vasculitis (ANCA-SVV). To avoid infections and adverse events from therapy, clinicians require improved markers of disease activity and impending relapse to guide immunosuppression strategies after rituximab treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The B cell phenotype was investigated in patients with active ANCA-SVV and in remission. From 2003 to 2009, 54 patients were followed longitudinally for 4-99 months and compared with 68 healthy controls. In a subset of 19 patients, the B cell immunophenotype was examined in samples after rituximab therapy. RESULTS: Patients with active ANCA-SVV had lower %CD5(+) B cells, whereas %CD5(+) B cells from patients in remission were indistinguishable from healthy controls. After rituximab, median time to relapse was 31 months in patients maintaining normalized %CD5(+) B cells, with or without maintenance immunosuppression. Among patients whose B cells repopulated with low %CD5(+) B cells or had a sharply declining %CD5(+) B cells, those who were on low or no maintenance immunosuppression relapsed sooner (median 17 months) than patients who were maintained on high levels of oral maintenance immunosuppression (29 months; P=0.002). CONCLUSIONS: The %CD5(+) B cells, as a component of the human B regulatory cell phenotype, is a useful indicator of disease activity, remission, and future relapse, and thus may guide remission maintenance therapy after rituximab treatment.

Bone marrow dendritic cells are reduced in patients with high-risk myelodysplastic syndromes.

Dendritic cells (DC) are antigen-presenting cells that play a pivotal role in coordinating functions of the immune system. Previous studies suggest that bone marrow (BM) failure in myelodysplastic syndromes (MDS) may be in part immune-mediated, and that the high propensity for relapse may reflect decreased immune surveillance. This study aimed to assess the frequency of DC in BM samples from well-annotated untreated MDS patients by using 4-colour flow cytometry. DC levels were markedly reduced in all subtypes of MDS. The clinical impact of this finding on therapy response and relapse after, e.g. allogeneic stem cell transplantation warrants further investigation.

High basal activity of the PTPN22 gain-of-function variant blunts leukocyte responsiveness negatively affecting IL-10 production in ANCA vasculitis.

Consequences of expression of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gain-of-function variant were evaluated in leukocytes from patients with anti-neutrophil cytoplasmic autoantibody (ANCA) disease. The frequency of the gain-of-function allele within the Caucasian patient cohort was 22% (OR 1.45), compared to general American Caucasian population (16.5%, p = 0.03). Examination of the basal phosphatase activity of PTPN22 gain-of-function protein indicated persistently elevated activity in un-stimulated peripheral leukocytes, while basal activity was undetectable in leukocytes from patients without the gain-of-function variant. To examine consequences of persistently high PTPN22 activity, the activation status of ERK and p38 MAPK were analyzed. While moderate levels of activated ERK were observed in controls, it was undetectable in leukocytes expressing PTPN22 gain-of-function protein and instead p38MAPK was up-regulated. IL-10 transcription, reliant on the ERK pathway, was negatively affected. Over the course of disease, patients expressing variant PTPN22 did not show a spike in IL-10 transcription as they entered remission in contrast to controls, implying that environmentally triggered signals were blunted. Sustained activity of PTPN22, due to the gain-of-function mutation, acts as a dominant negative regulator of ERK activity leading to blunted cellular responsiveness to environmental stimuli and expression of protective cytokines.

Analysis of colorectal cancer morphology in relation to sex, age, location, and family history.

BACKGROUND: Studies of colorectal cancer (CRC) have suggested different mechanisms of carcinogenesis in men and women, young and old patients, right- and left sided tumors, and sporadic and familial tumors. These differences might be reflected in morphology. METHODS: CRCs from 1613 patients operated on in 2004-2006 in Sweden were histologically reviewed. Morphology was examined in relation to sex, age groups, location, and family history. RESULTS: Tumors in the right colon were larger, of higher stage, more often poorly differentiated, more mucin-producing, more often had a peritumoral lymphocytic infiltrate and a high level of tumor-infiltrating lymphocytes (TILs), and more seldom had an infiltrating margin than tumors in the left colon and rectum (p < 0.0001 for most features). Young patients (<60 years) more seldom had multiple tumors but more often had perineural invasion, an infiltrative tumor margin, and high-stage tumors. Three features, TILs, medullary tumors, and invasive tumor margin, were related to sex. Only vascular invasion was related to familiality. CONCLUSION: Location is the factor that has the most influence on tumor morphology. The results support the idea that different carcinogenic mechanisms may be involved in the right and left colon. Age is the most important determinant for the presence of multiple tumors and is a crucial factor for the aggressiveness of the disease.

Anti-LAMP-2 antibodies are not prevalent in patients with antineutrophil cytoplasmic autoantibody glomerulonephritis.

Lysosomal membrane protein 2 (LAMP-2) is a target of antineutrophil cytoplasmic autoantibodies (ANCA) in addition to the more commonly known targets proteinase 3 and myeloperoxidase. The prevalence of anti-LAMP-2 antibodies and their relationship to disease in ANCA glomerulonephritis are not well described. We measured anti-LAMP-2 reactivity in 680 sera samples (two academic centers) from patients with ANCA glomerulonephritis (n=329); those with ANCA-negative glomerulonephritis (n=104); those with fimbriated, gram-negative Escherichia coli urinary tract infection (n=104); disease controls (n=19); and healthy volunteers (n=124). With levels in healthy controls used to define a reference range, anti-LAMP-2 reactivity was present in 21% of ANCA sera from two of the centers; reactivity was present in 16% of the control group with urinary tract infection. Western blotting and immunofluorescence microscopy did not verify positivity. Titers of anti-myeloperoxidase and anti-proteinase 3 antibodies were 1500-fold and 10,000-fold higher than anti-LAMP-2 titers, respectively. There was no correlation between anti-LAMP-2 antibodies and disease activity. Furthermore, Wistar Kyoto rats injected with anti-LAMP-2 antibodies did not develop glomerulonephritis. In conclusion, antibodies that react with LAMP-2 may exist at very low titers in a minority of patients with ANCA disease. These data do not support a mechanistic relationship between anti-LAMP-2 antibodies and ANCA glomerulonephritis.

The APC-PCI concentration as an early marker of activation of blood coagulation: a study of women on combined oral contraceptives.

BACKGROUND: The risk of venous tromboembolism (VTE) in women taking combined oral contraceptives (COCs) is attributed to changes in coagulation and fibrinolysis. The impact of the COCs may be greater in women with preexisting thrombophilic defects. Nevertheless most women who suffer from venous thrombosis do not have any of the well known hereditary or acquired risk factors. A simple and sensitive marker of"thrombogenicity" has not been identified. OBJECTIVES: To investigate the effects of two different monophasic combined oral contraceptives (COCs) on the plasma concentrations of activated protein C-inhibitor of protein C ( APC-PCI) and on comparable hemostatic factors in fertile women. METHOD: Forty four healthy nulliparous women with regular menstrual periods were included and randomly assigned to start with a monophasic preparation containing 30µg ethinylestradiol and 150µg levonogestrel (LNG/EE) or a preparation containing 30µg ethinylestradiol and 150 ug desogestrel (DG/EE). After a wash out period of two months, treatment with the alternate preparation was initiated and continued for two more cycles. RESULTS: The plasma concentration of the APC-PCI complex and thrombin-antithrombin complex (TAT) increased during treatment with the two COCs. During DG/EE treatment the APC-PCI complex increased significantly more than during LNG/EE (p<0,01).The plasma concentration of D-dimer did not increase during OC treatment. CONCLUSION: The APC-PCI complex concentration, which serves as a marker for thrombin generation and indicates hypercoagulability, was increased during COC treatment compared to baseline. The method is a sufficiently sensitive marker to detect even small differences in the activation of coagulation.

Impaired endothelial function and elevated levels of pentraxin 3 in early-onset preeclampsia.

OBJECTIVE: To study endothelial function in relation to anti-angiogenic biomarkers and the inflammatory process in preeclampsia. DESIGN: Observational study. SETTING: Data were obtained from pregnant women who were admitted to the obstetrical ward at the Karolinska University Hospital, Solna, Stockholm, Sweden. POPULATION: Thirty-five women with newly developed and untreated preeclampsia and 30 healthy controls. METHODS: Flow-mediated dilation of the brachial artery, levels of anti-angiogenic and inflammatory markers were measured in plasma during pregnancy and 3-6 months after delivery. Main outcome measures. Flow-mediated dilation of the brachial artery, anti-angiogenic and inflammatory markers. RESULTS: Flow-mediated dilation was decreased in the preeclamptic group at inclusion and at follow-up (p<0.05). Pentraxin 3 (PTX3) and ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) were elevated in women with preeclampsia during pregnancy (p<0.001). Furthermore flow-mediated dilation was lower and the ratio sFlt-1/PlGF and PTX3 were higher in early-onset preeclampsia than late preeclampsia (p=0.018, 0.002 and 0.039). Levels of PTX3 at inclusion correlated inversely with flow-mediated dilation at follow-up both in the preeclampsia and control groups (Spearman, r(s) =-0.47, p=0.02 and r(s) =-0.46, p=0.02 respectively). CONCLUSION: Impaired endothelial function and increased ratio sFlt/PlGF, elevated PTX3 is present in women with preeclampsia and is especially pronounced in women with early-onset preeclampsia.

An ecological approach of Constraint Induced Movement Therapy for 2-3-year-old children: a randomized control trial.

UNLABELLED: The aim was to evaluate the effect of Eco-CIMT in young children with unilateral cerebral palsy in a randomized controlled crossover design. The training was implemented within the regular pediatric services, provided by the child's parents and/or preschool teacher and supervised by the child's regular therapist. METHODS: Twenty-five children (mean age 28.8 months [SD 11.2], 72% male) participated. Assisting Hand Assessment (AHA) was used as the outcome measure. The Eco-CIMT was provided for 2h a day over a period of two months. Children were randomized into two groups and started either with Eco-CIMT or as controls with a four-month washout period before crossing over. RESULT: A significant effect of Eco-CIMT was found when compared to the control period, and the estimated treatment effect was 5.47 (95% C.I. 2.93-8.02) (including both Group 1 and Group 2) (p < 0.001). The non-significant estimated carryover effect allowed us to collapse the two groups based on estimates from the ANOVA model. No clear relationship to hours of training, age or general attitudes of mastery was found. CONCLUSION: Eco-CIMT influenced development more than ordinary treatment at this age when Eco-CIMT was performed by parents and preschool teachers supervised by the child's ordinary therapist.

DRB1*15 allele is a risk factor for PR3-ANCA disease in African Americans.

Anti-neutrophil cytoplasmic autoantibody (ANCA) disease rarely occurs in African Americans and risk factors for the disease in this population are unknown. Here, we genotyped MHC class II alleles and found that, among African Americans, those with proteinase 3-ANCA (PR3-ANCA) had 73.3-fold higher odds of having HLA-DRB1*15 alleles than community-based controls (OR 73.3; 95% CI 9.1 to 591). In addition, a disproportionate number of African American patients carried the DRB1*1501 allelic variant of Caucasian descent rather than the DRB1*1503 allelic variant of African descent. Among Caucasians, those with PR3-ANCA had 2.2-fold higher odds of carrying DRB1*1501 than controls (OR 2.2; 95% CI 1.2 to 4.0). A validation study supported by the Vasculitis Clinical Research Consortium confirmed the strong association between the DRB1*15 allele and PR3-ANCA disease, among African Americans. Furthermore, we found that DRB1*1501 protein binds with high affinity to amino acid sequences of sense-PR3, purportedly an antigenic epitope, and to the amino acid sequence complementary to this epitope in vitro. Peptides of sense-PR3 and complementary-PR3 also bound to TNF-α-induced surface expression of DRB1*1501 on peripheral neutrophils. Taken together, these data suggest HLA-DRB1*15 alleles contribute to the pathogenesis of PR3-ANCA disease.

Radiologic measurements of tumor response to treatment: practical approaches and limitations.

Objective response assessment is important to describe the treatment effect of anticancer drugs. Standardization by using a "common language" is also important for comparison of results from different trials. In contrast to clinical results, which can be subjective, diagnostic imaging provides a greater opportunity for objectivity and standardization. It was generally accepted that a decrease in tumor size correlated with treatment effect; as a result, imaging was adopted for lesion measurement in the World Health Organization (WHO) criteria in 1979. However, because of some limitations of the WHO criteria, the Response Evaluation Criteria in Solid Tumors (RECIST) were introduced in 2000. In RECIST, imaging was recognized as indispensable for response evaluation of solid tumors. Nevertheless, the widespread use of multidetector computed tomography and other imaging innovations have made RECIST outdated, with a concomitant need for modifications. Meanwhile, newer anticancer agents with targeted mechanisms of action have demonstrated an inherent limitation and unsuitability of anatomic tumor evaluation that assesses only lesion size. In addition, the effect of these new drugs changes the paradigm according to which tumor response or response rate is measured. Complete and partial responses cannot be the end points in all clinical trials; in some cases, disease control or progression-free survival may be the more relevant end point.

Intraarticular administration of ketorolac, morphine, and ropivacaine combined with intraarticular patient-controlled regional analgesia for pain relief after shoulder surgery: a randomized, double-blind study.

BACKGROUND: In this study we assessed the efficacy of intraarticular regional analgesia on postoperative pain and analgesic requirements. METHODS: Fifty-one patients undergoing shoulder surgery (Bankart) were recruited into this double-blind study. At the end of the operation, patients were randomized to three groups to receive intraarticularly via a catheter: Group 1: ropivacaine 90 mg (9 mL), morphine 4 mg (10 mL), and ketorolac 30 mg (1 mL) (total volume 20 mL); Groups 2 and 3: saline (20 mL). In addition, Groups 1 and 3 received 1 mL saline IV while Group 2 received ketorolac 30 mg (1 mL) IV. Postoperatively, Group 1 received pain relief using 10 mL 0.5% ropivacaine on demand via the intraarticular catheter while Groups 2 and 3 received 10 mL of saline intraarticularly. Group 3 was the Control group. RESULTS: Postoperative pain at rest and on movement were lower in Group 1 than in Groups 2 and 3 during the first 30 and 120 min, respectively. The time to first request for local anesthetic infusion was longer in Group 1 than in Groups 2 and 3 (P < 0.001). The median morphine consumption during the first 24 postoperative hours was less in Groups 1 and 2 than in Group 3 (P < 0.001). There was no significant difference in analgesic consumption between Group 1 and Group 2. The median satisfaction score was higher in Group 1 compared with Groups 2 (P < 0.05) and 3 (P < 0.001). CONCLUSIONS: A combination of intraarticular ropivacaine, morphine, and ketorolac followed by intermittent injections of ropivacaine as needed provided better pain relief, less morphine consumption, and improved patient satisfaction compared with the control group. The group that received IV ketorolac consumed less morphine and was more satisfied with treatment than patients in the control group.