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Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare and typically arise in young women. The optimal management of a pregnant woman suspected of having an SPN of the pancreas head is unclear. We report such a case where close monitoring for tumo

Background: Testosterone therapy (TTh) is recommended for postmenopausal women with hypoactive sexual desire disorder (HSDD); however, there remain insufficient data to support use of TTh in premenopausal women with sexual dysfunction., Aim: In this study, we used a large national database to evaluate prescribing trends of TTh for women with HSDD., Methods: We conducted a cohort analysis of information from electronic health records acquired from the data network TriNetX Diamond. The study cohort consisted of women 18-70 years of age with a diagnosis of HSDD. We analyzed trends of testosterone prescriptions, routes of testosterone administration, and coadministration of testosterone with estrogen., Outcomes: Despite an increase in rates of testosterone prescriptions for HSDD, there remains a high degree of variability in the duration of treatment, route of administration, and coadministration of estrogen with significant underprescription of testosterone., Results: Our query of the TriNetX database led to the identification of 33 418 women diagnosed with HSDD at a mean age of 44.2 ± 10.8 years, among whom 850 (2.54%) women received a testosterone prescription. The testosterone prescriptions were highly variable with regard to duration and route of administration and coadministration with estrogen. For all patients until 2015, the prevalence of testosterone prescriptions for HSDD showed a positive quadratic relation was observed. Since 2015 a linear increase in prevalence was observed, with the highest rate of increase for patients aged 41-55 years., Clinical Implications: The findings of this study reveal a significant need for further research investigating the optimal use of TTh to enhance the sexual health of women with HSDD, and further studies on the long-term effects of testosterone use must be undertaken to ensure that patients have access to safe and effective treatment., Strengths and Limitations: Limitations to this study include patient de-identification and lack of availability of testosterone dosage data. However, this study also has many strengths, including being the first, to our knowledge, to characterize the prescribing trends of testosterone for women with HSDD., Conclusion: Testosterone therapy should be considered as a potential therapy for premenopausal female patients with HSDD. Further studies on the long-term effects of testosterone use must be undertaken to address disparities in the management of HSDD and to ensure patients can access treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: COVID-19 infection is associated with significant morbidity in systemic lupus erythematosus but is potentially preventable by vaccination, although the impact of the myriad vaccines among SLE patients is not established. We aimed to assess the effectiveness, efficacy, acceptance and safety of COVID-19 vaccination in SLE., Methods: We performed a systematic review of PubMed, EMBASE, CENTRAL, and Scopus publications until 8 June 2022 without language, publication year or publication status restrictions. Reports with fewer than 5 patients or incomplete information on study outcomes were excluded. Risk of bias was assessed, and results reported according to the PRISMA 2020 guidelines., Results: We identified 32 studies (34 reports) comprising 8269 individuals with SLE. Post-vaccine COVID-19 infections ranged from 0 to 17% in 6 studies (5065 patients), while humoral and cellular immunogenicity was evaluated in 17 studies (976 patients) and 5 studies (112 patients), respectively. The pooled seropositivity rate was 81.1% (95% CI: 72.6, 88.5%, I2 = 85%, P < 0.01), with significant heterogeneity and higher rates for mRNA vaccines compared with non-mRNA vaccines. Adverse events and specifically lupus flares were examined in 20 studies (3853 patients) and 13 studies (2989 patients), respectively. Severe adverse events and moderate to severe lupus flares were infrequent. The pooled vaccine acceptance rate was 67.0% (95% CI: 45.2, 85.6%, I2=98%, P < 0.01) from 8 studies (1348 patients), with greater acceptance in older patients., Conclusion: Among SLE patients, post-vaccine COVID-19 infections, severe flares, and adverse events were infrequent, while pooled seropositivity and acceptance were high, with significant heterogeneity. These results may inform shared decision-making on vaccination during the ongoing COVID-19 pandemic., Trial Registration: PROSPERO, https://www.crd.york.ac.uk/PROSPERO/, CRD42021233366., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The return on investment for onboarding programs and their effect on attrition and engagement within health systems across the United States are unclear., Local Problem: The existing onboarding program for nurse practitioners (NPs) and physician assistants (PAs) at a hospital on the west coast was varied and lacked a clinician focus. A structured onboarding program was created to standardize their entry to our workforce., Methods: A needs assessment was completed with a stakeholder focus group, for which an onboarding curriculum was then created. Participants completed presurveys/postsurveys during the data collection period as the primary outcome. A Plan-Do-Study-Act approach was used to revise session content and improve participant experience. Onboarding costs and attrition were tracked as secondary outcomes., Interventions: From July 2017 through June 2019, newly hired NPs and PAs were invited to participate in the program. Six quarterly cohorts attended five in-person 2-hour onboarding sessions over 12 months., Results: One hundred twenty-nine eligible NPs and PAs completed an anonymous pre/post Qualtrics survey. The aggregate responses were significantly improved using Fisher exact test. Measured onboarding value was not significantly changed. Mean pre-onboarding attrition was 10.3% compared with 4.5% for onboarding participants. The annual cost for onboarding participants was $63,470 versus $256,826 as the estimated mean cost of one separation within their first year., Conclusions: Workforce engagement, standardized knowledge, and participant attrition revealed an improving trend with this structured onboarding program. The investment to formalize onboarding newly hired NPs and PAs was modest, and the findings suggest that an onboarding program has financial and engagement merit., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2023 American Association of Nurse Practitioners.)

Venothrombolism (VTE) prophylaxis is increasingly utilized in pediatric intensive care units (PICUs). Enoxaparin, a low-molecular weight heparin, is frequently used for this purpose. Enoxaparin can also be used for therapeutic anticoagulation in cases of known thrombus. In such cases, monitoring involves obtaining serum anti- Xa levels with a target value of 0.5-1 units/mL. No monitoring recommendations currently exist for enoxaparin when intended for pediatric VTE prophylaxis. We hypothesize that a clinically important number of patients on VTE prophylaxis with enoxaparin have serum anti-Xa levels consistent with values targeted for therapeutic anticoagulation. We found that over 20% of patients on VTE prophylaxis with enoxaparin had serum anti-Xa levels consistent with true therapeutic anticoagulation (anti-Xa level 0.5-1 units/mL) during their enoxaparin course and 5% achieved values of supratherapeutic anticoagulation (anti-Xa level >1 units/mL). Serum anti-Xa level did not correlate with once versus twice daily dosing, body mass index (BMI), or creatinine level. Blood urea nitrogen (BUN) was found to have a positive odds ratio for an anti-Xa level ≥ 0.5 units/mL. We believe that this incidence of unintended therapeutic anticoagulation indicates a clinically significant number and therefore routine anti-Xa evaluation while on VTE prophylaxis is warranted within our population., (Published by Elsevier Ltd.)

Breast cancer continues to be the second leading cause of cancer deaths in women in the United States. This is more noticeable in communities with pronounced healthcare disparities. The aim of this study was to investigate the different demographics that might play a role in the detection of breast cancer in a county hospital emergency department (ED). A retrospective study was conducted of female patients diagnosed with breast cancer over a five-year period (1/1/2015 to 12/31/2018). Patients with breast cancer as the primary or secondary diagnosis were identified. This study shows that 66 (73.3%) women diagnosed in the ED were Hispanic or African American. There was a significant delay (a median of 461 days) in the time between the diagnosis of suspected breast cancer in the ED to their follow-up visit with definitive diagnosis in a primary care clinic. These findings suggest that women with a suspected breast cancer diagnosis who are seen in a safety net hospital and have Medicaid funding may have significant delays before final diagnosis is made. Patient demographics could have an impact on the patients' access to screening and regular healthcare visits, hindering an early breast cancer diagnosis by a primary care provider., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Yee et al.)

Objectives: To characterise the outcomes of neoadjuvant chemotherapy (NAC) pre-treated patients found to be lymph node (LN)-positive at the time of radical cystectomy and pelvic lymph node dissection (RC/PLND) for urothelial carcinoma of the bladder (UCB)., Patients and Methods: Of 1484 patients treated with RC/PLND for UCB from 2000 to 2010, we analysed 198 patients with clinically non-metastatic (cN0M0) muscle-invasive UCB who were found to be LN-positive at RC/PLND. As patients not receiving perioperative chemotherapy were significantly older and comorbid, we compared LN-positive patients previously treated with NAC (32 patients) to LN-positive patients treated with adjuvant chemotherapy (AC, 49 patients) using Cox proportional hazards models. A sensitivity analysis was designed to account for the additional time to RC in NAC patients., Results: The 3-year recurrence-free survival estimate for LN-positive NAC patients was 26%, compared with 60% for LN-positive AC patients. LN-positive patients treated with NAC had significantly higher risks of disease recurrence and cancer-specific mortality in univariate analyses (hazard ratio [HR] 2.86, 95% confidence interval [CI] 1.58-5.19, P = 0.001 and HR 2.50, 95% CI 1.34-4.65, P = 0.004, respectively) and multivariable analyses adjusting for pathological stage and LN density (HR 3.11, 95% CI 1.59-6.07, P = 0.001 and HR 3.05, 95% CI 1.46-6.35, P = 0.003, respectively). Sensitivity analyses similarly demonstrated worse outcomes for NAC pre-treated LN-positive patients., Conclusion: LN-positive patients previously treated with NAC have a poor prognosis, significantly worse than LN-positive patients subsequently treated with AC, and should be considered for protocols using sandwich chemotherapy approaches or novel agents. These results should be considered in the interpretation of and stratification for clinical trials., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are emerging tools for applications such as drug discovery and screening for pro-arrhythmogenicity and cardiotoxicity as leading causes for drug attrition. Understanding the electrophysiology (EP) of hPSC-CMs is essential but conventional manual patch-clamping is highly laborious and low-throughput. Here we adapted hPSC-CMs derived from two human embryonic stem cell (hESC) lines, HES2 and H7, for a 16-channel automated planar-recording approach for single-cell EP characterization. Automated current- and voltage-clamping, with an overall success rate of 55.0 ± 11.3%, indicated that 90% of hPSC-CMs displayed ventricular-like action potential (AP) and the ventricular cardiomyocytes (VCMs) derived from the two hESC lines expressed similar levels of I Na , I CaL , I kr and I f and similarly lacked I to and I K1 . These well-characterized hPSC-VCMs could also be readily adapted for automated assays of pro-arrhythmic drug screening. As an example, we showed that flecainide (FLE) induced I Na blockade, leftward steady-state inactivation shift, slowed recovery from inactivation in our hPSC-VCMs. Since single-cell EP assay is insufficient to predict drug-induced reentrant arrhythmias, hPSC-VCMs were further reassembled into 2D human ventricular cardiac monolayers (hvCMLs) for multi-cellular electrophysiological assessments. Indeed, FLE significantly slowed the conduction velocity while causing AP prolongation. Our RNA-seq data suggested that cell-cell interaction enhanced the maturity of hPSC-VCMs. Taken collectively, a combinatorial approach using single-cell EP and hvCMLs is needed to comprehensively assess drug-induced arrhythmogenicity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) provide an unlimited source of donor cells for potential cardiac regenerative therapies. However, hPSC-CMs are immature. For instance, hPSC-CMs are only 1/10 of the physical size of their adult counterparts; the majority are mono- rather than bi- or multi-nucleated, which is an evolutionary adaptive feature in metabolically active cells such as adult CMs. Here, we attempted to increase the physical size and nucleation status of hPSC-derived ventricular (V) cardiomyocytes (hPSC-VCMs) using chemically-induced cell fusion, and examined the subsequent functional effects. Polyethylene glycol (PEG) was employed to fuse a 1:1 mixture of lentiviral vectors LV-MLC2v-GFP- or -tdTomato-labeled hPSC-VCMs, such that hPSC-VCMs fused syncytia (FS) were identified as doubly GFP + /tdTomato + multi-nucleated cells. These microscopically-identified FS were doubled in size as gauged by their capacitance when compared to the control mononucleated hPSC-VCMs using patch-clamp analysis. Reduced automaticity or action potential (AP) firing rate and moderately prolonged AP duration were observed in FS from day 6 post-fusion induction. However, Ca 2+ handling, mitochondrial biogenesis and the extent of apoptosis were not significantly altered. We conclude that larger, multi-nucleated hPSC-VCMs FS can be created by chemically-induced cell fusion but global maturation requires additional triggering cues., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Sarcoidosis is a systemic inflammatory granulomatous disease for which rheumatologists are uniquely trained and qualified to treat. Historically, sarcoidosis has been managed within silos of medical subspecialties, but with increased appreciation of the systemic nature of this disorder and the availability of more therapeutic options, it is clear that a multidisciplinary approach, with the rheumatologist as a key component, can offer more optimal care. This manuscript reviews clinically relevant immunology and pathophysiology, diagnostic issues, management decision-making, and therapeutics in the care of patients with sarcoidosis. Issues particularly relevant to rheumatologists are highlighted. These include aiding in establishing diagnosis; recognition of disease manifestations involving bone, joint, and muscle; management of calcium metabolism and metabolic bone disease; and formulation and implementation of anti-inflammatory and immunomodulatory therapies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Unlabelled: Urothelial carcinoma of the bladder (UCB) is genomically heterogeneous, with frequent alterations in genes regulating chromatin state, cell cycle control, and receptor kinase signaling. To identify prognostic genomic markers in high-grade UCB, we used capture-based massively parallel sequencing to analyze 109 tumors. Mutations were detected in 240 genes, with 23 genes mutated in ≥5% of cases. The presence of a recurrent phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation was associated with improved recurrence-free survival (RFS) (hazard ratio [HR]: 0.35; p=0.014) and improved cancer-specific survival (CSS) (HR: 0.35; p=0.040) in patients treated with radical cystectomy (RC). In multivariable analyses controlling for pT and pN stages, PIK3CA mutation remained associated with RFS (HR: 0.39; p=0.032). The most frequent alteration, TP53 mutation (57%), was more common in extravesical disease (69% vs 32%, p=0.005) and lymph node-positive disease (77% vs 56%, p=0.025). Patients with cyclin-dependent kinase inhibitor 2A (CDKN2A)-altered tumors experienced worse RFS (HR: 5.76; p<0.001) and worse CSS (HR: 2.94; p=0.029) in multivariable analyses. Mutations in chromatin-modifying genes were highly prevalent but not associated with outcomes. In UCB patients treated with RC, PIK3CA mutations are associated with favorable outcomes, whereas TP53 and CDKN2A alterations are associated with poor outcomes. Genomic profiling may aid in the identification of UCB patients at highest risk following RC., Patient Summary: Using next-generation sequencing, we identified genomic subsets of high-grade urothelial bladder cancer associated with favorable and unfavorable outcomes. These findings may aid in the selection of patients most likely to benefit from novel combined modality approaches., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The objective of this study is to evaluate discriminative validity of the Young Mania Rating Scale (YMRS) and Children's Depression Rating Scale-Revised (CDRS-R) in a clinical sample of children when administered in an unfiltered manner (i.e., regardless of whether symptoms occur in a mood episode). The Kiddie Schedule for Affective Disorders and Schizophrenia is the gold standard for assessing psychiatric disorders in children and was used to make diagnoses in this study. Using a sample of 707 treatment-seeking youth (ages 6-12 years, Mage = 9.7 years, 67.6% male), receiver operating curve analyses were performed and diagnostic likelihood ratios (DLRs) were calculated to evaluate the ability to change the odds and differentiate bipolar disorder from other disorders (using the YMRS) and depression from other disorders (using the CDRS-R). Using unfiltered administration, the YMRS achieved good discriminative validity when classifying bipolar disorder compared to other disorders (Area Under the Curve [AUC] = .86) and increased odds of a bipolar diagnosis given a score in the highest quintile (DLR = 6.12). Using unfiltered administration, the CDRS-R achieved moderate to good discriminative validity in classifying depressive disorders (DD) compared to other disorders (AUCBD in comparison = .78; AUCBD not in comparison = .84) and slightly increased odds of DD given a score in the highest quintile (DLRBD in comparison = 3.12; DLRBD not in comparison = 5.08). The YMRS and CDRS-R have moderate to good discriminative validity when administered in an unfiltered way in a sample of treatment seeking youth.

Purpose: Parastomal hernia is a frequent complication of stoma formation after radical cystectomy. We determined the prevalence and risk factors for the development of parastomal hernia after radical cystectomy., Materials and Methods: We conducted a retrospective study of 433 consecutive patients who underwent open radical cystectomy and ileal conduit between 2006 and 2010. Postoperative cross-sectional imaging studies performed for routine oncologic followup (1,736) were evaluated for parastomal hernia, defined as radiographic evidence of protrusion of abdominal contents through the abdominal wall defect created by forming the stoma. Univariable and multivariable Cox regression analyses were used to determine clinical and surgical factors associated with parastomal hernia., Results: Complete data were available for 386 patients with radiographic parastomal hernia occurring in 136. The risk of a parastomal hernia developing was 27% (95% CI 22, 33) and 48% (95% CI 42, 55) at 1 and 2 years, respectively. Clinical diagnosis of parastomal hernia was documented in 93 patients and 37 were symptomatic. Of 16 patients with clinical parastomal hernia referred for repair 8 had surgery. On multivariable analysis female gender (HR 2.25; 95% CI 1.58, 3.21; p<0.0001), higher body mass index (HR 1.08 per unit increase; 95% CI 1.05, 1.12; p<0.0001) and lower preoperative albumin (HR 0.43 per gm/dl; 95% CI 0.25, 0.75; p=0.003) were significantly associated with parastomal hernia., Conclusions: The overall risk of radiographic evidence of parastomal hernia approached 50% at 2 years. Female gender, higher body mass index and lower preoperative albumin were most associated with the development of parastomal hernia. Identifying those at greatest risk may allow for prospective surgical maneuvers at the time of initial surgery, such as placement of prophylactic mesh in selected patients, to prevent the occurrence of parastomal hernia., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Angiogenesis plays a major role in tumor growth and metastasis, with tumor perfusion regarded as a marker for angiogenesis. To evaluate antiangiogenic treatment response in vivo, we investigated arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure tumor perfusion quantitatively. Chronic and 24-h acute treatment responses to bevacizumab were assessed by ASL and dynamic-contrast-enhanced (DCE) MRI in the A498 xenograft mouse model. After the MRI, tumor vasculature was assessed by CD34 staining. After 39 days of chronic treatment, tumor perfusion decreased to 44.8 ± 16.1 mL/100 g/min (P < 0.05), compared to 92.6 ± 42.9 mL/100 g/min in the control group. In the acute treatment study, tumor perfusion in the treated group decreased from 107.2 ± 32.7 to 73.7 ± 27.8 mL/100 g/min (P < 0.01; two-way analysis of variance), as well as compared with control group post dosing. A significant reduction in vessel density and vessel size was observed after the chronic treatment, while only vessel size was reduced 24 h after acute treatment. The tumor perfusion correlated with vessel size (r = 0.66; P < 0.005) after chronic, but not after acute treatment. The results from DCE-MRI also detected a significant change between treated and control groups in both chronic and acute treatment studies, but not between 0 and 24 h in the acute treatment group. These results indicate that tumor perfusion measured by MRI can detect early vascular responses to antiangiogenic treatment. With its noninvasive and quantitative nature, ASL MRI would be valuable for longitudinal assessment of tumor perfusion and in translation from animal models to human., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

This article describes nine Chinese patients with Bietti's crystalline dystrophy, including two families, one consisting of three siblings and the other a pair of sisters. All patients had the classic refractile deposits located in all layers of the retina, with varying degrees of pigment epithelium atrophy. However, paralimbal crystals were not seen in the anterior corneal stroma. We describe clinical, angiographical and electrophysiological characteristics, and also review the literature on Bietti's crystalline dystrophy. All patients had full eye examination, including best corrected visual acuity, biomicroscopy, applanation tonometry and dilated funduscopy. Fluorescein angiography and indocyanine green angiography were performed, together with visual fields and electrophysiologic studies. All nine of our patients were phenotypically heterogeneous, with varying age and symptoms at presentation, as well as different degrees of progression. Age was not found to be a predictor of severity. The differences in disease severity, even within sibling groups, suggested that perhaps other factors were at play in phenotypic expression. We found that in early ICGA, all stages of BCD had delayed choroidal filling, which has not been previously described. We also observed a relative derangement of inner choroidal circulation as evidenced by late hypofluorescence on the ICGA. However, it is as yet unclear whether this circulatory disturbance is due to primary involvement of the posterior ciliary arteries, or secondary to choroidal and/or retinal pigment epithelial atrophy. While the FA and ICGA findings were similar, we found that the true extent of the atrophic areas was better delineated by ICGA. ICGA was also superior in outlining the degree and extent of choroidal vascular compromise.

Objective: To investigate the beneficial effect of constraint-induced movement therapy in improving the function of hemiplegic upper extremity in the early subacute stroke patients., Design: A prospective, single-blinded, randomized controlled study comparing the effectiveness of constraint-induced movement therapy or control treatment at post intervention and 12 weeks follow-up., Subjects: The inclusion criteria were 2-16 weeks after stroke, hemiparesis of the affected limb, minimal function of > or =20 degrees wrist extension and > or =10 degrees extension of all digits and Mini-Mental State Examination score > or =17., Interventions: The intervention group underwent a programme of 10 days upper extremity training (4 hours per day) with the unaffected limb being restrained ina shoulder sling and the control group received an equivalent duration of conventional rehabilitation therapy., Main Measures: Functional level for hemiparetic upper extremity, Motor Activity Log, Action Research Arm Test and modified Barthel Index., Results: There were 23 and 20 subjects respectively in the constraint-induced movement therapy and control groups. Significant improvements were seen at post intervention and 12 weeks after constraint-induced movement therapy in functional level for hemiparetic upper extremity (P= 0.001), and in the ;amount of use' (P= 0.001) and ;how well' (P= 0.021) subscales of the Motor Activity Log. The total Action Research Arm Test score, grasp (P= 0.004), grip (P= 0.004), pinch (P= 0.032) and gross (P= 0.006) components showed significant improvement over the control group at post intervention. The grip component (P=0.019) and the total Action Research Arm Test score (P= 0.009) were superior to the control group at 12 weeks., Conclusion: Significant improvement in hand function could be achieved with constraint-induced movement therapy in subacute stroke patients, which was maintained up to 12 week follow-up.

Introduction: Abdominal pain is the leading cause of patient visits to the emergency department. Although patients present to the emergency department in search of relief from pain, few experience complete pain relief. The purpose of this study was to describe patients' expectations for pain relief and how communication of their pain to nurses and physicians affected their overall pain relief., Methods: Questionnaires were completed by patients who reported abdominal pain and by their primary nurse and physician. Numeric rating scales were used to rate pain intensity from 0 (no pain) to 10 (worst possible pain) and actual and expected pain relief (0 = no pain relief, 10 = complete relief)., Results: Forty-four percent of patients reported that they expected complete relief of their abdominal pain. Over 98% of the patients told a provider that they were in pain, but only 33.3% asked for pain medication. No significant differences were found between the patients who asked for pain medication and those who did not in patients' expectation scores or relief scores., Discussion: The results of this study showed that patients with abdominal pain have high expectations for pain relief; however, their expectations were not associated with their tendency to ask for pain medication or report actual relief of pain.

Although the cytoplasmic domain of the human FcgammaRIa alpha-chain lacks tyrosine-based phosphorylation motifs, it modulates receptor cycling and receptor-specific cytokine production. The cytoplasmic domain of FcgammaRIa is constitutively phosphorylated, and the inhibition of dephosphorylation with okadaic acid, an inhibitor of type 1 and type 2A protein serine/threonine phosphatase, inhibits both receptor-induced activation of the early tyrosine phosphorylation cascade and receptor-specific phagocytosis. To explore the basis for these effects of the cytoplasmic domain of FcgammaRIa, we developed a series of human FcgammaRIa molecular variants, expressed in the murine macrophage cell line P388D1, and demonstrate that serine phosphorylation of the cytoplasmic domain is an important regulatory mechanism. Truncation of the cytoplasmic domain and mutation of the cytoplasmic domain serine residues to alanine abolish the okadaic acid inhibition of phagocytic function. In contrast, the serine mutants did not recapitulate the selective effects of cytoplasmic domain truncation on cytokine production. These results demonstrate for the first time a direct functional role for serine phosphorylation in the alpha-chain of FcgammaRIa and suggest that the cytoplasmic domain of FcgammaRI regulates the different functional capacities of the FcgammaRIa-receptor complex.

Background: Tumor necrosis factor-alpha (TNF-alpha) may have an important role in the clinical exacerbation of sarcoidosis., Objective: To treat sarcoidosis with infliximab, a chimeric human-murine anti-human TNF-alpha monoclonal antibody., Design: Case report., Setting: U.S. academic medical center., Patient: A 72-year-old woman with sarcoidosis presenting with severe protein-losing enteropathy, hypoalbuminemia, and proximal myopathy who had not responded adequately to corticosteroid therapy and whose clinical course was further complicated by acute tubular necrosis and renal failure requiring long-term hemodialysis., Intervention: Intravenous infusion of infliximab, 5 mg/kg of ideal body weight; infusion was repeated at 2 and 6 weeks., Measurements: Clinical response of enteropathic and myopathic symptoms and serum albumin level., Results: Enteropathic and myopathic symptoms resolved after infliximab therapy, and the serum albumin level also improved. However, the clinical course was complicated by the development of a hypercoagulable state associated with circulating anticardiolipin antibodies, which prompted discontinuation of infliximab therapy., Conclusions: Infliximab therapy was successful in a patient with sarcoidosis. Tumor necrosis factor-alpha may be an important mediator of clinical disease in sarcoidosis and could be an attractive target for therapeutic intervention. However, infliximab may cause adverse effects associated with cytokine cascade manipulation.

Human FcgammaRIIa has 2 codominantly expressed allotypes, which differ greatly in their ability to ligate immunoglobulin G2 (IgG2). Whereas FcgammaRIIa-R131 binds only weakly to IgG2, FcgammaRIIa-H131 binds to it efficiently and might be primarily responsible for the phagocytosis of IgG2-opsonized bacteria. IgG2 plays a pivotal role in defense against pneumococcal infection. This prospective study showed that 50% of patients with bacteremic pneumococcal pneumonia were homozygous for FcgammaRIIa-R131, compared with 28% with nonbacteremic pneumococcal pneumonia and 29% of uninfected controls (P<.05). The gene frequency of FcgammaRIIa-R131 was 0.67 in bacteremic patients, significantly higher than in the other groups (P<.05). All bacteremic patients who died within 1 week of hospitalization were homozygous for FcgammaRIIa-R131. Therefore, the severity of pneumococcal infection may, in part, be genetically mediated. Taken together with similar findings in cases of meningococcal disease, these results suggest that such genetic factors may be generalizable to infections caused by encapsulated bacteria.

A 22-year-old Caucasian woman with a 6 year history of persistently active, systemic onset juvenile rheumatoid arthritis (JRA) developed symptoms of headache, dry cough, nausea, vomiting, abdominal pain, diarrhea, and dehydration associated with a high fever, elevated liver enzymes, and lymphopenia. Subsequent investigation revealed acute infection with parvovirus B19. Following clinical improvement over 10-14 days solely with supportive care, her underlying disease remained in remission for about 7 months.

The gamma/zeta-chain family of proteins mediate cell activation for multiple immunoglobulin receptors. However, the recognition that these receptors may have distinct biologic functions suggests that additional signaling elements may contribute to functional diversity. We hypothesized that the cytoplasmic domain (CY) of the ligand binding alpha-chain alters the biological properties of the receptor complex. Using macrophage FcgammaRIa as a model system, we created stable transfectants expressing a full-length or a CY deletion mutant of human FcgammaRIa. Both receptors functionally associate with the endogenous murine gamma-chain. However, we have established that the CY of FcgammaRIa directly contributes to the functional properties of the receptor complex. Deletion of the FcgammaRIa CY leads to slower kinetics of receptor-specific phagocytosis and endocytosis as well as lower total phagocytosis despite identical levels of receptor expression. Deletion of the CY also converts the phenotype of calcium independent FcgammaRIa-specific phagocytosis to a calcium-dependent phenotype. Finally, deletion of the CY abrogates FcgammaRIa-specific secretion of interleukin-6 but does not affect production of interleukin-1beta. These results demonstrate a functional role for the CY of FcgammaRIa and provide a general model for understanding how multiple receptors that utilize the gamma-chain can generate diversity in function.

Objective: To assess the efficacy and role of adventitial stripping (i.e., digital sympathectomy) in patients with severe digital ischemia secondary to refractory Raynaud's phenomenon (RP)., Methods: A retrospective chart review of 13 consecutive cases of adventitial stripping in 9 patients with severe secondary RP was performed, examining patient characteristics, previous therapeutic interventions, and postoperative outcomes. An illustrative case is presented., Results: All identified patients had evidence of systemic disease. After adventitial stripping, sustained longterm improvement was achieved in all 13 ischemic digits, 8 of which showed amelioration of symptoms immediately after surgery. In 2 patients, sustained improvement was noted despite progressive ischemia in nonoperated digits. The mean followup time was 28 months (range 10 to 47). No postoperative complications were observed. Pre-operative sympathetic nerve blockade was performed in 12 of the cases, of which 10 showed no clinical response. Pathologic specimens revealed adventitial fibrosis that caused extrinsic compression of the digital arteries., Conclusion: Adventitial stripping of digital arteries is an extremely effective and safe option for patients with severe digital ischemia secondary to refractory RP. The efficacy of this procedure results not only from sympathetic denervation but also from decompression of the ischemic vessel through removal of a fibrotic and noncompliant adventitia. Because of the effects of this extrinsic vascular compression, lack of response to pre-operative sympathetic nerve blockade is not predictive of postoperative outcomes.

We conducted a longitudinal evaluation of a patient with systemic lupus erythematosus who constitutively exhibited elevated levels of circulating alpha-interferon (alpha-IFN). This study demonstrated that the serum levels of an activity that renders the endogenous alpha-IFN acid labile are positively correlated with disease activity. This IFN acid lability-inducing activity can also be found in the sera of systemic lupus erythematosus patients who have active disease but who do not have circulating alpha-IFN.

The physicochemical properties of apparently acid-labile IFN-alpha from patients with SLE have been studied. The antigenicity, apparent molecular size, and isoelectric point of SLE IFN-alpha are indistinguishable from those of conventional, previously characterized, acid-stable subspecies of IFN-alpha. However, after partial purification by anion-exchange chromatography, SLE IFN-alpha no longer exhibits acid lability, suggesting that other plasma factor(s) are responsible for the acid lability of SLE IFN-alpha. Addition of SLE plasma, but not normal plasma, to conventional acid-stable IFN-alpha renders the exogenous IFN-alpha acid labile. Preliminary results demonstrate that an acid-dependent IFN-inactivating activity can be partially purified from SLE plasma by anion-exchange chromatography.

The DNA polymerase of bacteriophage T4 is a multifunctional enzyme that harbors DNA-binding, DNA-synthesizing and exonucleolytic activities. We have cloned in bacterial plasmids about 99% of the structural gene for this enzyme (T4 gene 43). The gene was cloned in six contiguous 5'-terminal DNA fragments that defined seven intragenic mapping regions. Escherichia coli hosts harboring recombinant plasmids carrying the gene 43 subsegments were used in marker-rescue experiments that assigned a large number of ts and nonsense polymerase mutations to different physical domains of the structural gene. Conspicuously, only one missense mutation in a large collection of mutants mapped in the 5'-terminal 450 base-pair segment of the approximately 2700 base-pair gene. To test if this indicated a DNA polymerase domain that is relatively noncritical for biological activity, we mutagenized a recombinant plasmid carrying this 5'-terminal region and generated new conditional-lethal mutations that mapped therein. We identified five new ts sites, some having mutated at high frequency (nitrosoguanidine hot spots). New ts mutations were also isolated in phage genes 62 and 44, which map upstream of gene 43 on the T4 chromosome. A preliminary examination of physiological consequences of the ts gene 43 mutations showed that they exhibit effects similar to those of ts lesions that map in other gene 43 segments: some were mutators, some derepressed gene 43 protein synthesis and they varied in the severity of their effects on T4-induced DNA synthesis at nonpermissive temperatures. The availability of the gene 43 clones should make it possible to isolate a variety of lesions that affect different activities of the T4 DNA polymerase and help to define the different domains of this multifunctional protein.