Immune responses to human factor IX in haemophilia B mice of different genetic backgrounds are distinct and modified by TLR4.

Our laboratory develops protocols to prevent or reverse ongoing anti-hFIX IgG inhibitors in haemophilia B mice with a F9 gene deletion on BALB/c and C3H/HeJ backgrounds. C3H/HeJ F9(-/Y) mice develop high titre anti-hFIX IgG1 inhibitors and anaphylaxis, whereas most BALB/c F9(-/Y) mice have mild anti-hFIX IgG1 inhibitors and no anaphylaxis. Our aim was to determine if hFIX-specific B- and T-cell responses in BALB/c and C3H/HeJ F9(-/Y) mice trigger the difference in anti-hFIX immune responses. BALB/c and C3H/HeJ F9(-/Y) mice were challenged weekly with recombinant hFIX protein. Humoral immune responses were determined by IgG1 and IgG2a anti-hFIX ELISA, Bethesda assay for inhibitors and B-cell ELISpot on bone marrow and spleen cells. T-cell studies measured the TH 1 (IFN-γ) and TH 2 (IL-4) cytokine responses in splenocytes at the mRNA and protein level in response to hFIX protein. Antibody responses were also measured in C3H/HeJ/OuJ F9(-/Y) mice with restored toll-like receptor 4 (TLR4) function. BALB/c F9(-/Y) mice have a TH 2 skewed response and a reduction in anti-hFIX secreting plasma cells in the bone marrow. Independent antigen challenge revealed both strains generated equivalent IgG1 antibody titres to an intravenously delivered antigen. C3H/HeJ F9(-/Y) mice have a mixed TH 1 and TH 2 response (mainly TH 2). Importantly, TLR4 signalling has a modulatory role in the C3H background on the levels of anti-hFIX IgG1 and incidence of anaphylaxis. The background strain strongly impacts the immune response to hFIX, which can be significantly impacted by mutations in innate immune sensors.

Physical activity, alignment and knee osteoarthritis: data from MOST and the OAI.

OBJECTIVE: To determine the effect of physical activity on knee osteoarthritis (OA) development in persons without knee injury and according to knee alignment. DESIGN: We combined data from Multicenter Osteoarthritis (MOST) and Osteoarthritis Initiative (OAI), studies of persons with or at high risk of OA. Subjects had long limb and repeated posteroanterior knee radiographs and completed the physical activity survey for the elderly (PASE). We studied persons without radiographic OA and excluded knees with major injury and without long limb films. We followed subjects 30 months (in MOST) and 48 months (in OAI) for one of two incident outcomes: (1) symptomatic tibiofemoral OA (radiographic OA and knee pain), or (2) tibiofemoral narrowing. 'Active' persons were those with PASE score in the highest quartile by gender. We examined risk of OA in active group using logistic regression adjusting for age, gender, body mass index (BMI), Western Ontario and McMaster Arthritis Index (WOMAC) pain score, Kellgren and Lawrence (KL) grade (0 or 1), and study of origin. We also analyzed knees from malaligned and neutrally aligned limbs. RESULTS: The combined sample comprised 2,073 subjects (3,542 knees) with mean age 61 years. The cumulative incidence of symptomatic tibiofemoral OA was 1.12% in the active group vs 1.82% in the others (odds ratio (OR) among active group 0.6, 95% confidence interval (CI) 0.3, 1.3). Joint space narrowing occurred in 3.41% of knees in the active group vs 4.04% in the others (OR among active group 0.9 (95% CI 0.5, 1.5)). Results did not differ by alignment status. CONCLUSIONS: Physical activity in the highest quartile did not affect the risk of developing OA.

The role of a photographic atlas in reducing unanticipated healthcare utilization following circumcision.

INTRODUCTION: Circumcision is a common procedure that can evoke caregiver anxiety in the postoperative period due to unfamiliarity with the healing process. To mitigate unnecessary healthcare utilization such as phone calls and unanticipated clinic or emergency department (ED) visits, photographic atlases have been developed to better prepare caregivers for the recovery process. The objective of our study is to further investigate the efficacy of a photographic atlas in its ability to decrease postoperative healthcare utilization using an increased sample size and extended study period compared to previous studies. MATERIALS AND METHODS: In this study, we compared a prospective intervention cohort of patients undergoing circumcision at our institution who received a photographic atlas during postoperative teaching to a retrospective cohort of patients who had not received it. Our primary outcome was unanticipated healthcare utilization, defined as postoperative telephone calls and unanticipated presentations to the urology clinic or ED. RESULTS: The retrospective no-atlas cohort included 105 patients, and the prospective intervention atlas cohort included 80 patients. Both groups were similar with respect to age (p = 0.47) and other demographics. There was no statistically significant difference in healthcare utilization between the no-atlas and atlas cohort. Specifically, we identified no difference in the number of phone calls to clinic staff (12 [11.4%] vs. 11 [13.8%], p = 0.64) or unanticipated postoperative clinic or ED visits (2 [1.9%] vs. 4 [5.0%], p = 0.41). DISCUSSION: The use of a photographic atlas as part of caregiver support for circumcision patients did not demonstrate a statistically significant reduction in either postoperative phone calls or clinic/ED visits. The decrease in absolute number of caregiver phone calls was minimal (12-11), with a small increase in follow-up presentations (2-4). The lack of significant change may be due to the already infrequent occurrence of these events following circumcision, as demonstrated by the no-atlas cohort. Other potential advantages of the atlas, such as improved caregiver confidence and satisfaction, may have been present, but were not measured in this study. CONCLUSIONS: Adding to the mixed results of previous studies, these findings do not support that photographic atlases decrease unanticipated healthcare utilization in children undergoing a circumcision. However, utilization was found to be low. Additionally, further studies are needed to determine other significant benefits of this form of education, such as improved caregiver confidence and satisfaction.

Cyst-like lesions of the knee joint and their relation to incident knee pain and development of radiographic osteoarthritis: the MOST study.

OBJECTIVE: To determine whether intra- and periarticular cyst-like lesions of the knee are associated with incident knee pain and incident radiographic knee osteoarthritis (OA). DESIGN: The Multicenter Osteoarthritis (MOST) Study is a cohort of individuals who have or are at high risk for knee OA. Using a nested case-control study design, we investigated the associations of cyst-like lesions (Baker's, meniscal and proximal tibiofibular joint (PTFJ) cysts, and prepatellar and anserine bursitides) with (1) incident pain at 15- or 30-month follow-up and (2) incident radiographic OA at 30-month follow-up. Baseline cyst-like lesions were scored semiquantitatively using the Whole Organ Magnetic Resonance Imaging Score (WORMS). Conditional logistic regression models were used to assess the relation between these lesions and the outcomes, adjusting for potential confounding factors (i.e., cartilage loss, meniscal damage, bone marrow lesions, synovitis and joint effusion, which were also scored using WORMS). RESULTS: Incident knee pain study included 157 cases and 336 controls. Prevalence of meniscal and PTFJ cysts in the case group was twice that in the control group [9 (6%) vs 9 (3%) and 9 (6%) vs 10 (3%), respectively]. Incident radiographic OA study included 149 cases and 298 controls. Prevalence of grade 2 Baker's cysts and PTFJ cysts in the case group was approximately four times that in the control group [16(11%) vs 9 (3%) and 6 (4%) vs 3 (1%), respectively]. However, none of the cyst-like lesions was associated with incident pain or radiographic OA after fully adjusted logistic regression analyses and correction of P-values for multiple comparisons. CONCLUSION: None of the analyzed lesions was an independent predictor of incident knee pain or radiographic OA. Intra- and periarticular cyst-like lesions are likely to be a secondary phenomenon seen in painful or OA-affected knees, rather than a primary trigger for incident knee pain or radiographic OA.

The relation of plasma homocysteine to radiographic knee osteoarthritis.

OBJECTIVE: Homocysteine has been implicated in multiple diseases that involve changes in structural tissue. In vitro studies have found that it alters the structure of collagen cross-linking thus affecting stability and mineralization such as that occurring in bone tissue. In the present study we considered the possible relationship between plasma homocysteine levels and the development and progression of knee osteoarthritis (OA). METHODS: The study question was posed in 691 men and 966 women from the original and offspring cohorts of the Framingham Osteoarthritis Study. We divided individuals into three groups according to plasma homocysteine levels and compared their risk for the development of new and progression of existing OA. We adjusted for potential confounders including age, body mass index, weight change, and physical activity. RESULTS: In the crude analysis, men in the middle homocysteine tertile were found to be at a greater risk than men in the lowest tertile for incident OA [odds ratios of 1.9 (1.1-3.5)]. This result persisted after adjusting for covariates [odds: 2.0, (1.1-3.8)]. No significant correlation was seen in women for the development of OA. In the evaluation of progression no significant trends were seen for both men and women. CONCLUSIONS: Although cellular and molecular studies of homocysteine-related pathophysiology suggest a possible correlation between plasma homocysteine levels and OA, the present clinical study did not conclusively demonstrate such an association. However, further research is needed to explore the role of homocysteine in specific aspects of OA etiopathogenesis.

A single-institution experience of complete primary repair of bladder exstrophy in girls: risk factors for urinary retention.

INTRODUCTION: Historically after complete primary repair of exstrophy (CPRE) in girls, it had been more likely to observe urinary incontinence than retention. Following recent technical modifications of elongating the urethra and narrowing the bladder neck, the authors have observed a high rate of urinary retention in girls after CPRE. OBJECTIVE: The aim was to identify factors that may be responsible for this observation by reviewing historical and current outcomes. The authors hypothesized that differences in anatomic dimensions at the time of CPRE may contribute to urinary retention. STUDY DESIGN: A retrospective review of girls who underwent CPRE from December 1998 through September 2016 from a single institution was performed. Patients were deemed in retention if their clinical course was consistent with such, required a procedure to relieve urinary retention, and/or required clean intermittent catheterization. RESULTS: Nineteen girls underwent CPRE during this period. In 2012, a change to delaying CPRE to approximately 2 months of age was made, and this led the authors to divide their experience into CPRE performed as a newborn (<72 h of age, 8 patients) versus delayed (>72 h, 11 patients) subgroups. There were no girls with retention in the newborn group and three (38%) girls with retention in the delayed group. In the delayed group, girls had a longer urethral plate and narrower bladder neck compared with the newborn group. Long-term outcomes greater than 9 years are available for six girls in the newborn group and two (33%) required bladder neck procedures for incontinence. None in the delayed group have required incontinence procedures; however, follow-up is limited at 25 months. DISCUSSION: The absence of retention in the newborn group is concerning for the delayed group incurring a higher risk of retention after CPRE. This may be secondary to excessive compression of the urethra at the time of pubic symphysis approximation potentially leading to urethral ischemia. Different from the newborn CPRE girls, additional technical revision of CPRE, namely, elongation of the urethra and the dissection it involves and narrowing of the bladder neck, may increase the risk for retention. CONCLUSIONS: The multiple factors that were identified as potential contributors to post-CPRE urinary retention should result in a cautious reevaluation of female bladder exstrophy management at the time of CPRE. The authors now create a gradual tapered transition at the bladder neck and, similar to their previous experience, a more generous (wider) bladder neck and a shorter length for urethral plate.

Uncharted territory: navigating the pediatric urology job market.

INTRODUCTION: There is not a structured algorithm, timeline, or resource on how, when, and which programs are looking for a new staff pediatric urologist. We hypothesized that current and future pediatric urology fellows could benefit from the experiences of recently graduated fellows on navigating the urology job market. OBJECTIVE: The purpose of this study was to survey current and recent pediatric urology fellowship graduates about the process of finding their first job. STUDY DESIGN: A Research Electronic Data Capture (REDCap) online survey was designed and distributed through email to current fellows and 2012-2017 graduates. Results were evaluated using STATA. RESULTS: 153 participants were emailed, and 94 (61%) completed the survey. The plurality of applicants (44%) began the job search at the Spring American Urological Association meeting, 14 months before finishing (Figure). Of those who started 14 months before finishing, 33% wished they started earlier and 61% would have started at the same point. The median number of programs contacted for a position was 3-4 and the median number of programs visited and offers received was two. After the offer, 40% reported having >8 weeks to decide. Less than half (38.5%) hired an attorney for contract negotiation. Of those who hired an attorney, 68% felt it provided benefit. Regarding contract negotiation, 22% did not negotiate and 35% negotiated for salary. Unsurprisingly, 28% of those who took academic jobs thought negotiating for protected research/educational time was most important compared with only 4% of those who took non-academic jobs (P = 0.02). When asked how they learned about the job they accepted: 28% were contacted by the program, 25% cold called the program, 30% accepted where they did residency or fellowship, and 18% learned through society websites. The plurality (50%) thought the number of desirable positions during the process were as they expected. 41% however, thought the number of desirable positions were expectedly or surprisingly low. Regarding quality of life and satisfaction with job/career choice, 98% stated that they would still choose to subspecialize in pediatric urology. CONCLUSIONS: The results from this survey should provide guidance to fellows on how to approach the job search with respect to timing, expectations, contract negotiation, and initial job satisfaction.

Induction of tolerance to factor VIII by transient co-administration with rapamycin.

BACKGROUND: Formation of inhibitory antibodies is a frequent and serious complication of factor (F) VIII replacement therapy for the X-linked bleeding disorder hemophilia A. Similarly, hemophilia A mice develop high-titer inhibitors to recombinant human FVIII after a few intravenous injections. OBJECTIVE: Using the murine model, the study sought to develop a short regimen capable of inducing tolerance to FVIII. METHODS: A 1-month immunomodulatory protocol, consisting of FVIII administration combined with oral delivery of rapamycin, was developed. RESULTS: The protocol effectively prevented formation of inhibitors to FVIII upon subsequent intravenous treatment (weekly for 3.5 months). Control mice formed high-titer inhibitors and had CD4(+) T effector cell responses characterized by expression of IL-2, IL-4 and IL-6. Tolerized mice instead had a CD4(+)CD25(+)FoxP3(+) T cell response to FVIII that suppressed antibody formation upon adoptive transfer, indicating a shift from Th2 to Treg if FVIII antigen was introduced to T cells during inhibition with rapamycin. CD4(+) T cells from tolerized mice also expressed TGF-ß1 and CTLA4, but not IL-10. The presence of FVIII antigen during the time of rapamycin administration was required for specific tolerance induction. CONCLUSIONS: The study shows that a prophylactic immune tolerance protocol for FVIII can be developed using rapamycin, a drug that is already widely in clinical application. Immune suppression with rapamycin was mild and highly transient, as the mice regained immune competence within a few weeks.

Is obesity a risk factor for progressive radiographic knee osteoarthritis?

OBJECTIVE: To examine whether obesity increases the risk of progression of knee osteoarthritis (OA). METHODS: We used data from the Multicenter Osteoarthritis Study, a longitudinal study of persons with or at high risk of knee OA. OA was characterized at baseline and 30 months using posteroanterior fixed-flexion radiographs and Kellgren/Lawrence (K/L) grading, with alignment assessed on full-extremity films. In knees with OA at baseline (K/L grade 2 or 3), progression was defined as tibiofemoral joint space narrowing on the 30-month radiograph. In knees without OA at baseline (K/L grade 0 or 1), incident OA was defined as the development of radiographic OA at 30 months. Body mass index (BMI) at baseline was classified as normal (<25 kg/m(2)), overweight (25-<30 kg/m(2)), obese (30-<35 kg/m(2)), and very obese (>or=35 kg/m(2)). The risk of progression was tested in all knees and in subgroups categorized according to alignment. Analyses were adjusted for age, sex, knee injury, and bone density. RESULTS: Among the 2,623 subjects (5,159 knees), 60% were women, and the mean +/- SD age was 62.4 +/- 8.0 years. More than 80% of subjects were overweight or obese. At baseline, 36.4% of knees had tibiofemoral OA, and of those, only one-third were neutrally aligned. Compared with subjects with a normal BMI, those who were obese or very obese were at an increased risk of incident OA (relative risk 2.4 and 3.2, respectively [P for trend < 0.001]); this risk extended to knees from all alignment groups. Among knees with OA at baseline, there was no overall association between a high BMI and the risk of OA progression; however, an increased risk of progression was observed among knees with neutral but not varus alignment. The effect of obesity was intermediate in those with valgus alignment. CONCLUSION: Although obesity was a risk factor for incident knee OA, we observed no overall relationship between obesity and the progression of knee OA. Obesity was not associated with OA progression in knees with varus alignment; however, it did increase the risk of progression in knees with neutral or valgus alignment. Therefore, weight loss may not be effective in preventing progression of structural damage in OA knees with varus alignment.

[A critical analysis of the SNA, SNB and ANB angles in assessing orthodontic treatments]. / Kritische Analyse der Winkel SNA, SNB und ANB bei der Auswertung von kieferorthopädischen Behandlungen.

The purpose of this longitudinal cephalometric study was to evaluate the influence of growth changes at nasion (N) on the position of the reference line NSL and consequently on the measurements of the angles SNA, SNB and ANB. Lateral head films from 46 orthodontically treated patients were evaluated over an average period of 3.7 years. The NSL reference line was defined with respect to growth changes at the N-point: A: no consideration of growth; B: consideration of growth in the sagittal plane; C: consideration of growth in the sagittal and vertical planes. The results showed that growth changes at nasion had a decisive influence on the position of the reference line NSL and thus also on the angles SNA, SNB and ANB. In order to avoid misinterpretations in the evaluation of orthodontic treatment results the growth changes at nasion must be taken into consideration.

[Treatment of advanced kidney cancer]. / Die Behandlung des fortgeschrittenen Nierenkarzinoms.

The essential prolongation of the survival time of the patients with advanced renal carcinoma after the combined therapy by more than the threefold shows in comparison to the symptomatically treated patients that in these cases the nephrectomy with subsequent cytostatic therapy is indicated.

Anticentromere antibodies--clinical correlates.

We tested 11,594 consecutive sera for antinuclear antibodies and 1,502 were found to be positive; 68 patients (72 sera) had anticentromere antibodies. A retrospective analysis of the clinical characteristics and diagnoses of patients found to have anticentromere antibodies were correlated and showed a diverse array of findings. The association of anticentromere antibodies and the CREST variant of scleroderma may be less specific than originally thought when used as a screening test in an unselected population with rheumatic disease. Anticentromere antibody was present in patients with drug induced lupus, a finding not previously reported.

Laboratory observations on Plesiomonas shigelloides strains isolated from children with diarrhea in Peru.

Eleven strains of Plesiomonas shigelloides isolated from 10 Peruvian children with diarrhea were examined. All the strains were resistant to two or more antibiotics, most commonly ampicillin, gentamicin, erythromycin, kanamycin, and streptomycin. The strains were all negative in the Sereny and cell culture assays used to test for enteroinvasiveness. One strain showed cytotoxic activity on Vero cells. The strains showed no antigenic relationship with Shigella organisms. Both bioassays and enzyme-linked immunosorbent assays used for detection of Escherichia coli enterotoxins were negative. Nucleic acid probes for such toxins likewise gave negative results. The strains all possessed a large (approximately 200-megadalton) plasmid in addition to one or more other plasmids. Several different plasmid profiles were observed among these 11 P. shigelloides strains, indicating that the isolates were not acquired from a common source or from a single bacterial clone.

Iatrogenic morbidity accompanying suppression of temporal arteritis by adrenal corticosteroids.

The records of 19 patients receiving corticosteroid therapy for temporal arteritis were reviewed. Of 11 patients (58%) who suffered major corticosteroid related complications (group A), four died. Eight patients (group B) remained free of serious corticosteroid related complications. The average daily maintenance prednisone dose was 26.3 mg in group A and 13 mg in group B. Although all disease recrudescenses in both groups were treated by increasing the corticosteroid dose, a slower tapering of the dose to the pre-flare level was observed in group A. These findings emphasize the necessity of keeping the maintenance corticosteroid dose in patients with temporal arteritis at the lowest level consistent with suppression of disease activity.

The clinical features of elderly-onset rheumatoid arthritis. A comparison with younger-onset disease of similar duration.

Patients with elderly-onset rheumatoid arthritis (EORA) may represent a clinical subset of individuals who differ prognostically and therapeutically from patients with younger-onset disease (YORA). In order to test this hypothesis, we reviewed the records of 212 patients with rheumatoid arthritis and grouped them according to age at onset above or below 60 years old. Seventy-eight EORA patients and 134 YORA patients with disease duration of less than or equal to 10 years were used for a comparison of presenting features and disease outcome. Abrupt onset occurred somewhat more frequently in EORA, but was not associated with a significantly different clinical course than was an insidious presentation in this older group. There were no differences between the EORA and YORA groups in terms of mean initial joint score, although the scores for the YORA group had wider variation. An initial clinical presentation resembling polymyalgia rheumatica (PMR) was 4 times as frequent in EORA. Elderly patients were less likely to have subcutaneous nodules or rheumatoid factor at disease onset. At the final examination, the EORA patients had lower joint scores and higher health assessments despite similar courses of treatment. These outcome differences persisted when patients with PMR-like presentations were excluded. Multivariate analyses indicated that joint scores and disease duration made important contributions to a better outcome of EORA, whereas PMR presentation and abrupt onset did not. After an adjustment was made for these 4 features, age at onset was an important contribution to joint score outcome. These results confirm the existence of important differences in onset, clinical features, and prognosis between patients with EORA and those with YORA.