Sirolimus impairs wound healing

Background and aims Clinically, the immunosuppressive drug sirolimus, used in organ transplantation, appears to impair wound healing. Little is known about the mechanisms of action. We investigated the effect of sirolimus on wound healing, and we analyzed the expression of stimulating mediators of angiogenesis (VEGF, vascular endothelial growth factor) and collagen synthesis (nitric oxide) in wounds. Materials and methods Groups of ten rats underwent dorsal skin incision, and polyvinyl alcohol sponges were implanted subcutaneously. Beginning at the day of wounding, rats were treated with 0.5, 2.0, or 5.0 mg sirolimus/kg/day. Animals were killed 10 days later to determine wound breaking strength and reparative collagen deposition. Expression of VEGF and nitric oxide was studied in wounds. Results Splenic lymphocyte proliferative activity was significantly decreased by sirolimus (p < 0.05). Sirolimus levels in wound fluid were found to be approximately two- to fivefold higher than blood levels (p < 0.01). Sirolimus (2.0 and 5.0 mg kg⁻¹ day⁻¹) reduced wound breaking strength (p < 0.01) and wound collagen deposition (p < 0.05). This was paralleled by decreased expression of VEGF and nitric oxide in wounds. Conclusion Experimentally, our data show that sirolimus impairs wound healing, and this is reflected by diminished expression of VEGF and nitric oxide in the wound. Best abstracts — Surgical Forum 2007.     

The Four-Dimensional Symptom Questionnaire (4DSQ): a validation study of a multidimensional self-report questionnaire to assess distress, depression, anxiety and somatization

Background

The Four-Dimensional Symptom Questionnaire (4DSQ) is a self-report questionnaire that has been developed in primary care to distinguish non-specific general distress from depression, anxiety and somatization. The purpose of this paper is to evaluate its criterion and construct validity.

Methods

Data from 10 different primary care studies have been used. Criterion validity was assessed by comparing the 4DSQ scores with clinical diagnoses, the GPs' diagnosis of any psychosocial problem for Distress, standardised psychiatric diagnoses for Depression and Anxiety, and GPs' suspicion of somatization for Somatization. ROC analyses and logistic regression analyses were used to examine the associations. Construct validity was evaluated by investigating the inter-correlations between the scales, the factorial structure, the associations with other symptom questionnaires, and the associations with stress, personality and social functioning. The factorial structure of the 4DSQ was assessed through confirmatory factor analysis (CFA). The associations with other questionnaires were assessed with Pearson correlations and regression analyses.

Results

Regarding criterion validity, the Distress scale was associated with any psychosocial diagnosis (area under the ROC curve [AUC] 0.79), the Depression scale was associated with major depression (AUC = 0.83), the Anxiety scale was associated with anxiety disorder (AUC = 0.66), and the Somatization scale was associated with the GPs' suspicion of somatization (AUC = 0.65). Regarding the construct validity, the 4DSQ scales appeared to have considerable inter-correlations (r = 0.35-0.71). However, 30–40% of the variance of each scale was unique for that scale. CFA confirmed the 4-factor structure with a comparative fit index (CFI) of 0.92. The 4DSQ scales correlated with most other questionnaires measuring corresponding constructs. However, the 4DSQ Distress scale appeared to correlate with some other depression scales more than the 4DSQ Depression scale. Measures of stress (i.e. life events, psychosocial problems, and work stress) were mainly associated with Distress, while Distress, in turn, was mainly associated with psychosocial dysfunctioning, including sick leave.

Conclusion

The 4DSQ seems to be a valid self-report questionnaire to measure distress, depression, anxiety and somatization in primary care patients. The 4DSQ Distress scale appears to measure the most general, most common, expression of psychological problems.     

Extratesticular hemorrhage associated with torsion of the spermatic cord: sonographic demonstration

Using ultrasound (US), we studied seven patients with torsion of the spermatic cord associated with a large amount of extratesticular hemorrhage. In each case, US showed a large echogenic or complex extratesticular mass caused by the hemorrhage, in addition to a hypoechoic testis and scrotal skin thickening. This appearance should be recognized as part of the spectrum of sonographic appearances that can be seen in torsion.     

Association of HLA-DR7 with both antibody to SSA(Ro) and disease susceptibility in blacks with systemic lupus erythematosus

The relationship between HLA-DR antigens and various specific antinuclear antibodies was studied in 28 unselected black Americans with systemic lupus erythematosus (SLE). Anti-SSA(Ro) occurred with high frequency (61%) but was not associated with specific clinical features of SLE. HLA-DR7 was strongly associated with anti-SSA antibody; it was present in 13/17 patients with anti-SSA (76%) and 1/11 patients without it (9%). HLA-DR7 occurred in 14/28 of all SLE patients (50%) compared with 17% of 137 local controls (p corrected, less than 0.005). This association of HLA-DR7 with both susceptibility to SLE and a high frequency of anti-SSA antibody suggests a genetic link between the presence of anti-SSA antibody and susceptibility to SLE in the population studied.     

Herpes simplex virus antigen direct detection in standard virus transport medium by Du Pont Herpchek enzyme-linked immunosorbent assay.

A commercial 5-h direct herpes simplex virus (HSV) antigen detection enzyme immunoassay kit (Du Pont Herpchek) was compared with a cell culture isolation system by using primary rabbit kidney and MRC-5 cells with 779 clinical specimens received in virus transport medium and with stock tissue culture preparations of HSV types 1 and 2. In the first study of 422 specimens from symptomatic patients, Herpchek detected 110 of 111 HSV-positive specimens (26.3% of all specimens), with a sensitivity of 99% and a specificity of 100%. In the second study of 357 specimens primarily from asymptomatic pregnant women, however, Herpchek detected 70 of 119 HSV-positive specimens (33% of all specimens), with a sensitivity of 58.8% and a specificity of 99.5%. Stock virus dilution experiments showed that Herpchek was 10 to 100 times less sensitive than culture. Herpchek was found to be an acceptable test for symptomatic patients, but for asymptomatic patients shedding a low titer of HSV it was not as sensitive and cell culture of Herpchek-negative specimens is recommended for such cases.     

Impact of proteoglycan‐4 and parathyroid hormone on articular cartilage

Proteoglycan‐4 (Prg4) protects synovial joints from arthropathic changes by mechanisms that are incompletely understood. Parathyroid hormone (PTH), known for its anabolic actions in bone, increases Prg4 expression and has been reported to inhibit articular cartilage degeneration in arthropathic joints. To investigate the effect of Prg4 and PTH on articular cartilage, 16‐week‐old Prg4 mutant and wild‐type mice were treated with intermittent PTH (1–34) or vehicle control daily for six weeks. Analyses included histology of the knee joint, micro‐CT of the distal femur, and serum biochemical analysis of type II collagen fragments (CTX‐II). Compared to wild‐type littermates, Prg4 mutant mice had an acellular layer of material lining the surfaces of the articular cartilage and menisci, increased articular cartilage degradation, increased serum CTX‐II concentrations, decreased articular chondrocyte apoptosis, increased synovium SDF‐1 expression, and irregularly contoured subchondral bone. PTH‐treated Prg4 mutant mice developed a secondary deposit overlaying the acellular layer of material lining the joint surfaces, but PTH‐treatment did not alter signs of articular cartilage degeneration in Prg4 mutant mice. The increased joint SDF‐1 levels and irregular subchondral bone found in Prg4 mutant mice introduce novel candidate mechanisms by which Prg4 protects articular cartilage. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 183–190, 2013     

Comparative Efficacy of the Generalized Anxiety Disorder 7-Item Scale and the Edinburgh Postnatal Depression Scale as Screening Tools for Generalized Anxiety Disorder in Pregnancy and the Postpartum Period

Objective:

About 24.1% of pregnant women suffer from at least 1 anxiety disorder, 8.5% of whom suffer specifically from generalized anxiety disorder (GAD). GAD is often associated with major depressive disorder (MDD). During the perinatal period, the presence of physical and somatic symptoms often makes differentiation between depression and anxiety more challenging. To date, no screening tools have been developed to detect GAD in the perinatal population. We investigated the psychometric properties of the GAD 7-item Scale (GAD-7) as a screening tool for GAD in pregnant and postpartum women.

Methods:

Two hundred and forty perinatal women (n = 155 pregnant and n = 85 postpartum) referred for psychiatric consultation were enrolled. On the day of initial assessment, all women completed the GAD-7 and the Edinburgh Postnatal Depression Scale (EPDS). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–based diagnoses were made by experienced psychiatrists. Scores from the GAD-7 and EPDS were compared with the clinical diagnoses to evaluate the psychometric properties of the GAD-7 and EPDS when used as a screening tool for GAD.

Results:

The GAD-7 yielded a sensitivity of 61.3% and specificity of 72.7% at an optimal cut-off score of 13. Compared with the EPDS and the EPDS-3A subscale, the GAD-7 displayed greater accuracy and specificity over a greater range of cut-off scores and more accurately identified GAD in patients with comorbid MDD.

Conclusion:

Our findings suggest that the GAD-7 represents a clinically useful scale for the detection of GAD in perinatal women.     

Prolonged thrombocytosis in mice after 5-fluorouracil results from failure to down-regulate megakaryocyte concentration. An experimental model that dissociates regulation of megakaryocyte size and DNA content from megakaryocyte concentration

Rodents treated with 150 mg/kg of 5-fluorouracil (5-FU) exhibit a marked and prolonged rebound thrombocytosis, suggesting that feedback control of one or more megakaryocyte characteristics (size, polyploidy, or concentration) is altered. To determine the changes in megakaryocytes that lead to such a profound thrombocytosis, C3H mice were injected with 150 mg/kg 5-FU, and platelet and megakaryocyte responses were examined at frequent intervals from days 1 through 25. After 5-FU injection, all megakaryocyte indices decreased, as did platelet number. However, the decrease in platelets to one third of control was greater than the decreases in megakaryocyte indices, suggesting that thrombocytopoiesis was ineffective from days 3 through 7 post 5-FU. Megakaryocyte size began to recover on day 4, followed by polyploid DNA content on day 5, and megakaryocyte concentration and platelets at 7.5 days. Megakaryocyte size peaked on days 6 through 8 (1.25 x normal), followed by megakaryocyte polyploid DNA content on day 8, megakaryocyte concentration on days 9 through 12 (2 1/2 to 3x normal), and platelets on days 12 through 15 (2x normal). Platelet levels are thought to be important in the feedback regulation of megakaryocytes; however, only polyploid DNA content distributions showed a close inverse relationship to platelet counts during both the recovery and rebound thrombocytosis phases after 5-FU. In contrast, megakaryocyte size peaked before platelet recovery commenced, while megakaryocyte concentration increased in parallel with platelets from 7.5 to 10 days post 5-FU and continued to be maintained at 2 to 3 times normal through day 13, despite platelet levels that were more than twice normal. Both megakaryocyte size and polyploid DNA content distributions shifted toward lower values in response to the rebound thrombocytosis (DNA content on day 10 and size on days 12 and 13). Splenectomy did not substantially alter the pattern of post 5-FU rebound thrombocytosis or megakaryocyte response from that seen in intact mice, indicating that splenic megakaryocytes are not responsible for the prolonged thrombocytosis seen after this drug. In summary, the prolonged thrombocytosis after 5-FU administration results from failure to down-regulate the number of precursors entering the differentiating megakaryocyte compartment. These data indicate that megakaryocyte size and DNA content are responsive to different feedback controls than megakaryocyte concentration in this model system.