Animal Models of Sjögren’s Syndrome

Sjögren’s syndrome is an autoimmune, chronic inflammatory disease characterized by focal mononuclear cell infiltration of exocrine tissues, accompanied by loss of secretory function. The pathogenesis of autoimmune diseases is complex and, therefore, difficult to study in vitro. As of today, the role of initiating factors remains obscure, clinical symptoms develop late, and there are no tests for early diagnosis of SS. Hence, the disease is difficult to detect and treat. Animal models may provide insights into the identification of target antigens, narrowing the relevant pathological immune mechanisms, and to study the evolution of tissue pathology. This review summarizes current knowledge on murine strains, both spontaneous and induced models, used to study Sjögren’s syndrome. Special attention is paid to the characteristics of different strains regarding their properties to mimic specific aspects or stages of the disease.     

Pronounced depression by propofol on carotid body response to CO2 and K+-induced carotid body activation

Propofol is a commonly used anesthetic agent, and it attenuates hypoxic ventilatory response in humans. Propofol reduce in vivo and in vitro carotid body responses to hypoxia as well as to nicotine in experimental animals. In the present study we examined the effects of propofol on carotid body responses to hypercapnia and K(+)-induced carotid body activation and compared these effects with hypoxia in an in vitro rabbit carotid body preparation. Hypoxia, hypercapnia and potassium increased the carotid sinus nerve activity and propofol attenuated the chemoreceptor responses to all three stimuli. However, the magnitude of propofol-induced attenuation was greater for hypercapnic and K(+)-induced carotid body activation compared to the hypoxic response. These observations suggest that propofol-induced attenuation of the hypoxic response is partly secondary to depression of chemoreceptor response to hypercapnia inhibiting the synergistic interactions between O(2) and CO(2) and may involve CO(2)/H(+) sensitive K(+) channels.     

Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression

Heat-shock factors (HSFs) are associated with multiple developmental processes, but their mechanisms of action in these processes remain largely enigmatic. Hsf2-null mice display gametogenesis defects and brain abnormalities characterized by enlarged ventricles. Here, we show that Hsf2-/- cerebral cortex displays mispositioning of neurons of superficial layers. HSF2 deficiency resulted in a reduced number of radial glia fibers, the architectural guides for migrating neurons, and of Cajal-Retzius cells, which secrete the positioning signal Reelin. Therefore, we focused on the radial migration signaling pathways. The levels of Reelin and Dab1 tyrosine phosphorylation were reduced, suggesting that the Reelin cascade is affected in Hsf2-/- cortices. The expression of p35, an activator of cyclin-dependent kinase 5 (Cdk5), essential for radial migration, was dependent on the amount of HSF2 in gain- and loss-of-function systems. p39, another Cdk5 activator, displayed reduced mRNA levels in Hsf2-/- cortices, which, together with the lowered p35 levels, decreased Cdk5 activity. We demonstrate in vivo binding of HSF2 to the p35 promoter and thereby identify p35 as the first target gene for HSF2 in cortical development. In conclusion, HSF2 affects cellular populations that assist in radial migration and directly regulates the expression of p35, a crucial actor of radial neuronal migration.     

Effect of heterotopic noxious conditioning stimulation on electrical and pressure pain thresholds in two different anatomical regions

Objectives. The aims of the study were to investigate the influence of heterotopic noxious conditioning stimulation (HNCS) on pain thresholds in the orofacial and spinal regions and to find out whether there are gender differences in this respect. Material and Methods. Thirty healthy subjects (15 of each sex) with a mean (SD) age of 25.1 (4.4) years participated. Pain thresholds to electrical (EPT) and pressure stimuli (PPT) were recorded in the masseter muscle and 1st upper incisor (tooth), as well as in the fingertip, before, during, and 5 and 15 min after a cold pressor task to the contralateral hand immersed in ice-cold water for a maximum of 5 min. Results. With the exception of the EPT in the orofacial region, all pain thresholds increased during the HNCS and then returned to baseline during the 15 min follow-up. The significant changes in EPT were greater in the finger than in the tooth, while the changes in PPT were greater in the masseter muscle than in the finger. Electrical stimuli in the finger induced greater significant changes of pain thresholds than pressure. In the orofacial region, pressure induced greater significant changes in pain thresholds during HNCS than electrical stimuli did. The HNCS induced pain of high intensity and unpleasantness, i.e. varying between 5 and 10 on the numeric rating scale (NRS). There were no gender differences in the response to the HNCS. Conclusion. We conclude that, in general, HNCS induced by cold pressor stimulation increases pain thresholds, but the magnitude of the effect differs between the orofacial region and the finger and is influenced by the tissue and type of test stimuli.     

Do modern total knee replacements improve tibial coverage?

Purpose

The purpose of the present study is to compare newer designs of various symmetric and asymmetric tibial components and measure tibial bone coverage using the rotational safe zone defined by two commonly utilized anatomic rotational landmarks.

Methods

Computed tomography scans (CT scans) of one hundred consecutive patients scheduled for total knee arthroplasty were obtained pre-operatively. A virtual proximal tibial cut was performed and two commonly used rotational axes were added for each image: the medio-lateral axis (ML-axis) and the medial 1/3 tibial tubercle axis (med-1/3-axis). Different symmetric and asymmetric implant designs were then superimposed in various rotational positions for best cancellous and cortical coverage. The images were imported to a public domain imaging software, and cancellous and cortical bone coverage was computed for each image, with each implant design in various rotational positions.

Results

One single implant type could not be identified that provided the best cortical and cancellous coverage of the tibia, irrespective of using the med-1/3-axis or the ML-axis for rotational alignment. However, it could be confirmed that the best bone coverage was dependent on the selected rotational landmark. Furthermore, improved bone coverage was observed when tibial implant positions were optimized between the two rotational axes.

Conclusions

Tibial coverage is similar for symmetric and asymmetric designs, but depends on the rotational landmark for which the implant is designed. The surgeon has the option to improve tibial coverage by optimizing placement between the two anatomic rotational alignment landmarks, the medial 1/3 and the ML-axis. Surgeons should be careful assessing intraoperative rotational tibial placement using the described anatomic rotational landmarks to optimize tibial bony coverage without compromising patella tracking.

Level of Evidence

III.

     

The use of a rigid disc to protect exposed structures in wounds treated with negative pressure wound therapy: Effects on wound bed pressure and microvascular blood flow

There are increasing reports of deaths and serious complications associated with the use of negative pressure wound therapy (NPWT). Bleeding may occur in patients when NPWT is applied to a wound with exposed blood vessels or vascular grafts, possibly due to mechanical deformation and hypoperfusion of the vessel walls. Recent evidence suggests that using a rigid barrier disc to protect underlying tissue can prevent this mechanical deformation. The aim of this study was to examine the effect of rigid discs on the tissue exposed to negative pressure with regard to tissue pressure and microvascular blood flow. Peripheral wounds were created on the backs of eight pigs. The pressure and microvascular blood flow in the wound bed were measured when NPWT was applied. The wound was filled with foam, and rigid discs of different designs were inserted between the wound bed and the foam. The discs were created with or without channels (to accommodate exposed sensitive structures such as blood vessels and nerves), perforations, or a porous dressing that covered the underside of the discs (to facilitate pressure transduction and fluid evacuation). When comparing the results for pressure transduction to the wound bed, no significant differences were found using different discs covered with dressing, whereas pressure transduction was lower with bare discs. Microvascular blood flow in the wound bed decreased by 49 ± 7% when NPWT was applied to control wounds. The reduction in blood flow was less in the presence of a protective disc (e.g., ?6 ± 5% for a dressing‐covered, perforated disc, p = 0.006). In conclusion, NPWT causes hypoperfusion of superficial tissue in the wound bed. The insertion of a rigid barrier counteracts this effect. The placement of a rigid disc over exposed blood vessels or nerves may protect these structures from rupture and damage.     

Mobile app for treatment of stress urinary incontinence: A randomized controlled trial

Aims

To evaluate the effect of a mobile app treatment for stress urinary incontinence (SUI) in women.

Methods

Randomized controlled trial, conducted 2013‐2014 in Sweden. Community‐dwelling adult women with ≥1 SUI episode/week recruited through our website and randomized to app treatment (n = 62) or control group (postponed treatment, n = 61). One participant from each group was lost to follow‐up. Intervention was the mobile app Tät^® with a treatment program focused on pelvic floor muscle training (PFMT), and information about SUI and lifestyle factors. Primary outcomes, 3 months after randomization: symptom severity (International Consultation on Incontinence Modular Questionnaire Urinary Incontinence Short Form [ICIQ‐UI SF]); and condition‐specific quality of life (ICIQ Lower Urinary Tract Symptoms Quality of Life [ICIQ‐LUTSqol]).

Results

One hundred and twenty‐three women were included (mean age 44.7), with moderate/severe SUI (97.5%, 120/123), mean ICIQ‐UI SF score 11.1 (SD 2.8) and mean ICIQ‐LUTSqol score 34.4 (SD 6.1) at baseline. At follow‐up, the app group reported improvements in symptom severity (mean ICIQ‐UI SF score reduction: 3.9, 95% confidence interval 3.0‐4.7) and condition‐specific quality of life (mean ICIQ‐LUTSqol score reduction: 4.8, 3.4‐6.2) and the groups were significantly different (mean ICIQ‐UI SF score difference: ?3.2, ?4.3to ?2.1; mean ICIQ‐LUTSqol score difference: ?4.6, ?7.8 to ?1.4). In the app group, 98.4% (60/61) performed PFMT at follow‐up, and 41.0% (25/61) performed it daily.

Conclusions

The mobile app treatment was effective for women with SUI and yielded clinically relevant improvements. This app may increase access to first‐line treatment and adherence to PFMT.

     

Heterogeneous glycosylation patterns of human PAI-1 may reveal its cellular origin

The main inhibitor of intravascular fibrinolysis is plasminogen activator inhibitor 1 (PAI-1) which binds to and irreversibly inhibits tissue plasminogen activator (tPA). PAI-1 is present in blood, both in platelets and in plasma, and PAI-1 levels are associated with risk of atherothrombosis. Several tissues express PAI-1 but the source of plasma PAI-1 is not known. We recently found that platelets can de novo synthesize PAI-1 and the amount synthesized in vitro in 24 hours is 35-fold higher than required to maintain normal plasma levels. Recombinant human PAI-1 expressed in different cell types or secreted naturally by human cell lines, exhibit heterogeneous glycosylation patterns. The aim of this study was to investigate the hypothesis that platelets might be the source of plasma PAI-1 and that the cellular source of PAI-1 can be determined by its tissue-specific glycosylation pattern. PAI-1 was isolated from platelets, macrophages, endothelial cells, adipose tissue, as well as plasma from lean and obese subjects. The glycosylation was analyzed by nanoLC-MS/MS. PAI-1 isolated from cell lysates and conditioned media from macrophages, endothelial cells, and adipose tissue expressed heterogeneous glycosylation patterns. By contrast, no glycans were detected on PAI-1 isolated from plasma or platelets from healthy lean individuals. Hence, our data suggest that platelets may be the main source of plasma PAI-1 in lean individuals. Interestingly, plasma PAI-1 from obese subjects had a glycan composition similar to that of adipose tissue suggesting that obese subjects with elevated PAI-1 levels may have a major contribution from other tissues.