Aprepitant exerts anti-fibrotic effect via inhibition of TGF-β/Smad3 pathway in bleomycin-induced pulmonary fibrosis in rats

Bleomycin is a well-recognized antineoplastic drug. However, pulmonary fibrosis (PF) is considered to be the principal drawback that greatly limits its use. Here, we sought to investigate ability of the neurokinin receptor 1 blocker, aprepitant, to prevent PF caused by bleomycin. Male adult Wistar rat groups were given a single intratracheal injection of bleomycin, either alone or in combination with aprepitant therapy for 3 or 14 days. Collagen deposition and a rise in transforming growth factor beta (TGF-β) immunoreactivity in lung tissue serve as evidence of bleomycin-induced PF. The serum levels of lactate dehydrogenase, alkaline phosphatase, and total antioxidant improved after aprepitant therapy.Additionally, it reduced the protein expressions of interferon alpha, tumor necrosis factor alpha, and lung lipid peroxidation. Moreover, aprepitant treatment led to an increase in the antioxidant indices glutathione, glutathione peroxidase, and catalase. Aprepitant is postulated to protect against bleomycin-induced PF by decreasing TGF-β, phosphorylating Smad3, and increasing interleukin 37, an anti-fibrotic cytokine, and G Protein-coupled Receptor Kinase 2. Aprepitant for 14 days considerably exceeded aprepitant for 3 days in terms of improving lung damage and having an anti-fibrotic impact. In conclusion, aprepitant treatment for 14 days may be used as an adjuvant to bleomycin therapy to prevent PF, mostly through inhibiting the TGF-/p-Smad3 fibrotic pathway.     

The validity of using profile predictions for class III patients planned for bimaxillary orthognathic surgery

This study assessed whether preoperative class III patients could recreate their facial difference based on a profile photograph. Twenty class III pre-surgery bimaxillary orthognathic patients used CASSOS (SoftEnable Technology Ltd.) to manipulate a distorted soft tissue image of them until they felt it resembled their current soft tissue profile. Patients were able to move their upper lip and lower chin backward and forwards, as well as the lower chin up and down. Differences in the mean absolute distance between the patient-perceived position of the upper lip (Labrale superious) and chin (Pogonion) and the actual position of their upper lip and chin were measured on two occasions. Intra-patient reproducibility was found to be excellent (ICC 0.93 to 0.98). All differences were statistically significantly greater than 3mm, and would be clinically significant. Patients were better at re-creating their AP chin position rather than their AP upper lip and vertical chin positions. Approximately half of patients undergoing surgical correction of their class III skeletal pattern were unable to correctly identify their pre-surgical facial profile. Given the lack of awareness of their profile, this questions the validity of using profile planning for informed consent.     

Frequency-specific effects of low-intensity rTMS can persist for up to 2 weeks post-stimulation: A longitudinal rs-fMRI/MRS study in rats

BackgroundEvidence suggests that repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, alters resting brain activity. Despite anecdotal evidence that rTMS effects wear off, there are no reports of longitudinal studies, even in humans, mapping the therapeutic duration of rTMS effects.ObjectiveHere, we investigated the longitudinal effects of repeated low-intensity rTMS (LI-rTMS) on healthy rodent resting-state networks (RSNs) using resting-state functional MRI (rs-fMRI) and on sensorimotor cortical neurometabolite levels using proton magnetic resonance spectroscopy (MRS).MethodsSprague-Dawley rats received 10 min LI-rTMS daily for 15 days (10 Hz or 1 Hz stimulation, n = 9 per group). MRI data were acquired at baseline, after seven days and after 14 days of daily stimulation and at two more timepoints up to three weeks post-cessation of daily stimulation.Results10 Hz stimulation increased RSN connectivity and GABA, glutamine, and glutamate levels. 1 Hz stimulation had opposite but subtler effects, resulting in decreased RSN connectivity and glutamine levels. The induced changes decreased to baseline levels within seven days following stimulation cessation in the 10 Hz group but were sustained for at least 14 days in the 1 Hz group.ConclusionOverall, our study provides evidence of long-term frequency-specific effects of LI-rTMS. Additionally, the transient connectivity changes following 10 Hz stimulation suggest that current treatment protocols involving this frequency may require ongoing “top-up” stimulation sessions to maintain therapeutic effects.     

Platelets are important for the development of immune tolerance: Possible involvement of TGF‐β in the mechanism

Platelets have diverse roles in immune processes in addition to their key functions in haemostasis and thrombosis. Some studies imply that platelets may be possibly related to the immune tolerance induction. However, the role of platelets in the development of immune tolerance is not fully understood. The purpose of this study was to investigate the role of platelets in the development of regulatory mechanisms responsible for cutaneous inflammation using a mouse model of low zone tolerance (LZT). Mice were treated with 2,4,6‐trinitro‐1‐chlorobenzene (TNCB) 8 times every other day for tolerance induction with administration of anti‐platelet antibody or control antibody during the tolerance induction phase every 3 days. After the treatment for the tolerance induction, mice were sensitized and then challenged with TNCB. The contact hypersensitivity (CHS) was significantly decreased at 24 hours after challenge in the mice with LZT than in those without LZT. Platelet depletion via administration of anti‐platelet antibody reversed the inhibition of CHS and reduced the frequency of Foxp3⁺ Tregs in the inflamed skin and draining lymph nodes in mice with LZT. In addition, repeated low‐dose skin exposure resulted in elevated plasma levels of transforming growth factor (TGF)‐β1. Interestingly, platelet depletion reduced plasma TGF‐β1 levels of mice with LZT. Furthermore, the CHS response was reduced by administration of recombinant TGF‐β1 during platelet depletion in mice with LZT. Administration of anti‐TGF‐β antibody reversed the inhibition of the CHS responses. These results suggest that platelets are involved in the induction of immune tolerance via the release of TGF‐β1.     

The increase in bone mineral density by bisphosphonate with active vitamin D analog is associated with the serum calcium level within the reference interval in postmenopausal osteoporosis

Objectives: To examine the factors associated with increase in lumbar spine bone mineral density (LS-BMD) by bisphosphonates (BPs) with active vitamin D analog (aVD).

Methods: Two independent postmenopausal osteoporotic patients treated by BPs with aVD for 24 months (Study 1: n?=?93, Study 2: n?=?99) were retrospectively analyzed.

Results: In Study 1, LS-BMD of the patients significantly increased for 24 m (5.4%, p?r²: 0.088, p?=?.02). While average sCa of the patients was 9.2?mg/dL before treatment, it increased time-dependently to 9.6?mg/dL for 24 m by treatment. As each patient had their LS-BMD five times during the study, there were four instances of %LS-BMD in each patient, resulting in 372 instances of %LS-BMD in Study 1. The smallest Akaike’s information criterion value for the most appropriate cut-off levels of sCa for %LS-BMD by treatment every 6 m was 9.3?mg/dL. The %LS-BMD by treatment for 6 m during 24 m period in patients with sCa ≥9.3?mg/dL (1.5%) was significantly higher than that in patients with sCa <9.3?mg/dL (0.8%, p?=?.038). The results of Study 2 were similar to those of Study 1, confirming the phenomena observed.

Conclusion: sCa was associated with an increased LS-BMD by BPs with aVD.     

Derivation and Validation of a Model to Predict 30-Day Readmission in Surgical Patients Discharged to Skilled Nursing Facility

ObjectivesTo identify factors associated with 30-day all-cause readmission rates in surgical patients discharged to skilled nursing facilities (SNFs), and derive and validate a risk score.DesignRetrospective cohort.Setting and participantsPatients admitted to 1 tertiary hospital's surgical services between January 1, 2011, and December 31, 2014 and subsequently discharged to 110 SNFs within a 25-mile radius of the hospital. The first 2 years were used for the derivation set and the last 2 for validation.MethodsData were collected on 30-day all cause readmissions, patient demographics, procedure and surgical service, comorbidities, laboratory tests, and prior health care utilization. Multivariate regression was used to identify risk factors for readmission.ResultsDuring the study period, 2405 surgical patients were discharged to 110 SNFs, and 519 (21.6%) of these patients experienced readmission within 30 days. In a multivariable regression model, hospital length of stay [odds ratio (OR) per day: 1.03, 95% confidence interval (CI) 1.02-1.04], number of hospitalizations in past year (OR 1.24 per hospitalization, 95% CI 1.18-1.31), nonelective surgery (OR 1.33, 95% CI 1.18-1.65), low-risk service (orthopedic/spine service) (OR 0.32, 95% CI 0.25-0.42), and intermediate-risk service (cardiothoracic surgery/urology/gynecology/ear, nose, throat) (OR 0.69, 95% CI 0.53-0.88) were associated with all-cause readmissions. The model had a C index of 0.71 in the validation set. Using the following risk score [0.8 × (hospital length of stay) + 7 × (number of hospitalizations in past year) +10 for nonelective surgery, +36 for high-risk surgery, and +20 for intermediate-risk surgery], a score of >40 identified patients at high risk of 30-day readmission (35.8% vs 12.6%, P < .001).Conclusions/ImplicationsAmong surgical patients discharged to an SNF, a simple risk score with 4 parameters can accurately predict the risk of 30-day readmission.