Stability of direct renin concentration and plasma renin activity in EDTA whole blood and plasma at ambient and refrigerated temperatures from 0 to 72 hours.

OBJECTIVES: The aim of this study was to determine the appropriate transport and storage conditions for blood taken for direct renin concentration and plasma renin activity measurement, and whether cryoactivation of prorenin is seen at time points relevant to clinical practice. METHODS: Blood was extracted from n=10 volunteers into K2-EDTA tubes. Stability of renin was assessed in whole blood stored at room temperature (15-25 °C) and in the refrigerator (2-8 °C) at 0 h, 8 h, and 24 h. The stability of renin in plasma was determined under the same conditions at 0 h, 24 h and 72 h. RESULTS: Stability of plasma renin activity and direct renin concentration in whole blood stored at room temperature was found to be acceptable for up to 24 h. At refrigerated temperature, whole blood stability was acceptable for measurement of direct renin concentration up to 8 h and plasma renin activity up to 24 h. In contrast, plasma renin activity was not stable in plasma stored at either room or refrigerated temperatures up to 24 h; however, direct renin concentration had acceptable stability in plasma stored at room temperature for up to 24 h, but stability was unacceptable at refrigerated temperatures. CONCLUSIONS: Samples collected for plasma renin activity and direct renin concentration should be transported as whole blood to optimise stability. After sample processing, plasma can be kept at room temperature for up to 24 h for direct renin concentration, however, for determination of plasma renin activity separated plasma should be analysed or frozen as soon as possible.

The impact of external beam radiation therapy on shoulder surgical outcomes: a case series study.

HYPOTHESIS: External beam radiation therapy (XRT) is a commonly used treatment adjunct in patients with breast cancer and is known to cause soft tissue dysfunction. However, data on XRT as a preoperative risk factor for shoulder surgery is limited. The purpose of this study was to assess whether prior history of breast cancer treated with XRT has an impact on surgical complications or outcomes. We hypothesize that patients treated with XRT will have a higher rate of surgical complications and lower outcomes. METHODS: A 20-year retrospective chart review across a large, academic health care system was performed. Inclusion criterion comprised any patient with history of breast cancer of the upper-outer or axillary region treated with XRT. Patients also must have undergone a surgical procedure to the ipsilateral shoulder with at least 1-year postoperative follow-up. Patients were stratified by demographics, hand dominance, and surgery type. Postoperative outcomes including range of motion (ROM) and visual analog scale (VAS) scores for pain were also collected. RESULTS: Eighteen patients were identified (100% female) with an average age of 66.3 years (standard deviation 10.5 years). Ten shoulders underwent rotator cuff repair (RCR), 4 total shoulder arthroplasty (TSA), 3 reverse shoulder arthroplasty (RSA), and 1 arthroscopic superior labrum anterior to posterior (SLAP) repair. Four patients treated with RCR (40%) experienced postoperative complications related to their procedure. These included scapular winging, adhesive capsulitis, stiffness, and one retear. Two patients treated with shoulder arthroplasty (28.6%) experienced postoperative complications that included lymphedema and periprosthetic fracture following a mechanical fall in one RSA patient and periprosthetic infection in a TSA patient. ROM across all groups improved, most significantly in forward flexion and internal rotation among RCR patients (P < .001). Furthermore, a statistically significant improvement in VAS scores was achieved in each group (6.2 ± 2.14 preoperation, 1.06 ± 1.75 postoperation; P < .001). CONCLUSION: When compared to national averages, complication rates in our cohort were higher (40% vs. 10%-17% in RCR patients and 28.6% vs. 4%-14% in arthroplasty patients). On further scrutiny, many of these complications were independent of a history of XRT and many resolved with appropriate therapy. Most importantly, functional outcomes as measured by ROM and pain scores showed appropriate improvement consistent with normal populations without history of XRT. Thus, our results suggest that performing shoulder surgery after ipsilateral XRT for breast cancer is likely safe and may offer improved pain and ROM compared to forgoing surgery without necessarily increasing the risk for postoperative complication.

The relationship between shoulder range of motion and elbow stress in college pitchers.

HYPOTHESIS: College pitchers with increased external rotation gain (ERG) produce increased medial elbow torque (elbow stress) whereas those with reduced total rotational range of motion (ROM) have reduced medial elbow torque during pitching. METHODS: Pitchers were recruited from 3 college baseball teams. Players with prior injury or on pitching restrictions because of pain were excluded. Players were evaluated within 2 weeks before their first game of the season. Pitchers completed an intake survey, and shoulder and arm measurements were taken. Pitchers were fitted with a baseball sleeve that included a sensor at the medial elbow. The sensor calculated elbow torque, arm speed, arm slot, and shoulder rotation for each pitch, while a radar gun measured peak ball velocity. After adequate warm-up, pitchers threw 5 fastballs in a standardized manner off the mound at game-speed effort. The primary outcome evaluated the relationship between shoulder ROM and medial elbow torque. Additional outcomes evaluated pitcher characteristics and demographic characteristics in the context of shoulder ROM. RESULTS: Twenty-eight pitchers were included in the preseason analysis. The average age and playing experience were 20.1 years (standard deviation [SD], 1.3 years) and 15.3 years (SD, 1.8 years), respectively, with 2.5 years (SD, 1.2 years) playing at collegiate level. The dominant shoulder showed decreased internal rotation and increased external rotation (ER) relative to the nondominant side (P < .001). The average glenohumeral internal rotation deficit and ERG were 11.3° (SD, 9.87°) and 5.71° (SD, 8.8°), respectively. ERG ≥ 5° was a significant predictor of elbow stress during pitching (47.4 Nm [SD, 0.7 Nm] vs. 45.1 Nm [SD, 0.6 Nm], P = .014). Univariate associations showed that each additional degree of ER resulted in increased elbow torque (ß estimate, 0.35 ± 0.06 Nm; P = .003). Conversely, decreased medial elbow torque was found in pitchers with reduced shoulder ROM (glenohumeral internal rotation deficit ≥ 20°: 43.5 Nm [SD, 1.1 Nm] vs. 46.6 Nm [SD, 0.5 Nm], P = .011; loss of total rotational ROM ≥ 5°: 43.6 Nm [SD, 1.1 Nm] vs. 46.6 Nm [SD, 0.5 Nm], P = .013) and in those with greater arm length (P < .05). CONCLUSIONS: College pitchers with increased ER produce greater medial elbow torque during the pitching movement. Each degree of increased ER was found to correlate with increased elbow torque and ball velocity. On the contrary, arm length and reduced shoulder ROM were associated with reduced medial elbow torque. This study suggests that increased ER in pitchers is associated with greater elbow stress during pitching.

Yttrium-90 Radioembolization in Intrahepatic Cholangiocarcinoma: A Multicenter Retrospective Analysis.

PURPOSE: To report outcomes of yttrium-90 (90Y) radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: Retrospective review was performed of 115 patients at 6 tertiary care centers; 92 were treated with resin microspheres (80%), 22 were treated with glass microspheres (19%), and 1 was treated with both. Postintervention outcomes were compared between groups with χ2 tests. Survival after diagnosis and after treatment was assessed by Kaplan-Meier method. RESULTS: Grade 3 laboratory toxicity was observed in 4 patients (4%); no difference in toxicity profile between resin and glass microspheres was observed (P = .350). Clinical toxicity per Society of Interventional Radiology criteria was noted in 29 patients (25%). Partial response per Response Evaluation Criteria In Solid Tumors 1.1 was noted in 25% of patients who underwent embolization with glass microspheres and 3% of patients who were treated with resin microspheres (P = .008). Median overall survival (OS) from first diagnosis was 29 months (95% confidence interval [CI], 21-37 mo) for all patients, and 1-, 3-, and 5-year OS rates were 85%, 31%, and 8%, respectively. Median OS after treatment was 11 months (95% CI, 8-13 mo), and 1- and 3-year OS rates were 44% and 4%, respectively. These estimates were not significantly different between resin and glass microspheres (P = .730 and P = .475, respectively). Five patients were able to undergo curative-intent resection after 90Y radioembolization (4%). CONCLUSIONS: This study provides observational data of treatment outcomes after 90Y radioembolization in patients with unresectable ICC.

Risk Factors for Postoperative Opioid Use in Arthroscopic Shoulder Labral Surgery.

PURPOSE: To determine the correlation between preoperative and postoperative opioid use in patients undergoing arthroscopic shoulder labral repair, as well as patient risk factors associated with increased postoperative opioid use after the procedure. METHODS: A retrospective review of all patients undergoing arthroscopic shoulder labral surgery at a single institution between August 2013 and November 2017 was performed. Patients were stratified as opioid nonusers, acute users, or chronic users based on preoperative consumption. Patient demographic characteristics, injury characteristics, surgical interventions, and postoperative opioid use for the first 12 months after surgery were then analyzed. RESULTS: A total of 340 patients were included in this study. The average age was 26.3 years (range, 13-68 years), and the average body mass index was 27.5 (range, 18.4-45.0). Preoperative opioid users (acute and chronic) were found to continue to receive opioid medications at extended time points beyond 2 months postoperatively compared with nonusers (P < .001). Patients with intraoperatively identified SLAP tears experienced more preoperative pain and required more postoperative opioid prescriptions (P = .018). On stratification for other common shoulder instability injury patterns, no differences were found between the number of postoperative opioid prescriptions filled and the presence of Bankart lesion, Hill-Sachs lesion, reverse Hill-Sachs lesion, anterior labroligamentous periosteal sleeve avulsion, glenolabral articular disruption, or humeral avulsion of the glenohumeral ligament (P > .05). CONCLUSIONS: In patients undergoing arthroscopic labral surgery, the chronicity of preoperative opioid use, number of concomitant procedures at the time of initial surgery, and presence of biceps tenodesis were found to significantly increase postoperative opioid demand. Orthopaedic surgeons should recognize risk factors for increased opioid use postoperatively and adapt treatment strategies and patient counseling accordingly. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Risk Factors for Postoperative Opioid Use in Arthroscopic Meniscal Surgery.

PURPOSE: (1) To evaluate the influence of preoperative opioid use on postoperative consumption after arthroscopic meniscal surgery and (2) to determine preoperative patient factors associated with increased opioid use after meniscal surgery. METHODS: We performed a retrospective review of all patients with a primary diagnosis of a meniscal tear at a single institution between August 2013 and February 2017. Patients were classified as opioid nonusers if they had not received any opioid medications in the 3 months before meniscal surgery, as acute users if they received at least 1 opioid prescription within 1 month preceding meniscal surgery, or as chronic users if they received at least 1 opioid prescription within 3 months preceding meniscal surgery. Clinical records were reviewed for postoperative opioid use within a year after surgery. We also recorded patient demographic characteristics and the degree of knee osteoarthritis at the time of surgery using the Outerbridge classification. RESULTS: A total of 735 patients were included. The average age was 46.7 years (range, 12-79 years), and the average body mass index was 30.2 ± 6.2 (range, 13.3-55.4). Patients who were acute or chronic opioid users preoperatively were more likely to continue to use opioids beyond 1 month postoperatively (P < .001). A higher percentage of patients with advanced osteoarthritis (Outerbridge grade 3 or 4) were found to continue to use opioids at all time points beyond the first postoperative month (P < .05). Pair-wise comparisons showed that the number of total opioid prescriptions filled was significantly higher in the group with Outerbridge grade 1 or 2 and the group with Outerbridge grade 3 or 4 than the group with Outerbridge grade 0 (P = .023 and P = .014, respectively). No significant difference in postoperative opioid use was noted when we compared meniscal repair versus resection, primary procedure versus revision, different tear types, or concomitant procedures. CONCLUSIONS: In patients undergoing arthroscopic meniscal surgery, the chronicity of preoperative opioid intake and degree of knee osteoarthritis were found to have a significant effect on postoperative opioid use. LEVEL OF STUDY: Level III, retrospective comparative study.

Mosaic-pattern dedifferentiation in liposarcoma and chondrosarcoma: imaging features of an uncommon form of dedifferentiation.

The term "dedifferentiation" was classically used in sarcoma pathology to refer to tumors in which a high-grade, undifferentiated sarcoma, or a high-grade sarcoma showing heterologous differentiation, arises from a pre-existing neoplasm of borderline or low-grade malignancy. The best recognized examples of this include dedifferentiated liposarcoma, arising from atypical lipomatous tumor/well-differentiated liposarcoma, and dedifferentiated chondrosarcoma, arising from grade 1 hyaline chondrosarcoma of bone. In the overwhelming majority of cases, this dedifferentiated, high-grade sarcoma presents as a macroscopically visible mass, adjacent to and clearly distinct from the pre-existing low-grade lesion. It is less well appreciated that dedifferentiation may also occur in a so-called "mosaic pattern,' in which the high-grade component is intimately admixed with elements of the precursor lesion, forming only microscopically apparent foci. This mosaic or co-mingling pattern of dedifferentiation is also reflected in the MR imaging appearance. In contrast to the classic pattern of dedifferentiation in which there are two distinct juxtaposed masses with different signal intensities and enhancement patterns, such changes are not seen in mosaic dedifferentiation. The imaging features of this pattern of dedifferentiation have not been described. In this report we describe the imaging features of two patients with mosaic pattern dedifferentiation, one with liposarcoma and one with chondrosarcoma. In both cases the precursor lesion was correctly diagnosed by pre-biopsy imaging, but the presence of high-grade sarcoma was not recognized.

Ethanol-based proliposome delivery systems of paclitaxel for in vitro application against brain cancer cells.

In this study the anticancer activity of paclitaxel-loaded nano-liposomes on glioma cell lines was investigated. Soya phosphatidylcholine:cholesterol (SPC:Chol), hydrogenated soya phosphatidylcholine:cholesterol (HSPC:Chol) or dipalmitoylphosphatidylcholine:cholesterol (DPPC:Chol) in 1:1 mole ratio were used to prepare ethanol-based proliposomes. Following hydration of proliposomes, the size of resulting vesicles was subsequently reduced to nanometer scale via probe-sonication. The resulting formulations were characterized in terms of size, zeta potential and morphology of the vesicles, and entrapment efficiency of paclitaxel (PX) as well as the final pH of the preparations. DPPC-liposomes entrapped 35-92% of PX compared to 27-74% and 25-60% entrapped by liposomes made from SPC and HSPC formulations respectively, depending on drug concentration. The entrapment efficiency of liposomes was dependent on the lipid bilayer properties and ability of PX to modify surface charge of the vesicles. In vitro cytotoxicity studies revealed that PX-liposome formulations were more selective at inhibiting the malignant cells. The cytotoxicity of PX-liposomes was dependent on their drug-entrapment efficiency. This study has shown PX-liposomes generated from proliposomes have selective activity against glioma cell lines, and the synthetic DPPC phospholipid was most suitable for maximized drug entrapment and highest activity against the malignant cells in vitro.

Return to play after shoulder instability in National Football League athletes.

HYPOTHESIS: We hypothesized that National Football League (NFL) players sustaining a shoulder destabilizing injury could return to play (RTP) successfully at a high rate regardless of treatment type. METHODS: We identified and evaluated 83 NFL players who sustained an in-season shoulder instability event while playing in the NFL. NFL RTP, incidence of surgery, time to RTP, recurrent instability events, seasons/games played after the injury, and demographic data were collected. Overall RTP was determined, and players who did and did not undergo operative repair were compared. RESULTS: Ninety-two percent of NFL players returned to NFL regular season play at a median of 0.0 weeks in those sustaining a shoulder subluxation and 3.0 weeks in those sustaining a dislocation who did not undergo surgical repair (P = .029). Players who underwent operative repair returned to play at a median of 39.3 weeks. Forty-seven percent of players had a recurrent instability event. For players who were able to RTP, those who underwent surgical repair (31%) had a lower recurrence rate (26% vs. 55%, P = .021) and longer interval between a recurrent instability event after RTP (14.7 vs. 2.5 weeks, P = .050). CONCLUSION: There is a high rate of RTP after shoulder instability events in NFL players. Players who sustain shoulder subluxations RTP faster but are more likely to experience recurrent instability than those with shoulder dislocations. Surgical stabilization of the shoulder after an instability event decreases the chances of a second instability event and affords a player a greater interval between the initial injury and a recurrent event.

Development of Novel Octanoyl Chitosan Nanoparticles for Improved Rifampicin Pulmonary Delivery: Optimization by Factorial Design.

A novel hydrophobic chitosan derivative, octanoyl chitosan (OC) with improved organic solubility was synthesized, characterized, and employed for the preparation of rifampicin (Rif) encapsulated nanoparticle formulations for pulmonary delivery. OC was characterized to confirm acyl group substitution and cytotoxicity in A549 epithelial lung cells. OC nanoparticles were produced by the double emulsion solvent evaporation technique without cross-linking and characterized for particle size distribution, morphology, crystallinity, thermal stability, aerosol delivery, and drug release rate. OC was successfully synthesized with substitution degree of 44.05 ± 1.75%, and solubility in a range of organic solvents. Preliminary cytotoxicity studies of OC showed no effect on cell viability over a period of 24 h on A549 cell lines. OC nanoparticles were optimized using a 32 full factorial design. An optimized batch of OC nanoparticles, smooth and spherical in morphology, had mean hydrodynamic diameter of 253 ± 19.06 nm (PDI 0.323 ± 0.059) and entrapment efficiency of 64.86 ± 7.73% for rifampicin. Pulmonary deposition studies in a two-stage impinger following aerosolization of nanoparticles from a jet nebulizer gave a fine particle fraction of 43.27 ± 4.24%. In vitro release studies indicated sustained release (73.14 ± 3.17%) of rifampicin from OC nanoparticles over 72 h, with particles demonstrating physical stability over 2 months. In summary, the results confirmed the suitability of the developed systems for pulmonary delivery of drugs with excellent aerosolization properties and sustained-release characteristics.

Spray-Dried Proliposome Microparticles for High-Performance Aerosol Delivery Using a Monodose Powder Inhaler.

Proliposome formulations containing salbutamol sulphate (SS) were developed using spray drying, and the effects of carrier type (lactose monohydrate (LMH) or mannitol) and lipid to carrier ratio were evaluated. The lipid phase comprised soy phosphatidylcholine (SPC) and cholesterol (1:1), and the ratios of lipid to carrier were 1:2, 1:4, 1:6, 1:8 or 1:10 w/w. X-ray powder diffraction (XRPD) revealed an interaction between the components of the proliposome particles, and scanning electron microscopy (SEM) showed that mannitol-based proliposomes were uniformly sized and spherical, whilst LMH-based proliposomes were irregular and relatively large. Using a two-stage impinger (TSI), fine particle fraction (FPF) values of the proliposomes were higher for mannitol-based formulations, reaching 52.6%, which was attributed to the better flow properties when mannitol was used as carrier. Following hydration of proliposomes, transmission electron microscopy (TEM) demonstrated that vesicles generated from mannitol-based formulations were oligolamellar, whilst LMH-based proliposomes generated 'worm-like' structures and vesicle clusters. Vesicle size decreased upon increasing carrier to lipid ratio, and the zeta potential values were negative. Drug entrapment efficiency (EE) was higher for liposomes generated from LMH-based proliposomes, reaching 37.76% when 1:2 lipid to carrier ratio was used. The in vitro drug release profile was similar for both carriers when 1:6 lipid to carrier ratio was used. This study showed that spray drying can produce inhalable proliposome microparticles that can generate liposomes upon contact with an aqueous phase, and the FPF of proliposomes and the EE offered by liposomes were formulation-dependent.

A qualitative study exploring patients' experiences regarding insulin pump use.

BACKGROUND: Diabetes is a threat to peoples' lives around the world, particularly in the Middle East. Medicine misuse and poor glycaemic control are prevalent among patients with type 2 diabetes, especially insulin-dependent patients (Alsairafi et al., 2016). With advances in medical technology, insulin pumps became a treatment option for patients with type 1 diabetes and those with insulin-dependent type 2 diabetes. However, use of these devices is still lacking in Kuwait, particularly in patients with type 2 diabetes. Information on how patients manage these devices and their efficacy and safety from the perspectives of patients is also lacking (Alsaleh et al., 2016). OBJECTIVE: To examine the views and experiences of adults with type 2 diabetes regarding the use of insulin pumps compared to their previous insulin delivery methods, in terms of glycaemic control, quality of life, preference, convenience and adherence to doses. SETTING: The main five secondary-care hospitals in Kuwait: Mobarak Al-Kabeer, Al Amiri, Al Adan, Al Farwaniya and Al Jahra. METHOD: All adults with type 2 diabetes who used an insulin pump were invited to participate. Data were collected through semi-structured interviews. Data analysis was performed using MAXQDA-11. RESULTS: A total of eight patients were interviewed. Interviews with patients revealed that using an insulin pump improved patients' glycaemic control and quality of life as a consequence of improved satisfaction and adherence to doses. CONCLUSION: From the perspective of adults with type 2 diabetes, there are lots of benefits of using insulin pumps over other insulin delivery methods, mainly seen by the improvement of quality of life and patients' adherence to doses. Policy-makers and healthcare professionals (HCPs) must be aware of such benefits and should support the wider implementation of this technology in the country by including patients with type 2 diabetes. Results of this study will help to inform healthcare provision and guideline modifications and to provide guidance for new patients using this therapy.

How can lipid nanocarriers improve transdermal delivery of olanzapine?

The development of a transdermal nanocarrier drug delivery system with potential for the treatment of psychiatric disorders, such as schizophrenia and bipolar disorder, is described. Lipid nanocarriers (LN), encompassing various solid:liquid lipid compositions were formulated and assessed as potential nanosystems for transdermal delivery of olanzapine. A previously optimized method of hot high pressure homogenization (HPH) was adopted for the production of the LN, which comprised solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and nanoemulsions (NE). Precirol ® was selected as the solid lipid for progression of studies. SLN exhibited the best performance for transdermal delivery of olanzapine, based on in vitro release and permeation studies, coupled with results from physicochemical characterization of several solid:liquid lipid formulations. Stability tests, performed to give an indication of long-term storage behavior of the formulations, were in good agreement with previous studies for the best choice of solid:liquid lipid ratio. Overall, these findings highlight the SLN-based formulation as promising for the further inclusion in and production of transdermal patches, representing an innovative therapeutic approach.

Altered urothelial ATP signaling in a major subset of human overactive bladder patients with pyuria.

Overactive Bladder (OAB) is an idiopathic condition, characterized by urgency, urinary frequency, and urgency incontinence, in the absence of routinely traceable urinary infection. We have described microscopic pyuria (≥10 wbc/µl) in patients suffering from the worst symptoms. It is established that inflammation is associated with increased ATP release from epithelial cells, and extracellular ATP originating from the urothelium following increased hydrostatic pressure is a mediator of bladder sensation. Here, using bladder biopsy samples, we have investigated urothelial ATP signaling in OAB patients with microscopic pyuria. Basal, but not stretch-evoked, release of ATP was significantly greater from the urothelium of OAB patients with pyuria than from non-OAB patients or OAB patients without pyuria (<10 wbc/µl). Basal ATP release from the urothelium of OAB patients with pyuria was inhibited by the P2 receptor antagonist suramin and abolished by the hemichannel blocker carbenoxolone, which differed from stretch-activated ATP release. Altered P2 receptor expression was evident in the urothelium from pyuric OAB patients. Furthermore, intracellular bacteria were visualized in shed urothelial cells from ∼80% of OAB patients with pyuria. These data suggest that increased ATP release from the urothelium, involving bacterial colonization, may play a role in the heightened symptoms associated with pyuric OAB patients.

Musculin and TCF21 coordinate the maintenance of myogenic regulatory factor expression levels during mouse craniofacial development.

The specification of the skeletal muscle lineage during craniofacial development is dependent on the activity of MYF5 and MYOD, two members of the myogenic regulatory factor family. In the absence of MYF5 or MYOD there is not an overt muscle phenotype, whereas in the double Myf5;MyoD knockout branchiomeric myogenic precursors fail to be specified and skeletal muscle is not formed. The transcriptional regulation of Myf5 is controlled by a multitude of regulatory elements acting at different times and anatomical locations, with at least five operating in the branchial arches. By contrast, only two enhancers have been implicated in the regulation of MyoD. In this work, we characterize an enhancer element that drives Myf5 expression in the branchial arches from 9.5 days post-coitum and show that its activity in the context of the entire locus is dependent on two highly conserved E-boxes. These binding sites are required in a subset of Myf5-expressing cells including both progenitors and those which have entered the myogenic pathway. The correct levels of expression of Myf5 and MyoD result from activation by musculin and TCF21 through direct binding to specific enhancers. Consistent with this, we show that in the absence of musculin the timing of activation of Myf5 and MyoD is not affected but the expression levels are significantly reduced. Importantly, normal levels of Myf5 expression are restored at later stages, which might explain the absence of particular muscles in the Msc;Tcf21 double-knockout mice.

Design and development of novel mitochondrial targeted nanocarriers, DQAsomes for curcumin inhalation.

Curcumin has potent antioxidant and anti-inflammatory properties but poor absorption following oral administration owing to its low aqueous solubility. Development of novel formulations to improve its in vivo efficacy is therefore challenging. In this study, formulation of curcumin-loaded DQAsomes (vesicles formed from the amphiphile, dequalinium) for pulmonary delivery is presented for the first time. The vesicles demonstrated mean hydrodynamic diameters between 170 and 200 nm, with a ζ potential of approximately +50 mV, high drug loading (up to 61%) and encapsulation efficiency (90%), resulting in enhanced curcumin aqueous solubility. Curcumin encapsulation in DQAsomes in the amorphous state was confirmed by X-ray diffraction and differential scanning calorimetry analysis. The existence of hydrogen bonds and cation-π interaction between curcumin and vesicle building blocks, namely dequalinium molecules, were shown in lyophilized DQAsomes using FT-IR analysis. Encapsulation of curcumin in DQAsomes enhanced the antioxidant activity of curcumin compared to free curcumin. DQAsome dispersion was successfully nebulized with the majority of the delivered dose deposited in the second stage of the twin-stage impinger. The vesicles showed potential for mitochondrial targeting. Curcumin-loaded DQAsomes thus represent a promising inhalation formulation with improved stability characteristics and mitochondrial targeting ability, indicating a novel approach for efficient curcumin delivery for effective treatment of acute lung injury and the rationale for future in vivo studies.

Stability of parenteral nanoemulsions loaded with paclitaxel: the influence of lipid phase composition, drug concentration and storage temperature.

Paclitaxel was loaded into licensed parenteral nutrition nanoemulsions (Clinoleic® and Intralipid®) using bath sonication, and the stability of the formulations was investigated following storage for two weeks at room temperature or at 4 °C. In general, Clinoleic droplets were smaller than Intralipid droplets, being around 255 and 285 nm, respectively, for blank and freshly loaded emulsions. Regardless of storage temperature, the Clinoleic exhibited a very slight or no increase in droplet size upon storage, whilst the droplet size of the Intralipid emulsion increased significantly. The droplet size of both emulsions was minimally affected by paclitaxel concentration within the range of 0, 1, 3 and 6 mg/ml. The pH of both emulsions markedly decreased upon storage at room temperature, which was possibly attributed to the production of fatty acids resulting from phospholipid hydrolysis. However, at 4 °C, the pH of Clinoleic emulsion was unaffected by storage or paclitaxel concentration while the Intralipid emulsion demonstrated a trend for pH reduction. Both nanoemulsions had a negative zeta potential, with the Clinoleic formulations having the highest charge, possibly explaining the better size stability of this emulsion. Overall, this study has shown that paclitaxel was successfully loaded into clinically licensed parenteral emulsions and that Clinoleic showed greater stability than the Intralipid.

Fetal testosterone influences sexually dimorphic gray matter in the human brain.

In nonhuman species, testosterone is known to have permanent organizing effects early in life that predict later expression of sex differences in brain and behavior. However, in humans, it is still unknown whether such mechanisms have organizing effects on neural sexual dimorphism. In human males, we show that variation in fetal testosterone (FT) predicts later local gray matter volume of specific brain regions in a direction that is congruent with sexual dimorphism observed in a large independent sample of age-matched males and females from the NIH Pediatric MRI Data Repository. Right temporoparietal junction/posterior superior temporal sulcus (RTPJ/pSTS), planum temporale/parietal operculum (PT/PO), and posterior lateral orbitofrontal cortex (plOFC) had local gray matter volume that was both sexually dimorphic and predicted in a congruent direction by FT. That is, gray matter volume in RTPJ/pSTS was greater for males compared to females and was positively predicted by FT. Conversely, gray matter volume in PT/PO and plOFC was greater in females compared to males and was negatively predicted by FT. Subregions of both amygdala and hypothalamus were also sexually dimorphic in the direction of Male > Female, but were not predicted by FT. However, FT positively predicted gray matter volume of a non-sexually dimorphic subregion of the amygdala. These results bridge a long-standing gap between human and nonhuman species by showing that FT acts as an organizing mechanism for the development of regional sexual dimorphism in the human brain.

A novel mass spectrometry-based method for determining insulin-like growth factor 1: assessment in a cohort of subjects with newly diagnosed acromegaly.

OBJECTIVE: To develop an alternative method to immunoassay for the quantitative analysis of insulin-like growth factor 1 (IGF-1) using a mass spectrometry (MS)-based approach. STUDY DESIGN AND PATIENTS: A stable isotope dilution Ultra High Performance Liquid Chromatography tandem MS (uHPLC-MS/MS)-based method for the quantification of IGF-1 was developed. The method employed Selected Reaction Monitoring (SRM) of two tryptic peptides derived from IGF-1, and utilised solid phase extraction for enrichment of the peptide fraction containing IGF-1 rather than immunocapture, so was less susceptible to assay interference. Plasma samples from 25 consecutive unselected patients with newly diagnosed acromegaly, collected both before and after 24 weeks of primary medical therapy with Lanreotide Autogel(®), were analysed by a widely used commercial immunoassay (Siemens Immulite 2000(®)) and by uHPLC-MS/MS. RESULTS: The uHPLC-MS/MS method showed good correlation with the immunoassay over a wide range of IGF-1 concentrations. The Passing and Bablock regression was: uHPLC-MS/MS (nmol/l) = 1.37 (95% confidence interval: 1.26-1.46) × immunoassay (nmol/l) + 3.14 (95% confidence interval: -2.71 to 10.32). Six patients had discordant growth hormone (GH) and IGF-1 levels following primary medical therapy, and in all six the immunoassay and uHPLC-MS/MS platforms returned comparable results. The method was not affected by concentrations of IGFBP3 up to 12,500 ng/ml. CONCLUSIONS: uHPLC-MS/MS offers an independent method for determining/validating IGF-1 in subjects with acromegaly. Further studies, including the establishment of age- and sex-matched reference ranges and calibration to the new International IGF-1 standard IS 02/254, are now required to allow its introduction in to routine clinical use.

Valuing indigenous quality of life: A review of preference-based quality of life instruments and elicitation techniques with global older indigenous populations.

Indigenous perspectives of quality of life (QoL) are different to that of non-Indigenous populations. Determining how to identify and value what is important to QoL for people from diverse cultural backgrounds is crucial for assessing effective outcomes for quality assessment and health economic evaluation to guide evidence-based decision making. This is particularly important for older Indigenous people who have complex care and support needs within health and aged-care systems. This scoping review aims to assess the existing literature in this field by firstly identifying preference based instruments that have been applied with older Indigenous peoples and secondly, exploring the extent to which existing preference based instruments applied with older Indigenous peoples encompass older Indigenous peoples QoL perspectives in their design and application. The inclusion criteria for the review were studies using preference based QoL instruments with an Indigenous population where the cohort was aged 50 years or over. This resulted in the critical analysis of 12 studies. The review identified that preference based QoL instruments have rarely been applied to date with older Indigenous populations with most instruments found to be designed for non-Indigenous adults. Typically, instruments have not incorporated Indigenous worldviews of QoL into either the content of the descriptive system or the elicitation techniques and corresponding value sets generated. To encapsulate Indigenous cultural perspectives accurately in economic evaluation, further research is required as to how QoL domains in preference based instruments for Indigenous peoples can be reflective of Indigenous perspectives. It is imperative that the QoL preferences of older Indigenous peoples are adequately captured within preference based QoL instruments applied with this population.