Primary-gaze diplopia in patients with thyroid-related orbitopathy undergoing deep lateral orbital decompression with intraconal fat debulking: a retrospective analysis of treatment outcome.

Our goal was to investigate the incidence of postoperative primary gaze diplopia in patients with thyroid-related orbitopathy (TRO) undergoing deep lateral wall orbital decompression surgery with intraconal fat debulking in the Jules Stein Eye Institute over a period of 4(1/4) years. Overall 201 orbital decompression surgeries were performed in 116 patients (23 males, 93 females). All surgeries were performed by two of the authors (R.A.G. and J.D.M.) and in the noninflammatory phase of the disease. Exophthalmos decreased by an average of 3.4 +/- 2.7 mm from 23.8 +/- 3.2 mm (17-31) to 20.4 +/- 2.5 mm (14-29), p < 0.001, 95% confidence interval (CI) (3.0:3.8). 31% of patients had preoperative primary gaze diplopia and 28.4% had postoperative primary gaze diplopia. Thirty (83%) of the 36 patients with preoperative diplopia had also postoperative diplopia; 6 (16.7%) of the 36 patients had improvement in diplopia following deep lateral wall decompression. Of the 80 (69%) of patients without preoperative double vision 3 developed postoperative double vision in primary gaze (2.6% of all patients). These 3 patients were older (56 versus 46 years, p = 0.047), had more limitation in ocular movements (p = 0.017) and achieved more decrease in proptosis with surgery (6 versus 3.1 mm, p = 0.024). No complications were associated with orbital decompression. In conclusion deep lateral wall orbital decompression surgery with intraconal fat debulking is associated with a low rate (2.6%) of new-onset primary gaze diplopia. Some patients (5.2%) with preoperative diplopia actually had improvement in diplopia postoperatively. This surgery is effective in reduction of congestion and exophthalmos, and is not associated with detrimental effects on visual acuity.     

Increased efficiency of retroviral-mediated gene transfer and expression in primate bone marrow progenitors after 5-fluorouracil-induced hematopoietic suppression and recovery.

To define conditions for improved efficiency of retroviral-mediated gene transfer and expression in primate progenitor cells, four rhesus monkeys were treated with a 200 mg/kg intravenous bolus of 5-fluorouracil (5-FU). The kinetics of hematopoietic suppression and recovery were assessed in peripheral blood, bone marrow mononuclear cells, and bone marrow cells fractionated in an albumin density gradient. Bone marrow mononuclear cells were transduced with N2, a retroviral vector carrying the bacterial neomycin phosphotransferase gene (NPT), which confers resistance to the otherwise toxic neomycin analogue, G418. Circulating colony-forming units-granulocyte-macrophage (CFU-GM) disappeared at 2 days. CFU-GM, transducible CFU-GM, CD34+ cells, and the percent of cells in cycle decreased at 3 days in unfractionated bone marrow cells and in a light density population known to be enriched for these progenitors and for stem cells. NPT activity in the light-density fraction, marginally detectable before treatment, disappeared at 3 days as well. At day 7 the CFU-GM plating efficiency, the CD34+ cell content, and the percentage of cells in cell cycle began to increase in the light-density fraction. The NPT assay became faintly positive again but the CFU-GM were not yet transducible, implying that it was an earlier progenitor population that was dividing and differentiating. By day 15, there was a marked rebound in all of the progenitors measured, and transduction efficiency assessed by G418R CFU-GM and NPT assay rebounded to several times pretreatment levels. The data suggest that CFU-GM are optimally transduced at 15 days but that earlier progenitors are more likely cycling and transducible before 5 days, a time when a gene transfer experiment would probably have the best chance to succeed.     

The evolving art of hematopoietic stem cell transplantation: translational research in post-transplant immune reconstitution and immunosuppression

Immunologic Research - Allogeneic hematopoietic stem cell transplantation (SCT) offers the best chance for cure and/or long-term survival for a broad range of diseases, including many high-risk...     

Embolic protection device use and its association with procedural safety and long‐term outcomes following saphenous vein graft intervention: An analysis from the British Columbia Cardiac registry

• Coronary stents are commonly deployed using high pressure. However, the duration time of balloon inflation during deployment is still to be determined.
• Vallurupalli and coworkers, in this issue of CCI, show that the stent system takes an average of 33 sec to “accommodate” its pressure during in vitro deployment. In patients, the mean stent inflation time to achieve pressure stability was 104 seconds, ranging from 30 to 380 sec.
• These results challenge a rapid inflation/deflation approach for stent deployment. It is suggested that the duration of the inflation might be individualized, in a case‐by‐case approach.
• However, the findings must be interpreted with caution, as they cannot be directly extrapolated to more diverse clinical, angiographic, and interventional scenarios.

     

Pharmacokinetics of LFF571 and Vancomycin in Patients with Moderate Clostridium difficile Infections

Clostridium difficile infection causes diarrheal disease with potentially fatal complications. Although treatments are available, including vancomycin, metronidazole, and fidaxomicin, the recurrence of disease after therapy remains a problem. LFF571 is a novel thiopeptide antibacterial that shows in vitro potency against C. difficile that is comparable to or greater than that of other clinically used antibiotics. Here, we compare the pharmacokinetics (PK) of LFF571 and vancomycin in patients with C. difficile infection as part of an early efficacy study. This multicenter, randomized, evaluator-blind, and active-controlled study evaluated the safety, efficacy, and pharmacokinetics of LFF571 in adults with primary episodes or first relapses of moderate C. difficile infections. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The PK parameters were calculated from drug concentrations measured in serum and fecal samples. The systemic exposure following oral administration of 200 mg of LFF571 four times per day for 10 days in patients with C. difficile infection was limited. The highest LFF571 serum concentration observed was 41.7 ng/ml, whereas the levels in feces at the end of treatment were between 107 and 12,900 μg/g. In comparison, the peak vancomycin level observed in serum was considerably higher, at 2.73 μg/ml; the levels of vancomycin in feces were not measured. Similar to healthy volunteers, patients with C. difficile infections exhibited high fecal concentrations and low serum levels of LFF571. These results are consistent with the retention of LFF571 in the lumen of the gastrointestinal tract. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01232595","term_id":"NCT01232595"}}NCT01232595.)     

Axonal fusion via conduit-based delivery of hydrophilic polymers

Background

Hydrophilic polymers have been shown to improve physiologic recovery following repair of transected nerves with microsutures. Our study was designed to combine hydrophilic polymer therapy with nerve tubes (NT) to enhance polymer delivery to the site of nerve injury.

Methods

Using a rat sciatic nerve injury model, a single transection injury was repaired in an end-to-end fashion with NT + polyethylene glycol (PEG) to NT alone. Compound action potentials (CAPs) were recorded before nerve transection and after repair. Behavioral testing was performed for 5 weeks.

Results

PEG therapy restored CAPS in all, but one, animals, while no CAPS were recorded in animals not receiving PEG. Behavioral nerve function was measured using the standardized functional assessment technique and foot fault asymmetry scores (FF). FF scores were improved for the PEG therapy groups on postoperative days 7, 14, and 21. However, after expected eventual axonal outgrowth, the benefit was less noticeable at days 28 and 35. Immunohistochemistry of the distal axon segments showed an increase number of sensory and motor axons in the NT + PEG group as compared to NT alone.

Conclusion

These data suggest that PEG delivery via a conduit may provide a simple, effective way to fuse severed axons and regain early nerve function. For proximal nerve injuries in large animals, recovery of axonal continuity could dramatically improve outcomes, even if fusion only occurs in a small percentage of axons.     

Feasibility and acceptability of mobile phone short message service as a support for patients receiving antiretroviral therapy in rural Uganda: a cross-sectional study

Introduction

Mobile phone technologies have been promoted to improve adherence to antiretroviral therapy (ART). We studied the receptiveness of patients in a rural Ugandan setting to the use of short messaging service (SMS) communication for such purposes.

Methods

We performed a cross-sectional analysis measuring mobile phone ownership and literacy amongst patients of The AIDS Support Organisation (TASO) in Jinja, Uganda. We performed bivariate and multivariate logistic regression analyses to examine associations between explanatory variables and a composite outcome of being literate and having a mobile phone.

Results

From June 2012 to August 2013, we enrolled 895 participants, of whom 684 (76%) were female. The median age was 44 years. A total of 576 (63%) were both literate and mobile phone users. Of these, 91% (527/ 576) responded favourably to the potential use of SMS for health communication, while only 38.9% (124/319) of others were favourable to the idea (p<0.001). A lower proportion of literate mobile phone users reported optimal adherence to ART (86.4% vs. 90.6%; p=0.007). Male participants (AOR=2.81; 95% CI 1.83–4.30), sub-optimal adherence (AOR=1.76; 95% CI 1.12–2.77), those with waged or salaried employment (AOR=2.35; 95% CI 1.23–4.49), crafts/trade work (AOR=2.38; 95% CI 1.11–5.12), or involved in petty trade (AOR=1.85; 95% CI 1.09–3.13) (in comparison to those with no income) were more likely to report mobile phone ownership and literacy.

Conclusions

In a rural Ugandan setting, we found that over 60% of patients could potentially benefit from a mobile phone-based ART adherence support. However, support for such an intervention was lower for other patients.     

Nitric oxide modulates μ‐opioid receptor function in vitro

Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that develops as a consequence of prolonged hyperglycaemia‐induced injury to the long nerves. Apart from pain, PDN is also characterized by morphine hyposensitivity. Intriguingly, in streptozotocin (STZ)‐induced diabetic rats exhibiting marked morphine hyposensitivity, dietary administration of the nitric oxide (NO) precursor, L‐arginine at 1 g/d, progressively rescued morphine efficacy and potency over an 8‐week treatment period. In earlier work, single bolus doses of the furoxan nitric oxide (NO) donor, PRG150 (3‐methylfuroxan‐4‐carbaldehyde), evoked dose‐dependent pain relief in STZ‐diabetic rats but the efficacious doses were 3‐4 orders of magnitude higher in advanced diabetes than that required in early STZ diabetes. Together, these findings suggested a role for NO in the modulation of μ‐opioid (MOP) receptor signalling. Therefore, the present study was designed to assess a role for NO released from PRG150, in modulating MOP receptor function in vitro. Here, we show an absolute requirement for the MOP receptor, but not the δ‐opioid (DOP) or the κ‐opioid (KOP) receptor, to transduce the cellular effects of PRG150 on forskolin‐stimulated cAMP responses in vitro. PRG150 did not interact with the classical naloxone‐sensitive binding site of the MOP receptor, and its effects on cAMP responses in HEK‐MOP cells were also naloxone‐insensitive. Nevertheless, the inhibitory effects of PRG150 on forskolin‐stimulated cAMP responses in HEK‐MOP cells were dependent upon pertussis toxin (PTX)‐sensitive G_i/o proteins as well as membrane lipid rafts and src kinase. Together, our findings implicate a role for NO in modulating MOP receptor function in vivo.     

Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.