Characterization of in vitro antimurine thymocyte globulin-induced regulatory T cells that inhibit graft-versus-host disease in vivo

Antithymocyte/antilymphocyte globulins are polyclonal antihuman T-cell antibodies used clinically to treat acute transplant rejection. These reagents deplete T cells, but a rabbit antihuman thymocyte globulin has also been shown to induce regulatory T cells in vitro. To examine whether antithymocyte globulin-induced regulatory cells might be functional in vivo, we generated a corresponding rabbit antimurine thymocyte globulin (mATG) and tested its ability to induce regulatory cells in vitro and whether those cells can inhibit acute graft-versus-host disease (GVHD) in vivo upon adoptive transfer. In vitro, mATG induces a population of CD4(+)CD25(+) T cells that express several cell surface molecules representative of regulatory T cells. These cells do not express Foxp3 at either the protein or mRNA level, but do show suppressive function both in vitro and in vivo when adoptively transferred into a model of GVHD. These results demonstrate that in a murine system, antithymocyte globulin induces cells with suppressive activity that also function in vivo to protect against acute GVHD. Thus, in both murine and human systems, antithymocyte globulins not only deplete T cells, but also appear to generate regulatory cells. The in vitro generation of regulatory cells by anti-thymocyte globulins could provide ad-ditional therapeutic modalities for immune-mediated disease.     

Retrospective Analysis of Ponticulus Posticus in Indian Orthodontic Patients-A Lateral Cephalometric Study

Background

The lateral cephalogram is the most common diagnostic radiograph used in clinical orthodontics. Significant cervical spine pathology can be detected on the routine lateral cephalogram. The aim of this study is to sensitize clinicians for examining the cervical area of lateral cephalogram carefully and thus record anatomical variations.

Materials and Methods

The presence and types of ponticuli posticus were investigated on 650 lateral cephalograms which were randomly selected from archived records at AECS Maaruti College of Dental Sciences & Research Centre, Bangalore

Results

The prevalence rate of Ponticulus Posticus in our study was found to be 11.1%. Though there was slight female predominance of 11.7% as compared to 10.4% in males, difference was not statistically significant.

Conclusion

Ponticulus posticus is a common anomaly in the Indian population. If any such anomaly is detected or suspected, it must be documented in the patient''s health record and specialist consultation must be sought. The lateral cephalogram must thus be considered as one of the baseline screening tool for detecting anomalies and pathology in the cervical spine region.     

Neuroblastoma: Outcome over a 14 year period from a tertiary care referral centre in India

Purpose

To evaluate the outcome of children with neuroblastoma (NB) from a tertiary care referral centre in India.

Method

All children with NB registered from October 1996 through July 2009 were included in the study. INSS was used for staging. All children included in the study received chemotherapy and radiation therapy appropriate for stage. Tumor resection was done when feasible. The final outcome was overall survival and it was categorized as Complete Response (CR), Partial Response (PR); No Response (NR) and Progressive Disease (PD). Analysis of three-year overall survival was done using Kaplan Meier method and Log Rank test of significance. Multivariate analysis for significance of age, site and stage was performed.

Results

144 children in the age range of 1–132 months (median 36) were enrolled. Only 38 (26.4%) children were below 12 months. 112 (77.8%) of the tumors were abdominal and 32 (22.2%) were extra-abdominal. Stage distribution was 1 + 2 in 6 (4.2%); 3 in 58 (40.3%); 4 in 68 (47.2%); 4 s in 12 (8.3%). 83 (57.6%) underwent gross complete resection. At the time of last follow-up, 100 (69.4%) were alive [60 CR (41.7%); 33 PR; 7 PD/NR] and 44 (30.6%) were dead [1CR; 11PR; 32 PD/NR]. The three-year OS was 60.7% [95 CI 50.4–69.5]. The OS was 69.7% for those < 12 months of age [95 CI 51.8–82.0] and CR was achieved in 57.9%, while for those > 12 months the OS was 55.3% [95 CI 42.2–66.6] and CR was achieved in 35.8% (p = 0.73). All 6 (100%) patients with Stage 1 and Stage 2 disease were alive and disease free. The OS was 71.5% for Stage 3[95 CI 55.3–82.7] and CR was achieved in 56.9%, while for Stage 4 the OS was 35.7%[95 CI 19.3–52.4] and CR was achieved in 17.6% (p = 0.001). The OS was 83.3% for 4 s [95 CI 48.2–95.6] and CR was achieved in 75%.

Conclusion

All the six children with Stage 1 & 2 achieved CR and were alive, while 57% of Stage 3 could achieve CR and had an OS of 71.5%. The OS (35.7%) and CR (17.6%) for Stage 4 were significantly less (p = 0.001).     

Anti-HBs response to hepatitis B immunoglobulin prophylaxis in liver transplant recipients

Background

Hepatitis B virus (HBV) recurrence after a liver transplant (LT) is a global issue. Several strategies have been adopted to prevent this recurrence. Most strategies recommend a combination of hepatitis B immunoglobulin (HBIG) and or nucleos(t)ide analogue.

Aim of the Study

The aim of the study is to determine the anti-HBs response to HBIG among Indian patients who had undetectable pre-transplant HBV DNA.

Methods

Seven adult HBV-related LT recipients of Indian origin with low pre-transplant HBV titres who had a liver transplant between August 2009 and June 2012 were included in the study. The protocol followed for post-liver transplant HBIG dose was titrated to achieve an anti-HBs titre of at least 100 IU/L. All recipients were on entecavir. Anti-HBs titre, and HBsAg status was checked at regular intervals. A retrospective analysis of the anti-HBs response to a loading and maintenance dose of HBIG was done.

Results

Seven adult HBV-related LT recipients on post-transplant prophylaxis with HBIG and nucleoside analogue (entecavir) fulfilled the criteria for the study. The median anti-HBs response to the anhepatic and loading dose of HBIG was high at 555 IU/L. In two, the response was less than 100 IU/L. The median dose of HBIG reduced at end of 1 month to 800 IU, and the median titre was 223 IU/L. For the next 11 months, the median requirement of HBIG was 3,000 and 4,000 IU, and the titre was low at 53.8 and 60.9 IU/L at end of 6 and 12 months, respectively.

Conclusions

The anti-HBs response to HBIG was variable, and titres even below 100 IU/L did not result in HBV recurrence when HBIG was given in combination with entecavir.     

Endoscopic transmural necrosectomy for walled-off pancreatic necrosis: A systematic review and meta-analysis

BACKGROUND:

Endoscopic transmural necrosectomy (ETN) is emerging as a viable treatment option for walled-off pancreatic necrosis. This NOTES-type procedure is significantly less invasive than an extensive surgical debridement; however, published data regarding the success of ETN in treating pancreatic necrosis have varied.

OBJECTIVE:

To evaluate the published medical literature to determine the success of treating walled-off pancreatic necrosis with ETN.

METHODS:

Studies using ETN as a primary mode of therapy to treat organized pancreatic necrosis were selected. Success was defined as resolution of the necrotic cavity proven by radiology. Articles were searched in Medline, PubMed, Ovid journals, CINAH, old Medline, Medline nonindexed citations and the Cochrane controlled trials registry. The summary estimates were expressed as pooled proportions. First, the individual study proportions were transformed into a quantity using Freeman-Tukey variant of the arcsine square root transformed proportion. The pooled proportion was calculated as the back-transform of the weighted mean of the transformed proportions, using inverse arcsine variance weights for the fixed-effects model and DerSimonian-Laird weights for the random-effects model. Publication bias was calculated using the Begg-Mazumdar and Harbord bias estimators.

RESULTS:

The initial search identified 920 reference articles, of which 129 relevant articles were selected and reviewed. Data were extracted from eight studies (n=233) that met the inclusion criteria. Organization of pancreatic necrosis was determined by computed tomography scan in all of the studies. The mean time of ETN after onset of acute pancreatitis/abdominal pain was seven weeks. The weighted mean size of the necrotic cavity was 12.87 cm (95% CI 10.54 cm to 15.20 cm). The weighted mean number of endoscopic procedures needed to resolve the necrotic cavity was 4.09 (95% CI 2.31 to 5.87). Pooled proportion of successful resolution of pancreatic necrosis using ETN was 81.84% (95% CI 76.73% to 86.44%). The pooled proportion of recurrence in the form of necrotic cavity or pseudocyst after ETN was 10.88% (95% CI 7.27% to 15.11%). Complications were noted in 21.33% (95% CI 16.40% to 26.72%) of patients and included bleeding, sepsis and perforation. The weighted mean number of days in hospital after ETN was 32.85 days (95% CI 10.50 to 55.20 days). For pancreatic necrosis that did not resolve, surgery had to be performed in 12.98% (95% CI 9.05% to 17.51%) of patients. The fixed-effect model was used to report all of the pooled proportions. Estimates calculated using fixedand random-effects models were similar. Test of heterogeneity yielded P>0.10, indicating that the studies could be combined. The publication bias calculated using Begg-Mazumdar bias indicator yielded a Kendall’s tau b value of −0.07 (P=0.72) and the same using Harbord bias indicator gave a value of 0.33 (95% CI −1.35 to 2.01; P=0.60). Both of these indicators show that there was no publication bias.

CONCLUSION:

The present meta-analysis showed that ETN is safe and effective at treating patients with symptomatic walled-off necrosis. ETN offers the advantage of minimally invasive endoscopic treatment without transabdominal surgery; however, better techniques and equipment are still needed to improve procedural efficiency. Decisions to perform ETN should be made by advanced endoscopists in collaboration with a multidisciplinary team with the facilities and personnel to manage these complex patients.     

Icicle sign: autoimmune pancreatitis

Abdominal Radiology -     

Renal pyelic fusion with crossed solitary ureter: Case report and review of literature

Renal fusion anomalies are detected incidentally on imaging, with horseshoe kidney being the most common followed by crossed renal ectopia. We report a rare congenital anomaly of renal pyelic fusion with a solitary ureter. Both the renal units were in the normal position and location. This rare anomaly was associated with lumbar vertebral defects, neurogenic bladder, vesico‐ureteric reflux, upper tract dilatation and recurrent urinary tract infections.     

Targeting stents with local delivery of paclitaxel-loaded magnetic nanoparticles using uniform fields

The use of stents for vascular disease has resulted in a paradigm shift with significant improvement in therapeutic outcomes. Polymer-coated drug-eluting stents (DES) have also significantly reduced the incidence of reobstruction post stenting, a disorder termed in-stent restenosis. However, the current DESs lack the capacity for adjustment of the drug dose and release kinetics to the disease status of the treated vessel. We hypothesized that these limitations can be addressed by a strategy combining magnetic targeting via a uniform field-induced magnetization effect and a biocompatible magnetic nanoparticle (MNP) formulation designed for efficient entrapment and delivery of paclitaxel (PTX). Magnetic treatment of cultured arterial smooth muscle cells with PTX-loaded MNPs caused significant cell growth inhibition, which was not observed under nonmagnetic conditions. In agreement with the results of mathematical modeling, significantly higher localization rates of locally delivered MNPs to stented arteries were achieved with uniform-field–controlled targeting compared to nonmagnetic controls in the rat carotid stenting model. The arterial tissue levels of stent-targeted MNPs remained 4- to 10-fold higher in magnetically treated animals vs. control over 5 days post delivery. The enhanced retention of MNPs at target sites due to the uniform field-induced magnetization effect resulted in a significant inhibition of in-stent restenosis with a relatively low dose of MNP-encapsulated PTX (7.5 μg PTX/stent). Thus, this study demonstrates the feasibility of site-specific drug delivery to implanted magnetizable stents by uniform field-controlled targeting of MNPs with efficacy for in-stent restenosis.     

Co-existing fractures of the proximal humerus and humeral shaft without shoulder dislocation – a rare injury

Multiple fractures of the humerus are a rare injury and usually associated with high-energy trauma. We report an unusual injury with co-existing fractures of the proximal humerus and humeral shaft without shoulder dislocation. We discuss our experience in the diagnosis and treatment of a 39-year-old man with co-existing fractures of proximal humerus and ipsilateral humeral shaft with radial nerve deficit. He was successfully managed with open reduction and fixation of the fractures. At follow-up 1 year after injury, he is back at work and has a good range of shoulder movements. The radial nerve injury is showing signs of recovery. In high-energy trauma to the shoulder, unusual fracture patterns with associated neurovascular deficits may be seen and this case report describes our experience with one such rare injury.