Protection Against Type 1 Diabetes Upon Coxsackievirus B4 Infection and iNKT-Cell Stimulation: Role of Suppressive Macrophages

Invariant natural killer T (iNKT) cells belong to the innate immune system and exercise a dual role as potent regulators of autoimmunity and participate in responses against different pathogens. They have been shown to prevent type 1 diabetes development and to promote antiviral responses. Many studies in the implication of environmental factors on the etiology of type 1 diabetes have suggested a link between enteroviral infections and the development of this disease. This study of the pancreatropic enterovirus Coxsackievirus B4 (CVB4) shows that although infection accelerated type 1 diabetes development in a subset of proinsulin 2–deficient NOD mice, the activation of iNKT cells by a specific agonist, α-galactosylceramide, at the time of infection inhibited the disease. Diabetes development was associated with the infiltration of pancreatic islets by inflammatory macrophages, producing high levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α and activation of anti-islet T cells. On the contrary, macrophages infiltrating the islets after CVB4 infection and iNKT-cell stimulation expressed a number of suppressive enzymes, among which indoleamine 2,3-dioxygenase was sufficient to inhibit anti-islet T-cell response and to prevent diabetes. This study highlights the critical interaction between virus and the immune system in the acceleration or prevention of type 1 diabetes.Type 1 diabetes is characterized by the destruction of pancreatic islet β-cells by autoreactive CD4 and CD8 T cells, leading to low insulin production and incapacity to regulate blood glucose levels (1). Despite numerous studies, the etiology of type 1 diabetes remains elusive. Besides genetics (2–4), environmental factors such as viral infections have been suggested as triggers of type 1 diabetes (5–7). Most striking of these infections are the type B Coxsackieviruses belonging to the enterovirus genus whose genome and anti-Coxsackievirus antibodies were detected more frequently in the blood of recently diagnosed patients compared with healthy controls (8,9). Besides, enteroviral RNA or enteroviral particles were directly detected in the pancreas of type 1 diabetic patients, whereas they were undetectable in the pancreas of healthy donors (9,10). In a mouse model of type 1 diabetes, Serreze et al. (11) showed that diabetes can develop rapidly after Coxsackievirus B4 (CVB4) infection if mice had an advanced age and sufficient insulitis. Others have reported that inefficient islet β-cell response, viral dose, and replication rate as well as a lack of islet neogenesis could also promote accelerated diabetes development after CVB4 infection (12–14).Natural killer T (NKT) cells are CD1d-restricted, nonconventional T cells recognizing self and exogenous glycolipids. Most NKT cells express an invariant T-cell receptor α chain, Vα14-Jα18 (Vα14) in mice and Vα24-Jα18 in humans, and are named invariant NKT (iNKT) cells. They can promptly secrete copious amounts of interferon-γ (IFN-γ) and interleukin (IL)-4 and provide maturation signals to dendritic cells (DCs) and lymphocytes, thereby contributing to both innate and acquired immunity (15,16). iNKT cells are potent regulatory cells that can inhibit autoimmunity and promote immune responses against pathogens (1,17). Diabetes can be prevented in NOD mice by increasing iNKT cell numbers and by iNKT-cell stimulation with exogenous ligands such as α-galactosylceramide (αGalCer) (15,18,19). NOD mice protected from diabetes by iNKT cells have weak T helper 1 anti-islet β-cell responses (20). Indeed, iNKT cells can impair the differentiation of anti-islet CD4 and CD8 T cells, which become hyporesponsive or anergic (21). Contrary to their suppressive role in type 1 diabetes, iNKT cells can enhance immune responses to pathogens such as parasites, bacteria, and viruses (22,23).Our previous studies conducted in a murine model of type 1 diabetes with lymphocytic choriomeningitis virus infection revealed that iNKT cells could promote systemic antiviral CD8 T-cell responses while inhibiting deleterious anti-islet T-cell responses, thereby preventing type 1 diabetes (24,25). In the present study, we investigated the role of iNKT cells after CVB4 infection, revealing that diabetes development following CVB4 infection is associated with the infiltration of inflammatory macrophages into the pancreatic islets with subsequent activation of anti-islet T cells. However, the activation of iNKT cells during CVB4 infection results in the infiltration of suppressive macrophages into pancreatic islets. Indoleamine 2,3-dioxygenase (IDO) expressed by these macrophages was critical for the inhibition of diabetes development.     

Hip arthroplasty in failed intertrochanteric fractures in elderly

Background:

Failed intertrochanteric fractures in elderly patients are surgical challenge with limited options. Hip arthroplasty is a good salvage procedure even though it involves technical issues such as implant removal, bone loss, poor bone quality, trochanteric nonunion and difficulty of surgical exposure.

Materials and Methods:

30 patients of failed intertrochanteric fractures where hip arthroplasty was done between May 2008 and December 2011 were included in study. 13 were males and 17 were females with average age of 67.3 years. There were 2 cemented bipolar arthroplasties, 19 uncemented bipolar, 4 cemented total hip arthroplasty and 5 uncemented total hip arthroplasties. 16 patients had a trochanteric nonunion, which was treated by tension band principles. Total hip was considered where there was acetabular damage due to the penetration of implant.

Results:

The average followup was 20 months (range 6-48 months). Patients were followed up from 6 to 48 months with average followup of 20 months. None of the patients were lost to followup. There was no dislocation. All patients were ambulatory at the final followup.

Conclusion:

A predictable functional outcome can be achieved by hip arthroplasty in elderly patients with failed intertrochanteric fractures. Though technically demanding, properly performed hip arthroplasty can be a good salvage option for this patient group.     

Effects of benzalkonium chloride treatment on the intramural innervation of the upper urinary tract

OBJECTIVE: To establish a model for investigating the pathophysiology of pelvi-ureteric junction (PUJ) obstruction, using benzalkonium chloride (BCI) treatment of the upper urinary tract of rabbits, and thus further elucidate the pathophysiology of PUJ obstruction, the most common urinary tract obstruction in children. MATERIALS AND METHODS: Although various histological abnormalities have been described, PUJ obstruction may be functional. Defective innervation in PUJ has been suggested to be a major factor in the failure to transmit peristaltic waves across the PUJ. Previously established animal models of hydronephrosis deal mostly with surgical obstruction of the PUJ, which does not correlate with human congenital hydronephrosis. BCl has been used to ablate selectively neurones of the gastrointestinal myenteric plexus, which generated spastic segments with impaired peristalsis. Thus 12 rabbits were treated with BCl at the PUJ; the right upper urinary tract was dissected extraperitoneally and treated with a local application of 0.1% or 0.5% BCl (six each) for 15 min. The controls were four sham-operated animals treated with saline. The animals were assessed by intravenous urography (IVU) at 4 and 8 weeks after treatment, after which the animals were killed, the upper urinary tracts removed and whole-mounts prepared. Acetylcholinesterase (AChE) histochemistry, and neurofilament and tyrosine hydroxylase (TH) single-enzyme immunohistochemistry were used to detect the intrinsic innervation. RESULTS: None of the animals had hydronephrosis on the IVU or at death. AChE histochemistry, TH and neurofilament immunohistochemistry showed no or very few nerve fibres within the BCl-treated PUJs in both (0.1% and 0.5%) groups. After saline treatment there was normal development of the neuronal plexus within the submucosal, muscular and adventitial layers of the upper urinary tract. CONCLUSION: These results suggest that treatment with BCl is useful for ablating the intrinsic innervation in the upper urinary tract. Defective intrinsic innervation of the upper urinary tract did not lead to clinically or radiologically evident hydronephrosis. Further physiological studies using this model are needed to further elucidate the neuronal and myogenic influence on the development of PUJ obstruction.     

Is primary endoscopic puncture of ureterocele a long-term effective procedure?

Background/Purpose: For more than a decade, endoscopic puncture of ureterocele has been recommended as an initial and, in the majority of the patients, as a definitive procedure. This study evaluates the long-term effectiveness of primary endoscopic puncture of ureterocele. Methods: Over the last 18 years (1984 through 2001), 52 patients (median age 3 months) underwent primary endoscopic puncture of ureterocele. The median follow-up was 9 years (6 months to 18 years). Antenatal ultrasound scan detected hydronephrosis and led to the postnatal diagnosis of ureterocele in 12 (23%) children, whereas in the remaining 40 (77%) children the diagnosis was made on investigation for urinary tract infection (UTI). The ureterocele presented as a part of renal duplication in 48 (92%) patients and a single system in 4 (8%). Forty-four (92%) of the patients with duplication presented with non- or poorly functioning upper poles. Vesicoureteric reflux (VUR) was seen in the lower moiety of the ipsilateral kidney in 31 and in 18 of the contralateral kidney comprising 49 renal refluxing units (RRU). Results: Complete decompression of the ureterocele was achieved in 48 (92%) patients after the first endoscopic puncture. Four (8%) patients required a second puncture of ureterocele. Nine (17%) of the 52 patients underwent nephrectomy for a nonfunctioning kidney. Ten (19%) patients required upper pole partial nephrectomy owing to nonfunctioning upper pole. Twenty-nine (59%) of the 49 RRU showed spontaneous resolution of VUR. Sixteen (33%) RRU underwent endoscopic correction of VUR. One required ureteric reimplantation. The remaining 4 (8%) are maintained on prophylactic antibiotics. Five (10%) patients had VUR in the upper pole moieties after ureterocele puncture. Conclusions: Our data suggest that primary endoscopic puncture of ureteroceles is a simple, long-term, effective, and safe procedure avoiding complete reconstruction in the majority of the patients. J Pediatr Surg 38:116-119.     

Lateral retinacular release during primary total knee arthroplasty: effect on outcomes and complications

Intraoperative lateral retinacular release performed during primary total knee arthroplasty (TKA) can improve patellar tracking. This study compares the outcomes of patients who did and did not have lateral retinacular release during primary TKA. One thousand one hundred eight consecutive primary TKAs were reviewed. Lateral release was performed on 314 patients; 794 patients did not undergo release. Comparisons of range of motion, Knee Society Score, and postoperative complications were made between the 2 groups. At an average follow-up of 4.7 years, no statistically significant difference in range of motion, Knee Society Score, or postoperative complications of patella fracture, subluxation, postoperative manipulation, or wound complications was demonstrated. Lateral retinacular release to achieve improved patellar tracking does not compromise the clinical outcomes or complication rate of primary TKA.     

Decision making in primary sacral tumors

Background contextPrimary tumors of the sacrum are extremely rare lesions. Their management is governed by an interplay of complex factors. Appropriate decision making is crucial to obtain the best possible outcome in terms of maximizing disease control while attempting to minimize neurological dysfunction.PurposeOur study presents the results of a group of patients with primary tumors of the sacrum who were surgically treated by the same multidisciplinary team at a specialist oncology center over a relatively short period of time (5 years).Study design/settingPatients were identified by a retrospective review from a prospectively maintained database.Patient sampleBetween January 2000 and December 2005, 17 primary sacral tumors were surgically treated at our institution, a referral center for oncology.Outcome measuresWe evaluated the outcome in terms of local disease control, residual neurological dysfunction, and complications as a result of surgical intervention.MethodsThere were 12 males and 5 females. The diagnosis included chordoma in six patients, giant cell tumor in seven patients, aneurysmal bone cyst in two patients, and a chondrosarcoma and an osteoblastoma in one patient each. Sixteen of these patients were analyzed. Four lesions had their upper extent at S1, six lesions had their upper extent at S2, four lesions had their upper extent at S3, and two lesions were below S3. Ten cases were treated with wide excision and underwent partial sacral amputations. Five cases had a midline sacral amputation through S1, three through S2, and two through S3. Six benign lesions were treated with curettage. None of the patients received chemotherapy. Four cases received postoperative radiation. The follow-up duration ranged from 18 to 44 months with a mean of 31 months.ResultsNone of the six patients who presented with loss of bladder and bowel control regained it after surgery. Of the 10 patients who had intact bladder and bowel control preoperatively only 4 retained bladder and bowel control postoperatively. Of the six patients who lost bladder and bowel control postoperatively, four patients had a wide excision where bilateral S2 roots were sacrificed. The other two cases in whom the disease extended up to S1 had curettage. Local recurrence occurred in 4 of the 10 lesions treated with wide excision. All the patients who had inadequate margins recurred. Local recurrence occurred in two of the six lesions treated with curettage. Three of the four cases who received postoperative irradiation developed recurrence. Our wound complication rate was 13%.ConclusionWide resection with adequate margins gives the best chance of local control and should be the surgery of choice for all malignant primary sacral tumors and in benign lesions involving lower segments when preservation of both S3 roots is possible. Intralesional curettage has a higher risk of local recurrence without providing the certainty of retaining neurological function. To retain bladder and bowel control and minimize neurological dysfunction, it may be worthwhile managing benign sacral tumors that extend above S3 with serial embolization. The administration of parentral bisphosphonates may prove beneficial in cases of giant cell tumor managed with serial embolization.     

Nifedipine attenuates the intraocular pressure response to intubation following succinylcholine

Forty patients without eye disease, undergoing elective nonophthalmic surgery, were studied to evaluate the efficacy of sublingual nifedipine in attenuating the intraocular pressure response to succinylcholine administration, laryngoscopy and intubation. The patients were randomly given either nifedipine 10 mg or placebo sublingually 20 minutes before induction of anaesthesia. Intraocular pressure (IOP) and systolic blood pressure (SBP) were recorded before and after induction of anaesthesia. The IOP response to succinylcholine administration, laryngoscopy and intubation was significantly less in patients receiving nifedipine (P > 0.01). The mean maximum rise in IOP above basal level at one minute postintubation was 7.82 mmHg in the control group compared with 0.15 mmHg in the nifedipine pretreated group. These results suggest that sublingual nifedipine is effective in attenuating the IOP response after succinylcholine administration, laryngoscopy and intubation.     

Low-dose mitomycin C as a prophylaxis for corneal haze in myopic surface ablation

PURPOSE: To evaluate the efficacy of low-dose (0.002%) mitomycin C (MMC) vs no prophylactic MMC (control) in reducing corneal haze after surface laser ablation. DESIGN: Two-year retrospective follow-up study performed in Jaipur, India. METHODS: Ninety-two eyes with no MMC application and 83 eyes with 0.002% MMC application during laser epithelial keratomileusis (LASEK) were analyzed in a retrospective chart review with one month, two months, three months, six months, one year, and two years of postoperative follow-up. Postoperative haze, visual acuity, and efficacy ratio (EFFR) then were analyzed statistically. RESULTS: The no-dose MMC and low-dose MMC groups were statistically similar except for a thinner corneal pachymetry (P < .001), higher spherical equivalent error (P = .006), and smaller ablation zone (P = .009) in eyes not treated with MMC when subjected to univariate analysis. Multivariate analysis was used to overcome the preoperative statistical differences among the two groups. Eyes treated with low-dose MMC (0.002%) demonstrated statistically less haze at all postoperative time points and in each myopic subgroup (P < .001). The postoperative uncorrected visual acuity (UCVA) and EFFR, however, showed no difference between the groups, except for better EFFR with MMC at one month (P < .001) and two months (P = .034). CONCLUSIONS: Low-dose MMC (0.002%) in eyes after LASEK results in less corneal haze than in eyes not receiving this agent. Concerns regarding the potential toxicity of MMC make a 10-fold less concentration more desirable in refractive surgery. Further comparative study of low- vs higher-dose MMC is recommended to characterize its clinical benefit fully.