Transcriptional profiling reveals monocyte-related macrophages phenotypically resembling DC in human intestine.

The tissue dendritic cell (DC) compartment is heterogeneous, and the ontogeny and functional specialization of human tissue conventional DC (cDC) subsets and their relationship with monocytes is unresolved. Here we identify monocyte-related CSF1R+Flt3- antigen presenting cells (APCs) that constitute about half of the cells classically defined as SIRPα+ DCs in the steady-state human small intestine. CSF1R+Flt3- APCs express calprotectin and very low levels of CD14, are transcriptionally related to monocyte-derived cells, and accumulate during inflammation. CSF1R+Flt3- APCs show typical macrophage characteristics functionally distinct from their Flt3+ cDC counterparts: under steady-state conditions they excel at antigen uptake, have a lower migratory potential, and are inefficient activators of naïve T cells. These results have important implications for the understanding of the ontogenetic and functional heterogeneity within human tissue DCs and their relation to the monocyte lineage.

Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Laparoscopic ventral hernia repair: outcomes in primary versus incisional hernias: no effect of defect closure.

PURPOSE: Supposing divergent aetiology, we found it interesting to investigate outcomes between primary (PH) versus incisional (IH) hernias. In addition, we wanted to analyse the effect of defect closure and mesh fixation techniques. METHODS: 37 patients with PH and 70 with IH were enrolled in a prospective cohort-study, treated with laparoscopic ventral hernia repair (LVHR) and randomised to ± transfascial sutures. In addition, we analysed results from a retrospective study with 36 PH and 51 IH patients. Mean follow-up time was 38 months in the prospective study and 27 months in the retrospective study. RESULTS: 35 % of PH's and 10 % of IH's were recurrences after previous suture repair. No late infections or mesh removals occurred. Recurrence rates in the prospective study were 0 vs. 4.3 % (p = 0.55) and the complication rates were 16 vs. 27 % (p = 0.24) in favour of the PH cohort. The IH group had a mesh protrusion rate of 13 vs. 5 % in the PH group (p = 0.32), and significantly (p < 0.01) larger hernias and adhesion score, longer operating time (100 vs. 79 min) and admission time (2.8 vs. 1.6 days). Closure of the hernia defect did not influence rate of seroma, pain at 2 months, protrusion or recurrence. An overall increased complication rate was seen after defect closure (OR 3.42; CI 1.25-9.33). CONCLUSIONS: With PH, in comparison to IH treated with LVHR, no differences were observed regarding recurrence, protrusion or complication rates. Defect closure (raphe), when using absorbable suture, did not benefit long-term outcomes and caused a higher overall complication rate. (ClinicalTrials.gov number: NCT00455299).

Pancreas transplantation with enteroanastomosis to native duodenum poses technical challenges--but offers improved endoscopic access for scheduled biopsies and therapeutic interventions.

To facilitate endoscopic access for rejection surveillance and stenting of the pancreas, we have abandoned the duodenojejunostomy (DJ) in favor of duodenoduodenostomy (DD) in pancreas transplantation (PTx). From September 2012 to September 2013 we performed 40 PTx with DD; 20 solitary-PTx (S-PTx) and 20 simultaneous pancreas and kidney transplantation (SPK). We compared the outcomes with results from 40 PTx-DJ (10 S-PTx and 30 SPK) from the preceding era. The DD-enteroanastomoses were performed successfully. Endoscopic pancreas biopsies (endoscopic ultrasound examination [EUS]) yielded representative material in half of the cases. One exocrine fistula was treated by endoscopic stenting. PTxs-DD were associated with a higher rate of thrombosis compared to PTx-DJ (23% vs. 5%) and reoperations (48% vs. 30%), as well as inferior graft survival (80% vs. 88%). Time on waiting list, HLA A + B mismatches and reoperations were associated with graft loss. Only recipient age remained an independent predictor of patient death in multivariate analysis. PTx-DD showed a higher rate of thrombosis and inferior results, but facilitated a protocol biopsy program by EUS that was feasible and safe. Given that technical difficulties can be solved, the improved endoscopic access might confer long-term benefits, yet this remains to be proven.

Improved patient survival with simultaneous pancreas and kidney transplantation in recipients with diabetic end-stage renal disease.

AIMS/HYPOTHESIS: We aimed to determine whether simultaneous pancreas and kidney (SPK) transplantation would improve patient and kidney graft survival in diabetic end-stage renal disease (ESRD) compared with kidney transplantation alone (KTA). METHODS: Follow-up data were retrieved for all 630 patients with diabetic ESRD who had received SPK or KTA at our centre from 1983 to the end of 2010. Recipients younger than 55 years of age received either an SPK (n = 222) or, if available, a single live donor kidney (LDK; n = 171). Older recipients and recipients with greater comorbidity received a single deceased donor kidney (DDK; n = 237). Survival was analysed by the Kaplan-Meier method and in multivariate Cox regression analysis adjusting for recipient and donor characteristics. RESULTS: Patient survival was superior in SPK compared with both LDK and DDK recipients in univariate analysis. Follow-up time (mean ± SD) after transplantation was 7.1 ± 5.7 years. Median actuarial patient survival was 14.0 years for SPK, 11.5 years for LDK and 6.7 years for DDK recipients. In multivariate analyses including recipient age, sex, treatment modality, time on dialysis and era, SPK transplantation was protective for all-cause mortality compared with both LDK (p = 0.02) and DDK (p = 0.029) transplantation. After the year 2000, overall patient survival improved compared with previous years (HR 0.40, 95% CI 0.30, 0.55; p < 0.001). Pancreas graft survival also improved after 2000, with a 5 year graft survival rate of 78% vs 61% in previous years (1988-1999). CONCLUSIONS/INTERPRETATION: Recipients of SPK transplants have superior patient survival compared with both LDK and DDK recipients, with improved results seen over the last decade.

Targeting risk factors for impaired wound healing and wound complications after kidney transplantation.

BACKGROUND: Because of potent immunosuppression, impaired wound healing and complications are frequent features after kidney transplantation (KTx). OBJECTIVE: To investigate the incidence and nature of impaired wound healing and complications at a single transplantation center in Norway. PATIENTS: Of 226 patients who underwent KTx, 199 (87%) were followed up prospectively for 1 year (2005) via close and meticulous wound inspection. RESULTS: The study revealed a high rate of wound complications (200-250/y) in a high-volume center. Fifty-four patients (27%) experienced prolonged wound healing, defined as gaps, secretions, or wound complications, at 3 to 5 weeks posttransplantation, and 41 patients (21%) had impaired wound healing, defined as gaps, secretions, or wound complications after 5 weeks posttransplantation. In total, 50 patients (25%) required surgical or radiologic reintervention. Complications included lymphocele in 29 patients (14.6%), wound dehiscence in 16 (8.0%), bleeding or hematoma in 10 (5.0%), and infection in 9 (4.5%). Risk factors associated with wound complications included recipient older than 60 years, body mass index greater than 30, hemoglobin concentration less than 10 g/dL, albumin concentration less than 36 g/dL, duration of surgery more than 200 minutes, no subcutaneous sutures, and sirolimus or everolimus therapy. At nominal and logistic regression analysis, recipient older than 60 years, body mass index greater than 30, and no subcutaneous sutures were independent risk factors. CONCLUSION: Risk factor analysis and previous documentation suggest that wound complications might be counteracted using the following measures: subcutaneous sutures, predialysis transplantation, sealing or ligation of lymphatic trunks, prophylactic fenestration, reduction of corticosteroid load, and avoiding sirolimus/everolimus therapy.

Minimally invasive kidney transplantation: the first experience.

Minimally invasive procedures in recent years have gained widespread acceptance. Within the field of transplantation, laparoscopic living donor nephrectomy (LLDN), requiring a 6- to 10-cm incision, is now considered the optimal procedure. According to recent MEDLINE searches, no minimally invasive technique has been reported for kidney transplantation. Considering the rapid evolution of minimally invasive surgery during the last decade, there is little reason to believe that kidney transplantation in future will be excluded from this development. A novel minimally invasive technique for kidney transplantation (MIKT) is presented, restricted to a 7- to 9-cm incision and minimal dissection/tissue trauma. The kidney is meticulously prepared on the back table and placed in a fitted lateral, retroperitoneal pouch. All three anastomoses are performed with the kidney in its final "in situ" position, and ureter reimplantation is done by extravesical technique. Twenty-one patients have been transplanted by MIKT and followed in a prospective manner, along with a matched control group subjected to conventional kidney transplantation. Our results indicate that MIKT may be executed safely and quickly. Beneficial effects on postoperative pain/analgesia, recovery, and complications are suggested by this first MIKT experience. The technical solutions of MIKT are per se not unique. However, the incision is minimal and not larger than the one required for LLDN. Minimally invasive surgery seems particularly attractive in the immunosuppressed population, and even more so with the recent introduction of potent antiproliferative drugs.

Postoperative pain and convalescence in living kidney donors-laparoscopic versus open donor nephrectomy: a randomized study.

The aim of the present study was to compare postoperative pain and convalescence in patients randomized to laparoscopic or open donor surgery in a prospective, controlled trial. The donors were randomly assigned to undergo laparoscopic (n = 63) or open (n = 59) donor nephrectomy. Our end points were amount of administered analgesics in the recovery period, postoperative pain on the second postoperative day and at one month after surgery and duration of sick leave. There was a significant difference in favor of the laparoscopic group regarding administered analgesics on day of surgery (p < 0. 02). No difference was observed between groups regarding self-reported pain on the second postoperative day. One month post donation, significantly fewer donors in the laparoscopic group reported pain (p < 0. 02) or had used analgesics (p < 0.05). The duration of sick leave was significantly shorter in the laparoscopic group (p = 0.01). The laparoscopic group experienced a more rapid convalescence and a shorter period of sick leave. Although immediate postoperative pain can be managed efficiently regardless of procedure, a lower consumption of opioids and incidence of pain in the convalescent period suggest a clinically relevant patient-experienced benefit from a successful laparoscopic procedure.

Calcineurin inhibitor-free immunosuppression in renal allograft recipients with thrombotic microangiopathy/hemolytic uremic syndrome.

Thrombotic microangiopathy (TMA) and hemolytic uremic syndrome (HUS) represent serious threats to kidney allograft recipients. During a 4-year period, among 850 kidney transplantations, seven recipients with primary HUS and seven recipients (eight transplants) with previous or de novo TMA/HUS were identified and given calcineurin inhibitor (CNI)-free immunosuppression by sirolimus (SRL), mycophenolate mofetil and steroids. Thirteen out of 15 transplantations were successful in the long term; resulting in a mean creatinine of 101 mumol/L (16.4 months follow-up). In patients maintained on CNI-free regimen, no TMA/HUS recurrences were observed. A high rate of acute rejections (53%) may indicate insufficient immunosuppressive power and/or a causative relationship between TMA/HUS and rejection. Wound-related complications were abundant (60%), and call for surgical/immunosuppressive countermeasures. Our experience supports the idea that CNI's are major offenders in TMA/HUS induction. Total CNI elimination seems essential, as the nephrotoxic combination CNI + SRL may promote TMA. Features of TMA/HUS should be carefully explored in recurrent 'high responders'.

Should kidneys from older cadaveric donors be age-matched to the recipient?

Persistent shortage of kidneys for transplantation has forced most transplant centers to include procurement and use of kidneys from older donors. It is not clear whether the optimal use of these kidneys involve age-matching to the recipient. The aim of this study was to evaluate the clinical outcome of older cadaveric kidneys (>60 years), transplanted to young recipients (<50 years) and older recipients (>60 years). From 1989 through 2002, 252 first kidney grafts were procured from donors above the age of 60; 149 of the recipients to these grafts were above 60 years and 45 recipients were below 50. Minimum follow-up time was 12 months. Variables for waiting time to transplantation, DR mismatches, PRA, dialysis prior to transplantation, episodes of acute rejection, number of steroid-resistant rejections, creatinine levels, cold ischemia time, and causes of graft loss did not differ between the two groups. There was no significant difference in graft survival for young and older recipients receiving kidney from donors above 60 years of age. Graft survival at 1 year for young recipients was 90% and for older recipients 93% (NS). Five-year graft survival was 72% and 79%, respectively (NS). However, there was a significant positive effect on long-term graft survival if the donor kidney was less than 50 years. From our data, there is no evidence that age-matching of older donors has any beneficial effect on graft survival in kidney transplantation.

The use of specific dental school-taught restorative techniques by practicing clinicians.

In 1995, a survey requesting information about the utilization of certain prosthodontic techniques was mailed to 3,544 graduates of a midwestern dental school. Responses were received from 1,455 alumni, representing a 41 percent return rate. In general, the results are consistent with international and national trends and show significant disparity in the utilization rates of certain procedures between general dentists and prosthodontists, as well as a disconnect between what is taught in the undergraduate dental educational program and what is applied in practice. For example, while prosthodontists typically apply what was taught in their educational program, utilization rates of general dentists for the facebow was 29.64 percent; the custom tray 68.48 percent; border molding 58.67 percent; altered casts 24.10 percent; custom posts 49.29 percent; prefabricated posts 67.54 percent; and semi-adjustable articulators 50.64 percent. While no solutions to this disconnect are offered the authors do pose important questions that must be addressed by the dental educational community.

The effect of rim mandibulectomy configuration and residual segment size on postoperative fracture risk: an in vitro study.

PURPOSE: This study evaluated the effect that size and shape of rim mandibulectomy has on residual mandibular strength and resistance to fracture, with the ultimate goal of improving the use of this technique and establishing a threshold for the application of prophylactic internal fixation. MATERIALS AND METHODS: Ten partially dentate dry human mandibles were mounted in a manner replicating the pterygomasseteric musculature. Unilateral midbody serial rim excisions of increasing size were completed in both a curvilinear and right-angled fashion, and physiologic forces were gradually applied to a level of residual segment fracture. Dimensional measurements were taken of the specimens before and after fracture to understand which factors contributed to failure. RESULTS: On average, a curvilinear excision configuration resisted higher occlusal forces with a smaller residual segment than did the right-angled excision configuration. A residual inferior border thickness of less than 9 mm could not predictably withstand force application within the limits of the experimental model. CONCLUSION: These data support the use of a curvilinear excision configuration for rim mandibulectomies. Reproducibility of the location of the residual segment failure and other consistent residual segment dimensional information have implications regarding the limitations of this technique, beyond which the use of adjunctive support in the form of maxillomandibular fixation or prophylactic internal fixation may be indicated.

MicroCRP: a highly sensitive CRP method applied in the monitoring of renal allograft recipients.

A new ultrasensitive fluoroimmunometric assay for C-reactive protein (CRP), called MicroCRP assay, has a lower detection limit of 0.05 mg/l, and a CV of 7.6% at concentration 0.25 mg/l. The microCRP levels in healthy adults show a skewed distribution, median 0.90 mg/l and mean 1.4 mg/l, with 2.5th and 97.5th percentiles of 0.17 and 4.7 mg/l, respectively, and no gender-related or age differences. Serial microCRP was applied in the monitoring of 37 renal allograft recipients. The operative trauma gave rise to an initial CRP peak, usually on day 2 after transplantation, with a return to preoperative value 1 week after surgery. There were significant CRP elevations (>25%) in all cases of rejections, indicating 100% sensitivity. The microCRP values started to increase about 3 days (range -1 to 9 days) before the rise in creatinine. The microCRP peak tended to be higher in rejection episodes with a vascular component, compared with episodes of cellular rejection (p=0.05). A rise in microCRP at days 7-12 after transplantation seems to predict the risk of rejections later on, and probably reflects the primary immune response to the graft. Recipients without this primary CRP response (only 6 of 37 patients) subsequently had uncomplicated courses. Tracking of values below the traditional lower limit is essential in order to recognize the different CRP peaks. Serial monitoring of microCRP is well suited for clinical use and provides clinical information previously unattainable with other assay systems.

Osteoclast activation and recruitment after application of orthodontic force.

In this study, whole body radioactive cobalt 60 (Co60) irradiation was used in an orthodontic tooth movement model to investigate osteoclast activation and recruitment in adult rats. Seventy-five rats were divided into three groups and were irradiated with Co60 ranging from 10 to 26 Gray. An orthodontic appliance was fitted to each rat 12 days after initiation of irradiation. Identical appliances were fitted on an additional 25 unirradiated rats. Groups of rats were sacrificed 1 week before and on the day of appliance placement as well as 1, 2, 3, 4, or 5 weeks after appliance placement. Histologic sections from decalcified maxillary processes were prepared and osteoclasts were counted. Results showed that regardless of irradiation dosage, osteoclast number did not decrease during the first 3 weeks of orthodontic treatment; animals receiving lower (ie, 10 Gray) total irradiation actually showed a transient increase in the osteoclast number. In addition, regardless of dose in the irradiated rats, the total time osteoclasts were present in the periodontal membrane after orthodontic activation was reduced from 4 to 3 weeks. These findings lead us to hypothesize that osteoclasts involved in appliance-induced remodeling are initially from precursors in the periodontal membrane. During prolonged periods of orthodontic force application, replacement osteoclasts originate from bone marrow precursors. Although an orthodontic bone resorption cycle lasts 4 weeks, the life span of individual osteoclasts is limited to 9 to 10 days. The clinical significance of this finding remains to be elucidated.

The national kidney transplant program in Norway still results in unchanged waiting lists.

1. Of 2,670 patients starting renal replacement therapy for end-stage renal disease in Norway from 1989-1997, 76% were candidates for transplantation. The annual need for transplantations increased from 47 to 64 grafts PMP as the number of elderly patients increased. The national waiting list has remained almost stable during the period from 1989-1997 at levels of 25-30 PMP, but the dialysis population has increased from 57-105 PMP. 2. A total of 1,681 transplants was performed at an annual rate varying between 38 and 46 grafts PMP. The grafts were procured from LDs in 41% and CDs in 59% of cases. Totally 69% of all patients in need were transplanted and 54% of all patients requiring replacement therapy for end-stage renal disease received a transplant. 3. Graft survival rates in recipients of first LD grafts (n = 641) were 91% and 77% at one and 5 years, respectively. One-year graft survival was 97% in HLA-identical grafts (n = 71), 92% in haploidentical grafts (n = 419), 88% in 2 haplotype-mismatched related grafts (n = 43), and 87% in spousal donor grafts (n = 108). 4. Graft survival rates in recipients of first CD grafts (n = 801) were 84% and 65% at one and 5 years, respectively. The rates were 86% and 74% in younger (n = 557) versus 78% and 46% in older (> 65 years) (n = 244) patients. Death with a functioning graft caused approximately 45% and 75% of all graft losses in younger and older patients, respectively. Cardiovascular disease was the major cause of death. 5. A significant beneficial effect of HLA-DR matching was observed in CD grafts performed after 1989, in particular in patients older than age 65.