Urinary concentration and tissue messenger RNA expression of monocyte chemoattractant protein-1 as an indicator of the degree of hydronephrotic atrophy in partial ureteral obstruction

PURPOSE: To find a potential prognostic marker of the induction of hydronephrotic atrophy in congenital hydronephrosis we investigated whether the messenger (m)RNA expression and urinary concentration of monocyte chemoattractant protein-1 (MCP-1) correlated with the degree of partial ureteral obstruction, and subsequent hydronephrotic atrophy and interstitial fibrosis. MATERIALS AND METHODS: We created left partial ureteral obstruction in 96 juvenile Wistar rats and complete ureteral obstruction in 18, while 16 underwent sham operation. Depending on excretion of contrast medium into the renal pelvis after 3 days we defined 2 degrees of hydronephrosis. Renal mRNA expression of MCP-1, and renal pelvic and bladder urinary concentrations of MCP-1 were measured after 1, 2 and 3 weeks, and compared with the degree of hydronephrotic atrophy. RESULTS: Grade 1 partial ureteral obstruction resulted in mild histological changes. Grade 2 partial and complete obstruction resulted in significant hydronephrotic atrophy. MCP-1 mRNA expression in the kidney remained unchanged in grade 1 partial obstruction but was moderately increased in grade 2 partial obstruction and clearly over expressed in complete ureteral obstruction. The renal pelvic urinary concentration of MCP-1 was not higher in rats with grade 1 partial obstruction than in sham operated animals but it was significantly increased in those with grade 2 partial and complete obstruction. CONCLUSIONS: mRNA expression and the urinary concentration of MCP-1 correlate with the degree of obstruction and subsequent renal damage in hydronephrosis. They may serve as prognostic markers in children with congenital hydronephrosis.     

Molecular Characterisation of Foot‐and‐Mouth Disease Viruses from Pakistan, 2005–2008

Foot‐and‐mouth disease (FMD), an economically important disease of cloven‐hoofed animals, is endemic in Pakistan where three virus serotypes are present (O, A and Asia 1). Fifty‐eight clinical samples collected between 2005 and 2008 from animals with suspected FMD in various locations in Pakistan were subjected to virus isolation on primary cell culture, antigen ELISA and real‐time RT‐PCR (rRT‐PCR). Viruses were isolated from 32 of these samples and identified as FMDV type O (n = 31) or type A (n = 1). Foot‐and‐mouth disease virus (FMDV) genome was detected in a further 11 samples by real‐time RT‐PCR. Phylogenetic analyses of the VP1 nucleotide sequences showed that all of the type O viruses belonged to the MIDDLE EAST–SOUTH ASIA topotype with the majority belonging to the PanAsia‐2 lineage; a single example of the older PanAsia lineage was identified. The single FMDV type A virus belonged to the ASIA topotype, but did not cluster with known strains that are currently circulating (such as Iran‐05) and was not closely related to other type A viruses from the region. These findings demonstrate the widespread distribution of O‐PanAsia‐2 in Pakistan and the presence of undisclosed novel type A lineages in the region.     

Cross-linked ultra-high-molecular weight polyethylene liner and ceramic femoral head in total hip arthroplasty: a prospective study at 5 years follow-up

Background  

Recent data indicate that enhanced wear resistance can be obtained with new cross-linked ultra-high-molecular weight polyethylene (CL-UHMWPE) liners, in comparison with previous-generation liners. The current prospective, cohort study was undertaken to analyse whether the use of a new CL-UHMWPE (Rexpol) results in a lower wear rate than ultra-high-molecular weight polyethylene (UHMWPE) in a group of similar patients undergoing total hip arthroplasty (THA). This study provides the first clinical data with this particular CL-UHMWPE.     

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( ± SD) of C_max, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 ± 9 ng kg/mg ml, 210 ± 70 ng h kg/mg ml and 2.6 ± 0.9 ng kg/mg ml, respectively. For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rejection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/kg–150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mg/kg–100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ng/ml and 700 ng/ml. Received: 1 October 1997 Revised: 20 April 2001 Accepted: 7 June 2001     

Natural history of morbid obesity without surgical intervention.

BACKGROUND: To study the mortality among morbidly obese patients qualifying for bariatric surgery. Mortality from bariatric surgery for morbid obesity has been widely reported; however, little is known about the mortality in morbidly obese patients who defer surgery. METHODS: Consecutive patients evaluated for bariatric surgery with an initial encounter between 1997 and 2004 were identified. The Social Security Death Index and office records were used to identify mortality through 2006. We conducted telephone interviews to determine whether the 305 patients who did not undergo bariatric surgery at our institution had undergone the surgery elsewhere. Using Cox proportional hazards models, we compared the mortality in patients undergoing surgery with that of those who did not. To evaluate bias resulting from missing data, we conducted analyses assuming that all patients with missing data had (1) undergone surgery and (2) not undergone surgery. RESULTS: A total of 908 patients underwent bariatric surgery (880 patients at our institution and 28 patients elsewhere). A total of 112 patients did not undergo surgery. Data regarding surgery on 165 patients could not be obtained. The mortality in those patients who did not undergo surgery was 14.3% compared with 2.9% for those who did undergo surgery. Adjusting for age, gender, and body mass index, patients who had undergone surgery had an 82% reduction in mortality (hazard ratio 0.18, 95% confidence interval 0.09-0.35, P <.0001). Sensitivity analysis, assuming that all patients with missing data received surgery resulted in an 85% mortality reduction (P <.001) and assuming that patients did not receive surgery resulted in a 50% mortality reduction (P = .04). CONCLUSIONS: Mortality among morbidly obese patients without surgery was 14.3% during the study period. Surgical intervention offered a 50%-85% mortality reduction benefit.     

Lymphovascular Space Invasion in Robotic Surgery for Endometrial Cancer

Background:

Minimally invasive surgery has become a standard treatment for endometrial cancer and offers significant benefits over abdominal approaches. There are discrepant data regarding lymphovascular space invasion (LVSI) and positive peritoneal cytology with the use of a uterine manipulator, with previous small-scale studies demonstrating an increased incidence of these prognostically important events. We sought to determine if there was a higher incidence of LVSI in patients who underwent robot-assisted surgery for endometrial cancer.

Methods:

We performed a single-institution review of medical records for patients who underwent open abdominal or robot-assisted hysterectomy for endometrial cancer over a 24-month period. The following data were abstracted: age, tumor grade and stage, size, depth of invasion, LVSI, and peritoneal cytology. For patients with LVSI, slides were reviewed by 2 pathologists for confirmation of LVSI.

Results:

Of 104 patients identified, LVSI was reported in 39 (37.5%) and positive peritoneal cytology in 6 (4.8%). Rates of peritoneal cytology were not significantly different between the 2 groups (odds ratio, 0.55; 95% confidence interval, 0.10–3.17; P = .50). LVSI was reported in significantly fewer robot-assisted hysterectomies than open procedures (odds ratio, 0.39; 95% confidence interval, 0.17–0.92; P = .03). In subgroup analyses restricted to early-stage disease (stage ≤ II), there was no significant difference in LVSI between open and robot-assisted hysterectomies (odds ratio, 0.64; 95% confidence interval, 0.22–1.85; P = .43).

Conclusion:

In this retrospective study, we found that use of a uterine manipulator in robot-assisted surgery did not increase the incidence of LVSI.     

ERα signaling regulates MMP3 expression to induce FasL cleavage and osteoclast apoptosis

The benefits of estrogens on bone health are well established; how estrogens signal to regulate bone formation and resorption is less well understood. We show here that 17β‐estradiol (E2)‐induced apoptosis of bone‐resorbing osteoclasts is mediated by cleavage and solubilization of osteoblast‐expressed Fas ligand (FasL). U2OS‐ERα osteoblast‐like cells expressing an EGFP‐tagged FasL at the C‐terminus showed decreased fluorescence after E2 treatment, indicative of a cleavage event. Treatment of U2OS‐ERα cultures with a specific MMP3 inhibitor in the presence of E2 blocked FasL cleavage and showed an increase in the number of EGFP‐FasL⁺ cells. siRNA experiments successfully knocked down MMP3 expression and restored full‐length FasL to basal levels. E2 treatment of both human and murine primary osteoblasts showed upregulation of MMP3 mRNA expression, and calvarial organ cultures showed increased expression of MMP3 protein and colocalization with the osteoblast‐specific RUNX2 after E2 treatment. In addition, osteoblast cell cultures derived from ERαKO mice showed decreased expression of MMP3 but not MMP7 and ADAM10, two known FasL proteases, demonstrating that ERα signaling regulates MMP3. Also, conditioned media of E2‐treated calvarial osteoblasts showed an approximate sixfold increase in the concentration of soluble FasL, indicating extensive cleavage, and soluble FasL concentrations were reduced in the presence of a specific MMP3 inhibitor. Finally, to show the role of soluble FasL in osteoclast apoptosis, human osteoclasts were cocultured with MC3T3 osteoblasts. Both a specific MMP3 inhibitor and an MMP inhibitor cocktail preserved osteoclast differentiation and survival in the presence of E2 and demonstrate the necessity of MMP3 for E2‐induced osteoclast apoptosis. These experiments further define the molecular mechanism of estrogen's bone‐protective effects by inducing osteoclast apoptosis through upregulation of MMP3 and FasL cleavage. © 2013 American Society for Bone and Mineral Research     

A Coupled Approach for Fluid Dynamic Problems Using the PDE Framework Peano

We couple different flow models, i.e. a finite element solver for the Navier-Stokes equations and a Lattice Boltzmann automaton, using the framework Peano as a common base. The new coupling strategy between the meso- and macroscopic solver is presented and validated in a 2D channel flow scenario. The results are in good agreement with theory and results obtained in similar works by Latt et al. In addition, the test scenarios show an improved stability of the coupled method compared to pure Lattice Boltzmann simulations.     

Efficacy and safety of total lymphoid irradiation in different chronic lung allograft dysfunction phenotypes

Total lymphoid irradiation (TLI) is an alternative treatment for chronic lung allograft dysfunction (CLAD). However, data regarding its efficacy and tolerance are scarce. This study included patients with CLAD treated with TLI at our center between 2011 and 2018. Clinical characteristics before and after TLI and related complications were analyzed. Forty patients with CLAD (twenty-nine bronchiolitis obliterans syndrome [BOS], nine restrictive allograft syndrome [RAS], and two mixed) were included. Significant attenuation of the forced expiratory volume in 1-sec (FEV₁) decline slope was observed in all phenotypes, in both the BOS and RAS. The median FEV₁ 12, 6, and 3 months pre-TLI were as follows: 1980 (IQR 1720-2560), 1665 (IQR 1300-2340) and 1300 (IQR 1040-1740) ml (p < .001), while the median FEV₁ at 3, 6, and 12 months post-TLI was 1110 (IQR 810–1440), 1130 (IQR 860–1470), and 1115 (IQR 865–1490) ml (p = .769). No dropouts due to radiation toxicity were observed. The mean survival according to the Karnofsky Performance Status Scale (KPS) >70 or ≤70 at baseline was 1837 (IQR 259–2522) versus 298 (IQR 128–554) days (p < .0001), respectively. In conclusion, TLI may stop FEV₁ decline in both BOS and RAS. Moreover, a good KPS score may be an important prognostic factor.     

Channels, carriers, and pumps in the pathogenesis of sodium-sensitive hypertension

Sodium-sensitive hypertension is thought to be dependent on primary alterations in renal tubular sodium reabsorption. The major apical plasma membrane Na(+) transporters include the proximal tubular Na(+)-H(+) exchanger, the thick ascending limb Na(+)-K(+)-2Cl(-) cotransport system, the distal tubular Na(+)-Cl(-) cotransporter, and the collecting duct epithelial sodium channel (ENaC). This article explores the role of each transporter in the pathogenesis of hypertension. Although the contribution of the proximal tubule Na(+)-H(+) exchanger is not yet defined completely, more convincing data have been generated about the importance of the Na(+)-K(+)-2Cl(-). Indeed at least 2 forms of hypertension appear to be related to the up-regulation of the transporter: the so-called programmed hypertension induced by low-protein diet during pregnancy and the early phase of hypertension in the Milan strain of rats. With respect to the Na(+)-Cl(-) cotransporter this may be overactive caused by inactivating mutation of WNK4 as in the Gordon syndrome, although it is the main actor for the maintenance phase of the hypertension found in the Milan strain of rats. Finally, the contribution of the ENaC has been established clearly; indeed, in the Liddle syndrome the mutation of the ENaC gene leads to a longer retention of the channel on the cell surface of collecting duct principal cells, thus inducing stronger sodium reabsorption along this segment. All these examples clearly indicate that renal sodium transporters may be responsible for various types of sodium-sensitive hypertension.