In vitro mitogen-stimulated T-cell from hepatitis C virus-positive liver transplantation candidates, increases T-cell activation markers and T-cell proliferation

The incidence of acute rejection is significantly higher in hepatitis C virus (HCV) liver-transplant patients than in patients who have received a graft for other liver diseases, i.e., mainly alcoholic cirrhosis. The aim of this study was to assess T-cell function, i.e., intralymphocyte cytokine expression (IL-2 and TNF-alpha), T-cell activation [i.e., transferrin receptor (CD71) and interleukin (IL)-2 alpha-chain (CD25) expression], and T-cell proliferation using a flow-cytometry whole-blood assay in patients waiting for a liver transplantation (n=49). Our data suggest that, in mitogen-stimulated T-cells, (i) intra-lymphocyte cytokine expression is significantly higher in patients with liver disease than in healthy volunteers (n=25); (ii) the expression of T-cell activation markers is decreased in patients with liver cirrhosis compared to healthy volunteers, and (iii) the expression of T-cell activation markers and T-cell proliferation are increased in patients with HCV infection (n=15) compared to those without HCV infection (n=34), particularly compared to patients with alcoholic liver disease (n=19). Circulating CD19-positive cells count was also significantly higher in HCV-positive patients. In conclusion, in vitro, mitogen-stimulated T-cell seem to induce a higher immune response in the blood from patients waiting for a liver transplant for HCV-related liver disease than those without HCV infection, and particularly those with alcoholic liver disease.     

Quality of Life and Outcomes in African Americans with CKD

Low health-related quality of life (HRQOL) has been associated with increased risk for hospitalization and death in ESRD. However, the relationship of HRQOL with outcomes in predialysis CKD is not well understood. We evaluated the association between HRQOL and renal and cardiovascular (CV) outcomes in 1091 African Americans with hypertensive CKD enrolled in the African American Study of Kidney Disease and Hypertension (AASK) trial and cohort studies. Outcomes included CKD progression (doubling of serum creatinine/ESRD), CV events/CV death, and a composite of CKD progression or death from any cause (CKD progression/death). We assessed HRQOL, including mental health composite (MHC) and physical health composite (PHC), using the Short Form-36 survey. Cox regression analyses were used to assess the relationship between outcomes and five-point decrements in MHC and PHC scores using measurements at baseline, at the most recent annual visit (time-varying), or averaged from baseline to the most recent visit (cumulative). During approximately 10 years of follow-up, lower mean PHC score was associated with increased risk of CV events/CV death and CKD progression/death across all analytic approaches, but only time-varying and cumulative decrements were associated with CKD progression. Similarly, lower mean MHC score was associated with increased risk of CV events/CV death regardless of analytic approach, while only time-varying and cumulative decrements in mean MHC score was associated with CKD progression and CKD progression or death. In conclusion, lower HRQOL is associated with a range of adverse outcomes in African Americans with hypertensive CKD.     

Diagnostic criteria for testing for BRCA1 and BRCA2: the experience of the Department of Defense Familial Breast/Ovarian Cancer Research Project

The Department of Defense Familial Breast/Ovarian Cancer Research Project has offered genetic counseling and testing for BRCA1 and BRCA2 on a research basis to patients meeting specific diagnostic criteria, with risk for BRCA1 and BRCA2 mutations calculated based on the Couch model. In 2.5 years, 250 patients were evaluated and 101 patients met criteria requirements, including 33 who met criteria in more than one category. Ninety patients elected to undergo DNA testing. In this group of 90 patients, 14 mutations (15.5%) and 16 unclassified variants (17.7%) were identified. The most common inclusion criteria were onset of breast/ovarian cancer before age 45 years (n = 32) and onset of breast/ovarian cancer before age 45 years with strong family history (n = 21). However, when number of mutations and unclassified variants found were compared separately across all diagnostic criteria (including those of more than one capacity) using the chi 2 statistic, no significant differences were seen among the categories to suggest that one criterion was more predictive of mutations or variants than another. Couch risk values for patients with mutations showed a mean of 14% and ranged from 3.2 to 43.5% (range for all patients, 1.2-69.7%). These findings emphasize the importance of using multiple diagnostic criteria and suggest that a Couch risk value of > 3% may be useful in selecting patients for testing. The data also underscore the necessity of genetic counseling in the testing process, particularly given the large number of unclassified variants diagnosed and their uncertain status for disease predisposition.     

Robot-Assisted Transaxillary Thyroid Surgery in the United States: Is it Comparable to Open Thyroid Lobectomy?

Background  

The purpose of this study was to compare the outcome of robot-assisted transaxillary thyroid surgery (RATS) to the standard open technique for thyroid lobectomy in the U.S. population.     

Genetic testing for hereditary nonpolyposis colorectal cancer

Approximately 80 per cent of patients with colorectal cancer have sporadic disease whereas the remaining 20 per cent seem to have a genetic component. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common autosomal dominant hereditary syndrome predisposing to colorectal cancer. Various methods have been described to screen for HNPCC and to directly test for mismatch repair gene mutations. This study evaluates the initial results of 1) microsatellite instability (MSI) and immunohistochemistry (IHC) staining of tumors and 2) genetic sequencing for mismatch repair gene mutations in patients suspected to have HNPCC. Appropriate patients for HNPCC testing were identified through a high-risk colorectal cancer clinic. Of those patients screened only those who met Amsterdam criteria (AC) for HNPCC or were young age onset (YAO) (<40 years of age) were eligible for testing. The tumors underwent testing for MSI and had IHC performed in those patients with available tumor specimens. MSI was performed on the five markers approved by the NIH consensus conference. MSI-High (MSI-H) was defined as two or more markers being unstable. IHC was done with commercially available stains for MLH1 and MSH2. All patients had sequencing of the MLH1 and MSH2 genes performed to search for mutations by a commercial laboratory. Genetic counseling was provided and written informed consent was obtained. Fourteen patients were part of kindreds that met the AC. An additional 10 patients were <40 years of age at diagnosis of colorectal cancer but lacked any family history. Testing for MSI and IHC was performed on those available tissue blocks. Of the AC patients five had MSH2 mutations and two had MLH1 variants. Of the five with MSH2 mutations three of four had MSI-H tumors and all four had loss of expression of MSH2 on IHC. Of the MLH1 variants only one had MSI-H tumor and lacked expression of MLH-1 on IHC. Of those patients with no mutation identified three of six had MSI-H tumors. For those patients YAO no genetic mutations were identified. Two of the seven had MSI-H tumors. Genetic testing for HNPCC even in those patients fulfilling the rigid AC yielded mutations in only five of 14 patients with variants of unknown significance being found in an additional two patients. Only one MSH2 variant of unknown significance was identified in the 10 YAO patients, which would suggest that screening in this group of patients with MSI and/or IHC would be appropriate.     

Preoperative urodynamic evaluation may predict voiding dysfunction in women undergoing pubovaginal sling

PURPOSE: We determine which urodynamic parameters can best predict postoperative voiding dysfunction following pubovaginal sling surgery. MATERIALS AND METHODS: The records of 98 consecutive women who had undergone pubovaginal sling surgery with allograft fascia lata between July 1998 and July 2000 were reviewed. Urodynamic and followup data were sufficient for evaluation for 73 patients. Urodynamic and clinical parameters were correlated with urinary retention, time to return of efficient voiding and development of postoperative urgency symptoms. RESULTS: Average time to return of efficient voiding was 3.92 days (median 3). Of 21 women who voided without a detrusor contraction urinary retention developed in 4 (23%) versus 0 of 48 who voided with detrusor contraction (p = 0.007). Urinary retention was defined as the need to perform even occasional self-catheterization. All 4 women with urinary retention had a detrusor pressure of less than 12 cm. H(2)O (0 in 3, 4 in 1). None of the women with a detrusor pressure of greater than 12 cm. H(2)O had urinary retention (p = 0.047). The presence of Valsalva voiding in women without a detrusor contraction did not affect the incidence of urinary retention (11.1%) compared to those who did not demonstrate Valsalva voiding (5.1%) (p = 0.603). Peak flow rate, detrusor instability on preoperative urodynamics and post-void residual urine volume were not associated with postoperative urinary retention. Finally, post-void residual urine volume predicted delayed return to normal voiding (p = 0.001). There were no other urodynamic parameters that were significantly associated with urinary retention, delayed return to normal voiding or postoperative urgency symptoms including peak flow rate, capacity or compliance. CONCLUSIONS: Women who void without or with a weak detrusor contraction are most likely to have urinary retention postoperatively. Therefore, we conclude that preoperative urodynamic evaluation may be used to counsel women regarding the risk of urinary retention following the pubovaginal sling procedure.     

Major lower extremity amputation after multiple revascularizations: was it worth it?

Lower extremity revascularization is often described as excessively lesion-centric, with insufficient focus on the patient. We investigated patients' perspectives of multiple procedures for limb salvage that culminated in major lower extremity amputation. A prospective vascular surgery database was queried from January 2000 to December 2005 for patients who had undergone below-knee (BKA) or above-knee (AKA) amputation after failed lower extremity revascularization. Patients were surveyed via telephone by a vascular nurse regarding thoughts on undergoing multiple procedures for limb salvage, involvement in decision making, functional status (work, meal preparation, shopping, driving), use of prosthesis, and independence. The Social Security Death Index was utilized to verify patient survival. Amputations for infection were excluded. Seventy-eight patients underwent AKA or BKA after failed revascularization. Forty-six patients (59%) were alive at 5 years. Thirteen patients were lost to follow-up, leaving 33 available for survey. A total of 142 lower extremity revascularizations (median = 4/patient) were performed on these patients including 94 surgical bypasses (median = 3/patient) and 48 percutaneous interventions (median = 1/patient). Eighty-five percent (28 of 33 patients) of amputees surveyed would do everything to save the leg if faced with a similar scenario, regardless of the number of procedures. Fifty-four percent (18/33) of patients actively used a prosthesis, and 91% (30/33) resided at home. In retrospect, patients are willing to undergo multiple revascularizations--percutaneous or open--to attempt limb salvage even if the eventual result is major amputation. Independence and functional status appear to be obtainable in a majority of patients. Patient-oriented outcomes are necessary to guide revascularization, whether it is by a percutaneous or open technique.     

Tubular expression of angiotensin II receptors and their regulation in IgA nephropathy

Enhanced renal expression for the renin-angiotensin system (RAS) is detected in IgA nephropathy (IgAN). Previous data showed an altered glomerular expression of angiotensin II type 1 receptor (AT1R), suggesting a regulatory response to high intrarenal angiotensin II (Ang II) concentration in IgAN. In this study, the expression and regulation of Ang II receptors were examined in human proximal tubular epithelial cells (PTEC) in IgAN. Tubular expression of AT1R and Ang II type 2 receptor (AT2R) was increased in IgAN. In vitro culture experiment showed that the upregulation of Ang II receptors was not due to the direct effect of IgA but the indirect effect after IgA deposition on human mesangial cell. When PTEC were cultured with conditioned culture medium from human mesangial cells activated with IgA, Ang II production was upregulated, leading to inflammation and apoptosis via the AT1R and AT2R, respectively. Sequential expression of Ang II receptors determined the injury of PTEC induced by mediators in the conditioned medium. The initial interaction between Ang II and AT1R activated both protein kinase C and mitogen-activated protein kinase pathways, leading to inflammatory responses. This early AT1R-dependent event was followed by upregulation of AT2R expression and continued Ang II release. The interaction between Ang II and AT2R subsequently led to expression of cleaved poly[ADP-ribose] polymerase through downregulation of the mitogen-activated protein kinase pathway. The data suggest that appropriate control of Ang II receptor activities in PTEC may ameliorate tubulointerstitial injury in IgAN.     

Extracorporeal membrane oxygenation in infants with meconium aspiration syndrome: a decade of experience with venovenous ECMO

Background

Despite the emergence of new therapies for respiratory failure of the newborn with meconium aspiration syndrome (MAS), extracorporeal membrane oxygenation (ECMO) has a significant role as a rescue modality in these infants. Our objective was to compare the use of venovenous (VV) vs venoarterial (VA) ECMO in newborns with MAS who need ECMO and to ascertain the impact of new therapies in these infants during the last decade. We also evaluated how disease severity or time of ECMO initiation affected mortality and morbidity.

Methods

A report of 12 years experience (1990-2002) of a single center, comparing VV and VA ECMO, is given. Venovenous ECMO was the preferred rescue modality for respiratory failure unresponsive to maximal medical therapy. Venoarterial ECMO was used only when the placement of a VV ECMO 14-F catheter was not possible; 128 patients met ECMO criteria, 114 were treated with VV ECMO, and 12 with VA ECMO. Two patients were converted from VV to VA ECMO.

Results

Venovenous and VA ECMO patients had comparable birth weight (mean ± SEM, 3.48 ± 0.05 vs 3.35 ± 0.15 kg) and gestational age (40.3 ± 0.1 vs 40.7 ± 0.3 weeks). Before ECMO, there was no difference between VV and VA ECMO patients in oxygenation index (60 ± 3 vs 63 ± 8), mean airway pressure (19.5 ± 0.4 vs 20.8 ± 1.5 cm H₂O), alveolar-arterial O₂ gradient (630 ± 2 vs 632 ± 4 torr), ECMO cannulation age (median [25th-75th percentiles], 23 [14-47] vs 26 [14-123] hours), or in the % of patients who needed vasopressors/inotropes (98% vs 100%). From November 1994, inhaled nitric oxide (NO) was available. Before VV ECMO, 67% of the patients received NO, 24% received surfactant, and 48% were treated with high-frequency ventilation (HFV). There was no significant difference between VV and VA ECMO patients in survival rate (94% vs 92%), ECMO duration (88 [64-116] vs 94 [55-130] hours), time of extubation (9 [7-11] vs 14 [9-15] days), age at discharge (23 [18-30] vs 27 [15-41] days), or incidence of short-term intracranial complications (5.3% vs 16.7%). For the total cohort of 126 infants, indices of disease severity (oxygenation index, alveolar-arterial O₂ gradient, mean airway pressure) did not correlate with outcome measures. Delay in ECMO initiation (>96 hours) was associated with prolonged mechanical ventilation and hospitalization (P < .01). New therapies (NO, HFV, surfactant) in the second part of the decade were associated with a longer ECMO duration (98 [80-131] vs 87 [60-116] hours; P < .05), no delay in ECMO initiation time (23 [10-40] vs 24 [14-52] hours), and no significant change in survival (97% vs 92.5%). No patient was treated with VA ECMO after 1994.

Conclusions

Venovenous ECMO is as reliable as VA ECMO in newborns with MAS in severe respiratory failure who need ECMO. Delay in ECMO initiation may result in prolonged mechanical ventilation and increased length of hospital stay. The emergence of new conventional therapies (NO, HFV, surfactant) and particularly increased experience enable sole use of VV ECMO with no significant change in survival in infants with MAS.