Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost.

An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4(+) and CD8(+) T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of using in silico-designed centralized immunogens for global HIV-1 vaccine development strategies. IMPORTANCE: There is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1 acquisition. This nonhuman primate study demonstrates that in silico-designed global HIV-1 immunogens, designed for a human clinical trial, are capable of eliciting not only T lymphocyte responses but also potent anti-Env antibody responses.

Results of computer assisted navigation in Total Knee Arthroplasty (TKA): comparison with the conventional method

The aim of this retrospective study was to compare the clinical and radiographic results after TKA (PFC, DePuy), performed either by computer assisted navigation (CAS, Brainlab, Johnson&Johnson) or by conventional means. Material and methods: Between May and December 2006 we reviewed 36 conventional TKA performed between 2002 and 2003 (group A) and 37 navigated TKA performed between 2005 and 2006 (group B) by the same experienced surgeon. The mean age in group A was 74 years (range 62-90) and 73 (range 58-85) in group B with a similar age distribution. The preoperative mechanical axes in group A ranged from -13° varus to +13° valgus (mean absolute deviation 6.83°, SD 3.86), in group B from -13° to +16° (mean absolute deviation 5.35, SD 4.29). Patients with a previous tibial osteotomy or revision arthroplasty were excluded from the study. Examination was done by an experienced orthopedic resident independent of the surgeon. All patients had pre- and postoperative long standing radiographs. The IKSS and the WOMAC were utilized to determine the clinical outcome. Patient's degree of satisfaction was assessed on a visual analogous scale (VAS). Results: 32 of the 37 navigated TKAs (86,5%) showed a postoperative mechanical axis within the limits of 3 degrees of valgus or varus deviation compared to only 24 (66%) of the 36 standard TKAs. This difference was significant (p = 0.045). The mean absolute deviation from neutral axis was 3.00° (range -5° to +9°, SD: 1.75) in group A in comparison to 1.54° (range -5° to +4°, SD: 1.41) in group B with a highly significant difference (p = 0.000). Furthermore, both groups showed a significant postoperative improvement of their mean IKSS-values (group A: 89 preoperative to 169 postoperative, group B 88 to 176) without a significant difference between the two groups. Neither the WOMAC nor the patient's degree of satisfaction - as assessed by VAS - showed significant differences. Operation time was significantly higher in group B (mean 119.9 min.) than in group A (mean 99.6 min., p <0.000). Conclusion: Our study showed consistent significant improvement of postoperative frontal alignment in TKA by computer assisted navigation (CAS) compared to standard methods, even in the hands of a surgeon well experienced in standard TKA implantation. However, the follow-up time of this study was not long enough to judge differences in clinical outcome. Thus, the relevance of computer navigation for clinical outcome and survival of TKA remains to be proved in long term studies to justify the longer operation time. References 1 Stulberg SD. Clin Orth Rel Res. 2003;(416):177-84. 2 Chauhan SK. JBJS Br. 2004;86(3):372-7. 3 Bäthis H, et al. Orthopäde. 2006;35(10):1056-65.

Fractional hepatic de novo lipogenesis in healthy subjects during near-continuous oral nutrition and bed rest: a comparison with published data in artificially fed, critically ill patients.

BACKGROUND AND AIMS: In critically ill patients, fractional hepatic de novo lipogenesis increases in proportion to carbohydrate administration during isoenergetic nutrition. In this study, we sought to determine whether this increase may be the consequence of continuous enteral nutrition and bed rest. We, therefore, measured fractional hepatic de novo lipogenesis in a group of 12 healthy subjects during near-continuous oral feeding (hourly isoenergetic meals with a liquid formula containing 55% carbohydrate). In eight subjects, near-continuous enteral nutrition and bed rest were applied over a 10 h period. In the other four subjects, it was extended to 34 h. Fractional hepatic de novo lipogenesis was measured by infusing(13) C-labeled acetate and monitoring VLDL-(13)C palmitate enrichment with mass isotopomer distribution analysis. Fractional hepatic de novo lipogenesis was 3.2% (range 1.5-7.5%) in the eight subjects after 10 h of near continuous nutrition and 1.6% (range 1.3-2.0%) in the four subjects after 34 h of near-continuous nutrition and bed rest. This indicates that continuous nutrition and physical inactivity do not increase hepatic de novo lipogenesis. Fractional hepatic de novo lipogenesis previously reported in critically ill patients under similar nutritional conditions (9.3%) (range 5.3-15.8%) was markedly higher than in healthy subjects (P&lt;0.001). These data from healthy subjects indicate that fractional hepatic de novo lipogenesis is increased in critically ill patients.

An epidemiological and clinical approach to adolescent suicide. A comparison between suicidal and non-suicidal clinical groups in a health foundation center for French students.

Suicidal behaviour among young people represents a major public health problem. This study seeks to compare the major sociological, clinical, schooling and family features of suicidal and non-suicidal subgroups of adolescents hospitalised in the Health Foundation Center for French Students of neufmoutiers en Brie (France). All these adolescents suffered from the severe mental disorders. The adolescents from the suicidal subgroup presented significantly fewer psychoses and more mood disorders than those of the non-suicidal subgroup. Half of the patients from the suicidal subgroup presented some features of personality disorders, mostly borderline personality disorders. Nevertheless, their global functioning was more frequently improved between admission and discharge than was the case for the non-suicidal group.

Continuous Sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06).

BACKGROUND: Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and Child-Pugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12). RESULTS: Forty-five patients were enrolled. The median age was 63 years; 89% had Child-Pugh class A disease and 47% had distant metastases. PFS12 was rated successful in 15 patients (33%; 95% confidence interval, 20%-47%). Over the whole trial period, one complete response and a 40% rate of stable disease as the best response were achieved. The median PFS duration, disease stabilization duration, time to progression, and overall survival time were 1.5, 2.9, 1.5, and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent. None of the 33 deaths were considered drug related. CONCLUSION: Continuous SU treatment with 37.5 mg daily is feasible and has moderate activity in patients with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design (>13 PFS12 successes), the therapy is considered promising. This is the first trial describing the clinical effects of continuous dosing of SU in HCC patients on a schedule that is used in an ongoing, randomized, phase III trial in comparison with the current treatment standard, sorafenib (ClinicalTrials.gov identifier, NCT00699374).

Mechanisms of postprandial hyperglycemia in liver transplant recipients: comparison of liver transplant patients with kidney transplant patients and healthy controls.

Impaired glucose tolerance or diabetes mellitus are frequent complications after organ transplantation, and are usually attributed to glucocorticoid and immunosuppressive treatments. Liver transplantation results in total hepatic denervation which may also affect glucoregulation. We therefore evaluated postprandial glucose metabolism in a group of patients with liver cirrhosis before and after orthotopic liver transplantation. Seven patients with liver cirrhosis of various etiologies, 6 patients having received a kidney transplant, and 6 healthy subjects were studied. Their glucose metabolism was evaluated in the basal state and over 4 hours after ingestion of a glucose load with 6.6 (2) H glucose dilution analysis. The patients with liver cirrhosis were studied before, and again 4 weeks (range 2-6) and 38 weeks (range 20-76, n=6) after orthotopic liver transplantation. Basal glucose metabolism was similar in liver and kidney transplant recipients. Impaired glucose tolerance was present in both groups, but postprandial hyperglycemia was exaggerated and lasted longer in liver transplant patients. Postprandial insulinemia was lower in liver transplant recipients, while C-peptide concentrations were comparable to those of kidney transplant recipients, indicating increased insulin clearance. Glucose turnover was not altered in both groups of patients during the initial 3 hours after glucose ingestion, but was higher in liver transplant early after transplantation during the fourth hour. Postprandial hyperglycemia remained unchanged in liver transplant recipients 38 weeks after liver transplantation, despite substantial reduction of immunosuppressive and glucocorticoid doses. We conclude that liver transplant recipients have severe postprandial hyperglycemia which can be attributed to insulinopenia (secondary, at least in part, to increased insulin clearance) and a late increased glucose turnover. These changes may be secondary to hepatic denervation.

Detection of nandrolone metabolites in urine after a football game in professional and amateur players: a Bayesian comparison.

Nandrolone (19-nortestosterone) is a widely used anabolic steroid in sports where strength plays an essential role. Once nandrolone has been metabolised, two major metabolites are excreted in urine, 19-norandrosterone (NA) and 19-noretiocholanolone (NE). In 1997, in France, quite a few sportsmen had concentrations of 19-norandrosterone very close to the IOC cut off limit (2ng/ml). At that time, a debate took place about the capability of the human male body to produce by itself these metabolites without any intake of nandrolone or related compounds. The International Football Federation (FIFA) was very concerned with this problematic, especially because the World Cup was about to start in France. In this respect, a statistical study was held with all football players from the first and second divisions of the Swiss Football National League. All players gave a urine sample after effort and around 6% of them showed traces of 19-norandrosterone. These results were compared with amateur football players (control group) and around 6% of them had very small amounts of 19-norandrosterone and/or 19-noretiocholanolone in urine after effort, whereas none of them had detectable traces of one or the other metabolite before effort. The origin of these compounds in urine after a strenuous physical activity is still unknown, but three hypotheses can be put forward. First, an endogenous production of nandrolone metabolites takes place. Second, nandrolone metabolites are released from the fatty tissues after an intake of nandrolone, some related compounds or some contaminated nutritive supplements. Finally, the sportsmen may have taken something during or just before the football game.

Update of the BIPM comparison BIPM.RI(II)-K1.Cs-134 of activity measurements of the radionuclide 134Cs to include the 2008 results of the BEV (Austria), the 2009 result of the IRA (Switzerland) and the 2010 results of the NMISA (South Africa)

Purine nucleotide pyrophosphotransferase was purified to apparent homogeneity from a culture filtrate of Streptomyces morookaensis. It is a monomeric protein with a molecular weight of 24 000-25 000, and its isoelectric point is 6.9. The enzyme synthesizes purine nucleoside 5'-phosphate (mono, di, or tri) 3'-diphosphates such as pppApp, ppApp, pApp, pppGpp, ppGpp and pppIpp by transferring a pyrophosphoryl group from the 5'-position of ATP, dATP and ppApp to the 3'-position of purine nucleotides. The purified enzyme catalysed the formation of 435 mumol of pppApp and 620 mumol of pppGpp from ATP and GTP per min mg protein under the standard conditions. The enzyme requires absolutely a divalent cation for activity, and optimum pH for the enzyme activity lay above 10 for Mg2+, for Co2+ and Zn2+ from 9 to 9.5, and for Fe2+ from 7.5 to 8. The following Michaelis constants were determined: AMP, 2.78 mM; ADP, 3.23 mM; GMP, 0.89 mM; GDP, 0.46 mM and GTP, 1.54 mM, in the case of ATP donor. The enzyme is inhibited by guanine, guanosine, dGDP, dGTP, N-bromosuccinimide, iodacetate, sodium borate and mercuric acetate.

Risk of Bronchiolitis Obliterans Syndrome Is Twice as High in Cyclosporine Treated Patients in Comparison to Tacrolimus 3 Years after Lung Transplantation: Results of a Prospective Randomized International Trial of 248 Patients

Purpose: In this prospective randomized study efficacy and safety of two immunosuppressive regimens (Tac, MMF, Steroids vs. CsA, MMF, Steroids) after Lung Transplantation were compared. Primary objective was the incidence of bronchiolitis obliterans syndrome (BOS). Secondary objectives were incidence of acute rejection and infection, survival and adverse events. 248 patients with a complete 3 year follow-up were included in the analysis. Methods and Materials: Patients were randomized to treatment group A: Tac (0.01-0.03 mg/kg/d iv-0.05-0.3 mg/kg/d po) or B: CsA (1-3 mg/kg/d iv-2-8 mg/kg/d po). MMF dose was1-4 mg/d in both groups. No induction therapy was given. Patients were stratified for cystic fibrosis. Intention to treat analysis was performed in patients who were switched to a different immunosuppressive regimen. Results: 3 of 123 Tac patients and 41 of 125 CsA patients were switched to another immunosuppressive regimen and were analyzed as intention to treat. Three year follow-up data of the complete patient cohort were included in this final analysis. Groups showed no difference in demographic data. Kaplan Meier analysis revealed significantly less BOS in Tac treated patients (p=0.033, log rank test, pooled over strata). Cox regression showed a twice as high risk for BOS in the CsA group (factor 2.003). Incidence of acute rejection was 67.5% (Tac) and 75.2% (CsA) (p=0.583). One- and 3-year-survival-rates were not different (85.4% Tac vs. 88.8% CsA, and 80.5% Tac vs. 83.2% CsA, p=n.s.). Incidence of infections and renal failure was similar (p=n.s.). Conclusions: Tac significantly reduced the risk for BOS after 3 years in this intention to treat analysis. Both regimens have a good immunosuppressive potential and offer a similar safety profile with excellent one and three year survival rates. Acute rejection rates were similar in both groups. Incidence of infections and renal failure showed no difference.

Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research.

PURPOSE: This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy. PATIENTS AND METHODS: Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric carcinoma, a performance status <or= 1, and adequate hematologic, hepatic, and renal function randomly received <or= eight 3-weekly cycles of ECF (epirubicin 50 mg/m(2) on day 1, cisplatin 60 mg/m(2) on day 1, and fluorouracil [FU] 200 mg/m(2)/d on days 1 to 21), TC (docetaxel initially 85 mg/m(2) on day 1 [later reduced to 75 mg/m(2) as a result of toxicity] and cisplatin 75 mg/m(2) on day 1), or TCF (TC plus FU 300 mg/m(2)/d on days 1 to 14). Study objectives included response (primary), survival, toxicity, and quality of life (QOL). RESULTS: ORR was 25.0% (95% CI, 13% to 41%) for ECF, 18.5% (95% CI, 9% to 34%) for TC, and 36.6% (95% CI, 23% to 53%) for TCF (n = 119). Median overall survival times were 8.3, 11.0, and 10.4 months for ECF, TC, and TCF, respectively. Toxicity was acceptable, with one toxic death (TC arm). Grade 3 or 4 neutropenia occurred in more treatment cycles with docetaxel (TC, 49%; TCF, 57%; ECF, 34%). Global health status/QOL substantially improved with ECF and remained similar to baseline with both docetaxel regimens. CONCLUSION: Time to response and ORR favor TCF over TC for further evaluation, particularly in the neoadjuvant setting. A trend towards increased myelosuppression and infectious complications with TCF versus TC or ECF was observed.

Comparison of the efficacy and longevity of nonpenetrating glaucoma surgery with and without a new, nonabsorbable hydrophilic implant.

BACKGROUND AND OBJECTIVE: To compare the efficacy and longevity of nonpenetrating glaucoma surgery with and without the use of a nonabsorbable hydrophilic implant at the Oxford Eye Centre, Johannesburg, South Africa, and the Glaucoma Unit, Jules Gonin Ophthalmic Hospital, Lausanne, Switzerland. PATIENTS AND METHODS: In a nonrandomized, prospective study between March 1997 and December 2001, 48 eyes of 32 patients aged 18 to 86 years with primary open-angle glaucoma underwent nonpenetrating glaucoma surgery; 25 eyes with the implant and 23 eyes without it. Intraocular pressure (IOP) was recorded preoperatively and postoperatively at 1, 7, and 14 days, at 1, 3, and 6 months, and thereafter every 6 months. RESULTS: The mean preoperative IOP was 27.5 +/- 11.8 mm Hg (range, 20 to 64 mm Hg) in the implant group and 24.8 +/- 7.1 mm Hg (range, 16 to 38 mm Hg) in the control group. During the first 18 months of follow-up, both groups showed identical IOP progression and the mean IOP remained less than 14 mm Hg. After 2 years of follow-up, the IOP started to rise in the control group but remained stable in the implant group. After 30 months, the mean IOP was 12.4 +/- 2 mm Hg and the IOP decrease in percentage was 62% +/- 6% in the implant group (n = 13) versus 16.1 +/- 3 mm Hg and 34% +/- 13% in the control group (n = 15) (mean IOP, P = .0022; mean IOP decrease in percentage, P = .01). CONCLUSIONS: During the first 18 months, there was no difference in the outcomes between the two groups. After 2 years of follow-up, the mean IOP was lower and the IOP decrease in percentage was greater in the implant group compared with the control group.

Comparison of results of intravenous infusion of anistreplase versus streptokinase in acute myocardial infarction.

This randomized study compares the coronary perfusion rate in patients with acute myocardial infarction (AMI) treated with 2 different intravenous thrombolytic agents: streptokinase 1.5 million U given over 60 minutes and anisoylated human plasminogen streptokinase activator complex (anistreplase) administrated as a bolus of 30 U over 5 minutes. One hundred seventy-five patients (149 men and 26 women, mean age 54 years) have been included in this study. Eighty-nine patients were treated with anistreplase and 86 patients with streptokinase. AMI was inferior in 54 patients (61%) in the anistreplase group and in 54 patients (63%) in the streptokinase group. It was anterior in 35 (40%) and 32 (37%) patients, respectively. Coronary angiography and ventriculography were performed at a mean time (+/- SEM) of 207 +/- 11 minutes after the beginning of thrombolysis in 170 patients. A perfusion score grade of 2 or 3 according to the Thrombolysis in Myocardial Infarction trial was found in 63 patients (72%) in the anistreplase group and in 56 patients (68%) in the streptokinase group (p = NS). Severe bleeding occurred in 7 patients (8%) after anistreplase and in 6 patients (7%) after streptokinase. No cerebral hemorrhage occurred. Nine patients (5%) died during their hospital stay: 6 after anistreplase and 3 after streptokinase. It is concluded that intravenous administration of anistreplase or streptokinase is efficient and safe. Coronary patency 207 minutes after fibrinolysis, incidence of adverse events and mortality are similar in both groups.

Surgery for Hirschsprung's disease: comparison between the Duhamel method and the transanal endorectal pull-through based on 59 patients and a review of the literature

Background:¦Hirschsprung's disease (HSCR) is a congenital malformation of the enteric nervous system due to the¦arrest of migration of neural crest cells to form the myenteric and submucosal plexuses. It leads to an anganglionic intestinal segment, which is permanently contracted causing intestinal obstruction. Its incidence is approximately 1/5000 birth, and males are more frequently affected with a male/female ratio of 4/1. The diagnosis is in most cases made within the first year of life. The rectal biopsy of the mucosa and sub-mucosa is the diagnostic gold standard.¦Purpose:¦The aim of this study was to compare two surgical approaches for HSCR, the Duhamel technique and the transanal endorectal pull-through (TEPT) in term of indications, duration of surgery, duration of hospital stay, postoperative treatment, complications, frequency of enterocolitis and functional outcomes.¦Methods:¦Fifty-nine patients were treated for HSCR by one of the two methods in our department of pediatric¦surgery between 1994 and 2010. These patients were separated into two groups (I: Duhamel, II: TEPT), which were compared on the basis of medical records. Statistics were made to compare the two groups (ANOVA test). The first group includes 43 patients and the second 16 patients. It is noteworthy that twenty-four patients (about 41% of all¦patients) were referred from abroad (Western Africa). Continence was evaluated with the Krickenbeck's score.¦Results:¦Statistically, this study showed that operation duration, hospital stay, postoperative fasting and duration of postoperative antibiotics were significantly shorter (p value < 0.05) in group II (TEPT). But age at operation and length of aganglionic segment showed no significant difference between the two groups. The continence follow-up showed generally good results (Krickenbeck's scores 1; 2.1; 3.1) in both groups with a slight tendency to constipation in group I and soiling in group II.¦Conclusion:¦We found two indications for the Duhamel method that are being referred from a country without¦careful postoperative surveillance and/or having a previous colostomy. Even if the Duhamel technique tends to be replaced by the TEPT, it remains the best operative approach for some selected patients. TEPT has also proved some advantages but must be followed carefully because, among other points, of the postoperative dilatations. Our postoperative standards, like digital rectal examination and anal dilatations seem to reduce the occurrence of complications like rectal spur and anal/anastomosis stenosis, respectively in the Duhamel method and the TEPT technique.

Second non-breast primary cancer following adjuvant therapy for early breast cancer: a report from the International Breast Cancer Study Group.

The incidence of second non-breast primary cancer following adjuvant treatment was evaluated using data from patients enrolled from 1978 to 1999 in four International Breast Cancer Study Group (IBCSG) trials. The occurrence of these tumours as sites of the first failure was assessed separately for two treatment comparisons: toremifene versus tamoxifen for 5 years in 1035 patients in IBCSG Trials 12-93 and 14-93 with a median follow-up of 8 years and endocrine therapy (toremifene or tamoxifen) versus chemo-endocrine therapy (CMF or AC plus toremifene or tamoxifen) in 1731 patients from IBCSG Trials III, VII and 12-93, with a combined median follow-up of 14 years. No significant differences in second non-breast primary tumours were observed in either comparison. In particular, the incidences of second primary uterine tumours with toremifene and tamoxifen were similar and no significant increase of secondary leukaemias was observed with chemo-endocrine therapy compared with endocrine therapy.