Quantile regression for the statistical analysis of immunological data with many non-detects

Background

Hemolytic uremic syndrome (HUS) leading to acute kidney failure, is a condition linked to the production of primarily Shiga toxin 2 (Stx2) by some E. coli serotypes. We have previously shown that Stx2 A subunit-specific human monoclonal antibody (HuMAb) 5C12, and B subunit-specific HuMAb 5H8 inhibit cultured cell death, and protect mice and piglets from fatal Stx2-intoxication. We have also shown that 5H8 blocks binding of Stx2 to its cell-surface receptor globotriaosyl ceramide (Gb₃), whereas Stx2 when complexed with 5C12 binds Gb₃ with higher affinity than Stx2. The mechanism by which 5C12 neutralizes Stx2 in vitro involves trapping of Stx2 in the recycling endosomes and releasing it into the extracellular environment. Because of the clinical implications associated with the formation of Stx2/antibody complexes and the potential for trapping and clearance through a severely damaged kidney associated with HUS, we investigated the likely site(s) of Stx2/antibody localization and clearance in intoxicated mice treated with antibody or placebo.

Results

Mice were injected with radiolabeled Stx2 (¹²⁵I-Stx2) 4 hours after administration of 5C12, 5H8, or phosphate buffered saline (PBS) and the sites of localization of labeled Stx2, were investigated 3, 24 and 48 hours later. The liver recorded statistically much higher concentrations of labeled Stx2 for groups receiving 5C12 and 5H8 antibodies after 3, 24 and 48?hours, as compared with the PBS group. In contrast, highest levels of labeled Stx2 were detected in the kidneys of the PBS group at all 3 sampling times. Mice receiving either of the two HuMAbs were fully protected against the lethal effect of Stx2, as compared with the fatal outcome of the control group.

Conclusions

The results suggest that HuMAbs 5C12 and 5H8 promoted hepatic accumulation and presumably clearance of toxin/antibody complexes, significantly diverting Stx2 localization in the kidneys, the target of Stx2 and the cause of HUS. This is in contrast to the fatal outcome of the control group receiving PBS. The results also confirm earlier observations that both HuMAbs are highly and equally protective against Stx2 intoxication in mice.     

Sporting activity after hip resurfacing: changes over time

The evolution of patient sporting activities after hip resurfacing has not yet been studied. A scoring algorithm to quantify sporting activity was developed to compare type of activity, frequency, duration, and overall activity level in the early postoperative period and at mid- to long-term follow-up. Quantification of sporting activity is a challenging undertaking but should become a useful tool to study the relationship between failure rates and the use of prosthesis.     

Survivorship of Conserve® Plus monoblock metal-on-metal hip resurfacing sockets: radiographic midterm results of 580 patients

Resurfacing systems use press-fit, monoblock, cobalt chrome alloy acetabular sockets because of the material's ability to withstand stresses while accommodating a large femoral head. Despite the widespread use of these types of sockets for both hip resurfacing and total hip replacement, there is a paucity of literature assessing the outcomes of these cups in particular. The 10 year survivorship of the Conserve? Plus monoblock acetabular component used in this study was 98.3% with small pelvic osteolytic lesions suspected in only 2.3%. This study highlights the excellent radiographic survivorship profile of the Conserve? Plus socket.     

Failure modes of 433 metal-on-metal hip implants: how, why, and wear

Metal-on-metal total hip replacements (THRs) and hip resurfacings are coming under increasing scrutiny in light of concerns that they fail because of high wear and elevated metal ions. The aim of this study was to investigate the modes of failure in a collection of 433 metal-on-metal THRs and hip resurfacings and to examine the correlations between the reasons for revision and a range of patient and implant variables considered relevant to implant wear.     

Mid-to-long term follow-up of Transcend metal-on-metal versus Interseal metal-on-polyethylene bearings in total hip arthroplasty

Second-generation metal-on-metal total hip arthroplasty (THA) was introduced in the early 1990s to address osteolysis and aseptic loosening resulting from polyethylene wear. We present a comparison between the Transcend metal-on-metal and Interseal metal-on-polyethylene THAs. Thirty-seven hips with Transcend metal bearings and 36 hips with Interseal polyethylene acetabular liners but identical acetabular shells were reviewed to determine clinical performance, radiographic changes, and survivorship. Patients with higher anticipated activity levels were selected to receive the Transcend bearing. Mean follow-up time was 107.0 months for the Transcend group, and 90.4 months for the Interseal group. There were no significant differences between the Transcend and Interseal groups for mode of failure and survivorship, which is notable considering the younger and more active Transcend group. However, the Transcend group showed significantly better clinical scores, which may have been a result of the selection methods. Neither surface was differentially implicated in osteolysis, aseptic loosening, or adverse local tissue reaction (ALTR). Our study shows a favorable and comparable performance for both systems.     

Neutralizing antibodies to interferon-α and circulating interferon in patients with chronic hepatitis C non-responding to pegylated interferon plus ribavirin re-treated by pegylated interferon-α-2a and ribavirin (ANRS HC16 GAMMATRI substudy)

A lack of antiviral response in patients with chronic hepatitis C treated with pegylated (PEG)‐interferon (IFN)‐α‐2a + ribavirin (RIBA) may be explained by neutralizing antibodies to IFN‐α‐2a. The aim of this study was to assess neutralizing antibodies to IFN‐α‐2a and IFN levels in non‐responder patients who were re‐treated by PEG IFN‐α‐2a and RIBA for 12 weeks. Non‐responders to a first‐line treatment of PEG IFN‐α‐2a + RIBA were included for treatment with PEG IFN‐α‐2a (180 µg/week) + RIBA (1,000 mg/day if <75 kg, 1,200 mg otherwise) for 48 weeks. HCV RNA was measured at week 12. IFN levels and neutralizing antibodies to IFN‐α‐2a were measured retrospectively on stored sera at baseline and weeks 4 and 12, using a quantitative sandwich ELISA for neutralizing antibodies to IFN‐α‐2a. Twenty‐three patients were non‐responders and 19 patients were responders at week 12 of the initial phase of the second‐line treatment. Non‐responders and responders did not differ statistically: baseline age (median age 47 vs. 50 years), HCV RNA (median 6.8 vs. 6.4 log₁₀ copies/ml), gender (70% vs. 73% males), genotype (genotype 1: 91% vs. 80%). The median IFN‐α‐2a levels (pg/ml) at weeks 0, 4, and 12 (interquartile range) did not differ between the 19 responders to initial phase of second‐line treatment and the 23 non‐responders: <3.3 (<3.3–371.4), 1457.3 (106.8–3284.8), and 1,652 (90.8–5,000); 84.5 (3.3–277.4), 1407.4 (120.2–2443.4), and 1620.1 (120.2–2287.1), respectively. Among non‐selected consecutive non‐responder patients, re‐treatment with PEG IFN‐α‐2a + RIBA is associated with virological response regardless of the presence of antibody‐mediated resistance to conventional IFN treatment. J. Med. Virol. 82:2027–2031, 2010. © 2010 Wiley‐Liss, Inc.     

Malabsorption and nutritional balance in the ICU: fecal weight as a biomarker: a prospective observational pilot study

Introduction  

Malabsorption, which is frequently underdiagnosed in critically ill patients, is clinically relevant with regard to nutritional balance and nutritional management. We aimed to validate the diagnostic accuracy of fecal weight as a biomarker for fecal loss and additionally to assess fecal macronutrient contents and intestinal absorption capacity in ICU patients.     

Morphine: double-faced roles in the regulation of tumor development

Morphine, a highly potent analgesic, is one of the most effective drugs for the treatment of severe pain associated with cancer. It directly acts on the central nervous system to relieve pain, but also cause secondary complications, such as addiction, respiratory depression and constipation due to its activities on peripheral tissues. Besides pain relief, morphine is of great importance on cancer management with its effect on tumor development being the subject of debate for many years with some contradictory findings. Morphine has shown both tumor growth-promoting and growth-inhibiting effects in many published research studies. And various signaling pathways have been suggested to be involved in these effects of morphine. Based on a thorough literature review, we summarized the double-faced effects of morphine in tumor development, including tumor cell growth and apoptosis, metastasis, angiogenesis, immunomodulation and inflammation. And we attempted to optimize morphine administration in cancer patients to attenuate its tumor growth-promoting effects.     

T lineage lymphocytes in nude mice born from homozygous nu/nu parents.

T lineage cells are found in the spleen of neonatal nu/nu mice born from nu/nu x nu/nu matings, and also in old, healthy nude mice obtained from the usual nu/+ x nu/nu matings. Their presence in neonatal nude mice which were never in contact with mother or normal littermate thymus products shows that commitment of stem cells towards the T lineage does not require the influence of the thymus.