Frequent occurrence of identical heavy and light chain Ig rearrangements

Single-cell PCR analyses of expressed Ig H and L chain sequences presented here show that certain rearrangements occur repeatedly and account for a major segment of the well-studied repertoire of B-1 cell autoantibodies that mediate the lysis of bromelain-treated mouse erythrocytes, i.e. antibodies reactive with phosphatldyicholine (PtC). We repeatedly isolated at least 10 different types of VH region rearrangements, involving three distinct germline genes, among FACS- sorted PtC-binding B-1 cells from three strains of mice (C57BL/6J, BALB/c and C.B-17). The predominant rearrangement, VH11-DSP-JH1 (VH11 type 1), has been previously found in anti-PtC hybridomas in several studies. We show that within each of six mice from two strains (C57BL/6J and BALB/c), unique instances of IgH/IgL pairing arose either from different B cell progenitors prior to IgH rearrangement or from pre-B cells which expanded after IgH rearrangement but prior to IgL rearrangement. Together with other recurrent rearrangements described here, our findings demonstrate that clonal expansion of mature B cells cannot account for all repeated rearrangements. As suggested by initial studies of dominant idiotype expression, these findings confirm that clonal expansion is only one of the mechanisms contributing to the establishment of recurrent rearrangements.      

LAPAROSCOPIC SURGERY

The speed of adoption and popularity of laparoscopic cholecystectomy is without precedence in modern surgical history. This has resulted in therapeutic and diagnostic laparoscopy being attempted in almost every field of surgery to substitute open surgical procedures. The list is endless. It will take time to evaluate the safety and advantages of many of these procedures as reports of controlled studies and long term follow up results are awaited. While certain procedures like gall bladder surgery and appendicectomy will establish their many fold advantages over open surgery, many other procedures like repair of hernias, radical resection of bowel for malignancy etc may fail to do so once the initial enthusiasm wanes away. Any way the concept of minimally invasive surgery is going to be a dominant factor in the surgery of this decade and one should prepare to face this fascinating challenge. Further developments in laparoscopic instruments, optical system and video imaging techniques will add to the progress and safety of laparoscopic surgical procedures in the days ahead.KEY WORDS: Laparoscopic Surgery     

Stability of platelet and plasma HLA concentrations in healthy adults or random-donor platelet concentrates

The quantitative differences between the platelet HLA antigens of different individuals are potentially significant in determining the survival of transfused platelets in allosensitized patients. To learn whether platelet HLA concentration is sufficiently stable to be documented for each donor and used for donor selection, platelet and plasma HLA concentrations in five healthy adults were measured monthly for 5 consecutive months. HLA concentrations were measured by using a competitive enzyme-linked immunoassay. The results showed that both platelet and plasma HLA concentrations varied within +/- 20 percent of the mean values in each individual. Changes in plasma and platelet HLA concentrations were also studied in 5 units of random-donor platelets during in vitro storage. HLA concentrations were determined every other day over a 5-day period. There was no significant quantitative change in the platelet and plasma HLA concentrations during the 5 days of in vitro storage. Thus, platelet HLA concentrations in healthy individuals are stable and may be quantitatively documented for donor selection.     

Classical galactosaemia in Chinese: A case report and review of disease incidence

We report a case of galactose-1-phosphate uridyl transferase (GALT) deficiency in a full-term Chinese neonate, who presented with atypical biochemical features of hyperammonaemia in addition to the classical presenting features of jaundice and lethargy after feeding. Red cell GALT activity was virtually absent in the patient while 50% of normal activity was found in parents and a sibling. Mutation screening excluded both Q188R and N314D as the causative mutation in GALT gene, which suggested a possible genetic segregation among ethnic groups. Data from a Taiwan screening program suggested that the incidence of the disease was approximately 1 in 400 000 in the Chinese population which was a sixth of that in Caucasian populations.     

DOUBLE-BLIND STUDY COMPARING THE LONG-TERM EFFICACY OF THE COX-2 INHIBITOR NIMESULIDE AND NAPROXEN IN PATIENTS WITH OSTEOARTHRITIS

This double-blind one-year study compares the long-term efficacy and safety of nimesulide with naproxen in patients with osteoarthritis (OA) of the knee or hip. Patients were randomised to nimesulide 100 mg twice daily (n=183) or naproxen 250 mg morning, 500 mg evening (n=187). The primary efficacy variable was change in pain intensity (WOMAC A scale) at 6 months. Nimesulide tablets showed at least equivalent efficacy to naproxen tablets in reducing pain intensity at 6 and 12 months (nimesulide -22.5% at 6 and 12 months; naproxen -22.4% at 6 months, -19.9% at 12 months; non-inferiority proven). At 6 months the investigator assessed efficacy as ‘good’ or ‘excellent’ in 59.3% of nimesulide and 56.4% of naproxen-treated patients, with corresponding values for patient assessment of 57% and 52.7%. Both treatments were well tolerated, with fewer related gastrointestinal adverse events reported with nimesulide (77 cases, 47.5%) than with naproxen (96 cases, 54.5%). This study shows nimesulide to be as effective as naproxen in the long-term treatment of OA and to be associated with fewer gastrointestinal side-effects.     

A novel, orally active LPA1 receptor antagonist inhibits lung fibrosis in the mouse bleomycin model

Background and purpose:

The aim of this study was to assess the potential of an antagonist selective for the lysophosphatidic acid receptor, LPA₁, in treating lung fibrosis We evaluated the in vitro and in vivo pharmacological properties of the high affinity, selective, oral LPA₁-antagonist (4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid (AM966).

Experimental approach:

The potency and selectivity of AM966 for LPA₁ receptors was determined in vitro by calcium flux and cell chemotaxis assays using recombinant and native cell cultures. The in vivo efficacy of AM966 to reduce tissue injury, vascular leakage, inflammation and fibrosis was assessed at several time points in the mouse bleomycin model.

Key results:

AM966 was a potent antagonist of LPA₁ receptors, with selectivity for this receptor over the other LPA receptors. In vitro, AM966 inhibited LPA-stimulated intracellular calcium release (IC₅₀ = 17 nM) from Chinese hamster ovary cells stably expressing human LPA₁ receptors and inhibited LPA-induced chemotaxis (IC₅₀ = 181 nM) of human IMR-90 lung fibroblasts expressing LPA₁ receptors. AM966 demonstrated a good pharmacokinetic profile following oral dosing in mice. In the mouse, AM966 reduced lung injury, vascular leakage, inflammation and fibrosis at multiple time points following intratracheal bleomycin instillation. AM966 also decreased lactate dehydrogenase activity and tissue inhibitor of metalloproteinase-1, transforming growth factor β1, hyaluronan and matrix metalloproteinase-7, in bronchoalveolar lavage fluid.

Conclusions and implications:

These findings demonstrate that AM966 is a potent, selective, orally bioavailable LPA₁ receptor antagonist that may be beneficial in treating lung injury and fibrosis, as well as other diseases that are characterized by pathological inflammation, oedema and fibrosis.     

Preoperative identification of anomalous arterial anatomy at pancreaticoduodenectomy

The understanding of abdominal vascular anatomy and its anatomical variations is of considerable importance in upper abdominal surgery. We present the rare finding of a common hepatic artery arising from the superior mesenteric artery and passing anterior to the pancreatic gland in a patient undergoing a pancreaticoduodenectomy.     

Inter-hospital transfers and outcomes of critically ill patients with severe acute kidney injury: a multicenter cohort study

Introduction

Patients with severe acute kidney injury (AKI) who are hospitalized at centers that do not provide renal replacement therapy (RRT) are frequently subjected to inter-hospital transfer for the provision of RRT. It is unclear whether such transfers are associated with worse patient outcomes as compared with the receipt of initial care in a center that provides RRT. This study examined the relationship between inter-hospital transfer and 30-day mortality among critically ill patients with AKI who received RRT.

Methods

We conducted a retrospective cohort study of all critically ill patients who commenced RRT for AKI at two academic hospitals in Toronto, Canada. The exposure of interest was inter-hospital transfer for the administration of RRT. We evaluated the relationship between transfer status and 30-day mortality (primary outcome) and RRT dependence at 30 days following RRT initiation (secondary outcome), by using multivariate logistic regression with adjustment for patient demographics, clinical factors, biochemical indices, and severity of illness.

Results

Of 370 patients who underwent RRT for AKI, 82 (22.2%) were transferred for this purpose from another hospital. Compared with non-transferred patients who started RRT, transferred patients were younger (61 ± 15 versus 65 ± 15 years, P = 0.03) and had a higher serum creatinine concentration at RRT initiation (474 ± 295 versus 365 ± 169 μmol/L, P = 0.002). Inter-hospital transfer was not associated with mortality (adjusted odds ratio 0.61, 95% confidence interval 0.33 to 1.12) or RRT-dependence (adjusted odds ratio 1.64, 95% confidence interval 0.70 to 3.81) at 30 days.

Conclusions

Within the limitations of this observational study and the potential for residual confounding, inter-hospital transfer of critically ill patients with AKI was not associated with a higher risk of death or dialysis dependence 30 days after the initiation of acute RRT.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0513-1) contains supplementary material, which is available to authorized users.