Plasma-derived mannose-binding lectin shows a direct interaction with C1-inhibitor

MBL-deficiency has been associated with an increased frequency and severity of infection, in particular in children and under immunocompromized conditions. In an open uncontrolled safety and pharmacokinetic MBL-substitution study using plasma-derived MBL (pdMBL) in MBL-deficient pediatric oncology patients, we found that despite MBL trough levels above 1.0 μg/ml MBL functionality was not efficiently restored upon ex vivo testing.     

A Novel Catechol-O-Methyltransferase Variant Associated with Human Disc Degeneration

Background: Disc degeneration and its associated low back pain are a major health care concern causing disability with a prominent role in this country''s medical, social and economic structure. Low back pain is devastating and influences the quality of life for millions. Low back pain lifetime prevalence approximates 80% with an estimated direct cost burden of $86 billion per year. Back pain patients incur higher costs, greater health care utilization, and greater work loss than patients without back pain.Methods: Research was performed following approval of our Institutional Review Board. DNA was isolated, processed and amplified using routine techniques. Amplified DNA was hybridized to Affymetrix Genome-Wide Human SNP Arrays. Quality control and genotyping analysis were performed using Affymetrix Genotyping Console. The Birdseed v2 algorithm was used for genotyping analysis. 2589 SNPs were selected a priori to enter statistical analysis using lotistic regression in SAS.Results: Our objective was to search for novel single nucleotide polymorphisms (SNPs) associated with disc degeneration. Four SNPs were found to have a significant relationship to disc degeneration; three are novel. Rs165656, a new SNP found to be associated with disc degeneration, was in catechol-O-methyltransferase (COMT), a gene with well-recognized pain involvement, especially in female subjects (p=0.01). Analysis confirmed the previously association between COMT SNP rs4633 and disc degeneration. We also report two novel disc degeneration-related SNPs (rs2095019 and rs470859) located in intergenic regions upstream to thrombospondin 2.Conclusions: Findings contribute to the challenging field of disc degeneration and pain, and are important in light of the high clinical relevance of low back pain and the need for improved understanding of its fundamental basis.     

Incidence of calcaneal apophysitis in the general population

Background

Calcaneal apophysitis, or Sever’s disease, is a traction apophysitis. It is a frequent cause of heel pain in children. Knowledge about the exact incidence of calcaneal apophysitis in the general population, however, is lacking.

Design

Cross-sectional study.

Methods

From 34 general practices, records of patients between 6 and 17 years old, visiting the general practitioner (GP), were analysed. Diagnoses of calcaneal apophysitis were counted using computerised registration networks of GPs in 2008, 2009 and 2010.

Results

There were 16,383 SOAP files searched and a number of 61 children with calcaneal apophysitis were established over the years 2010, 2009 and 2008, showing an incidence of 3.7 in 1,000 registered patients.

Conclusion

This is the first report on incidence rates of calcaneal apophysitis in general practice. With an incidence of 3.7 in 1,000 registered patients, it is a common pathologic entity, which requires more research on pathophysiology and therapy. The actual incidence may even be higher due the strict inclusion criteria of this study.     

Angelman syndrome in adulthood

We studied the clinical and EEG-findings in 28 adult patients (aged 20–53 years) with Angelman syndrome (AS). Twenty-three showed a maternal chromosome 15q11–13 deletion; in 5, the diagnosis was based on a combination of typical clinical findings. Compared to the clinical manifestations present in childhood, “coarsening” of facial traits (100%), thoracic scoliosis (71%), and being wheelchair-bound (39%) were found more frequently. Paroxysms of laughter were still observed in adulthood (79%), but less frequently than in childhood. Most adult patients could feed themselves, but needed help with many daily activities. The majority (82%) had epileptic seizures. Abnormal EEG-activity consisting of 2–3/s rhythmic triphasic waves of high amplitude with a maximum over the frontal regions, which has been identified in many AS children, was found in 67% of these adult patients. © 1996 Wiley-Liss, Inc.     

Coculture of rat embryonic proprioceptive sensory neurons and myotubes

With the aim to study the cellular mechanisms underlying the process of muscle spindle (re)generation, dorsal root ganglia (DRG) neurons derived from 16-day rat embryos were cocultured with developing myotubes in a compartmentalized culture device. To accomplish the selective survival and neurite formation of the proprioceptive subpopulation, the neurotrophic factor, neurotrophin-3, was added to the culture medium. It appeared that the proprioceptive DRG neurons could develop specialized, Ia afferent terminal-like contacts with myotubes. However, these interactions were scarce and did not result in the induction of differentiation of the contacted myotubes into intrafusal fibers as normally occurs during in vivo development. The present coculture setup apparently lacks appropriate regulatory factors essential for the proper matching of sensory axons and intrafusal fiber precursors and the induction of a functional sensory myoneural connection. © 1996 John Wiley & Sons, Inc.     

Pretransplantation Donor–Recipient Pair Seroreactivity Against BK Polyomavirus Predicts Viremia and Nephropathy After Kidney Transplantation

Kidney transplant donors are not currently implicated in predicting BK polyomavirus (BKPyV) infection in kidney transplant recipients. It has been postulated, however, that BKPyV infection originates from the kidney allograft. Because BKPyV seroreactivity correlates with BKPyV replication and thus might mirror the infectious load, we investigated whether BKPyV seroreactivity of the donor predicts viremia and BKPyV‐associated nephropathy (BKPyVAN) in the recipient. In a retrospective cohort of 407 living kidney donor–recipient pairs, pretransplantation donor and recipient sera were tested for BKPyV IgG levels and correlated with the occurrence of recipient BKPyV viremia and BKPyVAN within 1 year after transplantation. Donor BKPyV IgG level was strongly associated with BKPyV viremia and BKPyVAN (p < 0.001), whereas recipient BKPyV seroreactivity showed a nonsignificant inverse trend. Pairing of high–BKPyV‐seroreactive donors with low‐seroreactive recipients resulted in a 10‐fold increased risk of BKPyV viremia (hazard ratio 10.1, 95% CI 3.5–29.0, p < 0.001). In multivariate analysis, donor BKPyV seroreactivity was the strongest pretransplantation factor associated with viremia (p < 0.001) and BKPyVAN (p = 0.007). The proportional relationship between donor BKPyV seroreactivity and recipient infection suggests that donor BKPyV seroreactivity reflects the infectious load of the kidney allograft and calls for the use of pretransplantation BKPyV serological testing of (potential) donors and recipients.     

The anti‐C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID‐19

Recently, we reported the phase II portion of the adaptive phase II/III PANAMO trial exploring potential benefit and safety of selectively blocking C5a with the monoclonal antibody vilobelimab (IFX‐1) in patients with severe coronavirus disease 2019 (COVID‐19). The potent anaphylatoxin C5a attracts neutrophils and monocytes to the infection site, causes tissue damage by oxidative radical formation and enzyme releases, and leads to activation of the coagulation system. Results demonstrated that C5a inhibition with vilobelimab was safe and secondary outcomes appeared in favor of vilobelimab. We now report the pharmacokinetic/pharmacodynamic (PK/PD) analysis of the phase II study. Between March 31 and April 24, 2020, 30 patients with severe COVID‐19 pneumonia confirmed by real‐time polymerase chain reaction were randomly assigned 1:1 to receive vilobelimab plus best supportive care or best supportive care only. Samples for measurement of vilobelimab, C3a and C5a blood concentrations were taken. Vilobelimab predose (trough) drug concentrations in plasma ranged from 84,846 to 248,592 ng/ml (571 to 1674 nM) with a geometric mean of 151,702 ng/ml (1022 nM) on day 2 and from 80,060 to 200,746 ng/ml (539 to 1352 nM) with a geometric mean of 139,503 ng/ml (939 nM) on day 8. After the first vilobelimab infusion, C5a concentrations were suppressed in the vilobelimab group (median 39.70 ng/ml 4.8 nM, IQR 33.20–45.55) as compared to the control group (median 158.53 ng/ml 19.1 nM, IQR 60.03–200.89, p = 0.0006). The suppression was maintained on day 8 (p = 0.001). The current PK/PD analysis shows that vilobelimab efficiently inhibits C5a in patients with severe COVID‐19.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

High concentrations of the potent anaphylatoxin C5a have been reported in patients with severe coronavirus disease 2019 (COVID‐19), and the C5a–C5aR1 signaling axis has been suggested to be crucial in COVID‐19 associated inflammation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does the anti‐C5a antibody vilobelimab efficiently inhibit C5a in patients with severe COVID‐19?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The current pharmacokinetic/pharmacodynamic analysis of the phase II part of the adaptive phase II/III PANAMO trial shows that vilobelimab efficiently inhibits C5a in patients with severe COVID‐19. Our results confirm that C5a is strongly elevated in patients with severe COVID‐19.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results suggest a potential important role of C5a‐inhibition for patients with severe COVID‐19. With our previous report on the clinical outcome, this underlines the need to investigate, within the currently enrolling phase III trial, whether C5a‐inhibition may positively impact 28‐day survival in critically ill patients with COVID‐19.     

Clinical aspects of induced hypothermia in full term neonates with perinatal asphyxia

Moderate hypothermia is a novel neuroprotective therapy for full term neonates with severe perinatal asphyxia. Although the therapy appears to be safe, admission to a level III neonatal intensive care unit of these patients is justified. Potential complications include hypotension, tube obstruction due to sticky secretions, severe bradycardia, and thrombocytopenia. Furthermore, doses of commonly used drugs such as sedatives, anticonvulsants and antibiotics should be adjusted during hypothermia and on rewarming, and should be monitored carefully. Further studies aiming at optimizing onset, duration, and depth of hypothermia in neonates are necessary. Combination of hypothermia with drugs may further improve neuroprotection in asphyxiated full term neonates.