The Molecular Mechanism of B Cell Activation by toll-like Receptor Protein RP-105

The B cell–specific transmembrane protein RP-105 belongs to the family of Drosophila toll-like proteins which are likely to trigger innate immune responses in mice and man. Here we demonstrate that the Src-family protein tyrosine kinase Lyn, protein kinase C β I/II (PKCβI/II), and Erk2-specific mitogen-activated protein (MAP) kinase kinase (MEK) are essential and probably functionally connected elements of the RP-105–mediated signaling cascade in B cells. We also find that negative regulation of RP-105–mediated activation of MAP kinases by membrane immunoglobulin may account for the phenomenon of antigen receptor–mediated arrest of RP-105–mediated B cell proliferation.     

Improving programme-led and focused interventions for eating disorders: An experts' consensus statement—A UK perspective

Objective

Eating disorders are associated with significant illness burden and costs, yet access to evidence-based care is limited. Greater use of programme-led and focused interventions that are less resource-intensive might be part of the solution to this demand-capacity mismatch.

Method

In October 2022, a group of predominantly UK-based clinical and academic researchers, charity representatives and people with lived experience convened to consider ways to improve access to, and efficacy of, programme-led and focused interventions for eating disorders in an attempt to bridge the demand-capacity gap.

Results

Several key recommendations were made across areas of research, policy, and practice. Of particular importance is the view that programme-led and focused interventions are suitable for a range of different eating disorder presentations across all ages, providing medical and psychiatric risk are closely monitored. The terminology used for these interventions should be carefully considered, so as not to imply that the treatment is suboptimal.

Conclusions

Programme-led and focused interventions are a viable option to close the demand-capacity gap for eating disorder treatment and are particularly needed for children and young people. Work is urgently needed across sectors to evaluate and implement such interventions as a clinical and research priority.     

Cochlear implants in the management of hearing loss in Neurofibromatosis Type 2

Objective: Review of cochlear implant (CI) outcomes in patients with Neurofibromatosis Type 2 (NF2), implanted in the presence of an ipsilateral vestibular schwannoma (VS). Hearing restoration was combined in some cases with a Bevacizumab regime.

Method: Retrospective review of 12 patients, managed over the period 2009–2016, at a tertiary referral multidisciplinary NF2 clinic. The patients are grouped by hearing outcomes to explore likely protective factors, and to generate a proposed decision-making tool for the selection of either CI or Auditory Brainstem Implant (ABI).

Results: Four of the 12 patients achieved speech discrimination without lip-reading. In these individuals there is reason to think that the mechanism of their hearing loss was cochlear dysfunction. A further four patients received benefit to lip-reading and awareness of environmental sound. For such patients their hearing loss may have been due to both cochlear and neural dysfunction. Two patients gained access to environmental sound only from their CI. Two patients derived no benefit from their CIs, which were subsequently explanted. Both these latter patients had had prior ipsilateral tumour surgery, one just before the CI insertion.

Conclusion: Cochlear implantation can lead to open set speech discrimination in patients with NF2 in the presence of a stable VS. Use of promontory stimulation and intraoperative electrically evoked auditory brainstem response testing, along with case history, can inform the decision whether to implant an ABI or CI.     

Nerve Growth Factor Plasma Levels and Ventricular Repolarization in Rett Syndrome

Rett syndrome is a severe neurological developmental disorder. In this syndrome, the high incidence of sudden death is correlated with an alteration of ventricular repolarization. The purpose of this study was to evaluate plasmatic levels of nerve growth factor (NGF) in Rett patients with prolonged corrected QT (QTc) interval in comparison with those of Rett patients with normal QTc. We observed 23 female Rett patients (9.9 ± 4.7 years). NGF plasma levels and QTc interval were measured in all patients. Student t-test was performed for statistical analysis. NGF plasma levels were significantly lower in Rett patients with QTc interval prolongation (QTc > 0.44 sec) in comparison with Rett patients with a normal QTc interval (4.5 ± 4.5 vs 11 ± 8.3 pg/ml, p = 0.02). The alteration of NGF levels, observed in Rett patients with a long QTc interval, may explain the presence of an altered ventricular repolarization associated with a higher risk of cardiac arrhythmias.     

Polymorphisms in the insulin receptor substrate-1 (IRS-1) gene and the insulin receptor substrate-2 (IRS-2) gene influence glucose homeostasis and body mass index in women with polycystic ovary syndrome and non-hyperandrogenic controls

BACKGROUND: We aimed to evaluate the influence of the Gly972Arg variant of the insulin receptor substrate-1 gene (IRS-1) and the Gly1057Asp variant in IRS-2 on insulin resistance and glucose tolerance in women with polycystic ovary syndrome (PCOS) and healthy controls. METHODS: Genotypes, allelic frequencies, indexes of insulin resistance, glucose tolerance and hormone profiles were studied in a large sample of Spanish PCOS (n = 103) women compared with a control group (n = 48) of healthy women matched for body mass index. RESULTS: No differences in genotype or allelic frequencies were found between PCOS patients and healthy controls. When considering control subjects and PCOS patients as a whole, IRS-1 Arg972 carriers also presented with increased fasting insulin (133 +/- 60 versus 95 +/- 67 pmol/l, P = 0.008) and insulin resistance measured by homeostasis model assessment (4.3 +/- 2.1 versus 3.1 +/- 2.4, P = 0.009) compared with subjects homozygous for Gly972 alleles. These differences were even higher when restricting the analysis to PCOS patients. Subjects homozygous for the Gly1057 allele of IRS-2 presented with increased 60 and 90 min oral glucose tolerance test (OGTT) glucose levels compared with carriers of one or two Asp1057 alleles (7.9 +/- 2.1 versus 7.1 +/- 2.1 mmol/l, P = 0.042 and 7.0 +/- 2.1 versus 6.0 +/- 1.8 mmol/l, P = 0.014), and a similar tendency was observed for 120 min OGTT glucose levels. CONCLUSIONS: The Gly972Arg in IRS-1 and Gly1057Asp in IRS-2 polymorphisms influence glucose homeostasis in premenopausal women, but are not associated with PCOS.     

PCR study of a series of ASCUS cases HPV-positive by HCII

Most guidelines currently recommend the testing of human papillomavirus (HPV) in ASCUS cases. The most used method for this purpose is Hybrid Capture II (HCII), but PCR techniques with GP5+/6+ primers can be also applied. Furthermore, the HCII high‐risk probe test for detection of HPV shows cross‐reactivity with low‐risk HPV. Although this cross‐reactivity has been studied in screening populations, it has received little attention in ASCUS cases. To compare the performance of the HCII high‐risk probe test and PCR for the detection of HPV in ASCUS cases. We randomly selected 83 ASCUS cases that were positive for high‐risk HPV by HCII and applied the PCR test using MYO9‐11 and GP5+/6+ primers to samples from these cases. Our results show cross‐reactivity with low‐risk HPV in 25.3% (21/83) of the HCII+ PCR+ cases. Regarding the follow‐up our results emphasize the importance of HPV typing, especially for HPV 16 infection. We propose the use of PCR techniques using GP5+/6+ consensus primers for the screening of HPV in ASCUS. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.     

Evaluation of late cognitive impairment and anxiety states following traumatic brain injury in mice: The effect of minocycline

Comorbidity of cognitive and stress disorders is a common clinical sequel of traumatic brain injury (TBI) that is essentially determined by the site and severity of the insult, but also by the extent of the ensuing neuroinflammatory response. The present study sought to examine the late effects of closed-head TBI on memory function and anxiety in mice, in order to further examine the potential efficacy of an acute anti-inflammatory treatment with minocycline. The mouse model of closed-head injury by mechanical percussion was applied on anesthetized Swiss mice. The treatment protocol included three injections of minocycline (i.p.) at 5 min (90 mg/kg), 3 h and 9 h (45 mg/kg) post-TBI. The Novel Object Recognition Test as well as the Elevated Plus Maze (EPM) and Elevated Zero Maze (EZM) tasks were employed to assess post-TBI memory and anxiety respectively. Our results revealed a recognition memory deficit that was significant up to at least 13 weeks post-TBI. However, neither EPM nor EZM revealed any alteration in post-TBI anxiety levels albeit some mild disinhibition. Most importantly, minocycline was able to attenuate the memory impairment in an effective and lasting manner, highlighting its therapeutic potential in TBI.