Nerve growth factor and the physiology of pain: lessons from congenital insensitivity to pain with anhidrosis

Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder characterized by insensitivity to pain, anhidrosis (the inability to sweat) and mental retardation. Nerve growth factor (NGF) is a well-known neurotrophic factor essential for the survival and maintenance of NGF-dependent neurons, including primary afferent neurons with thin fibers and sympathetic postganglionic neurons, during development. NGF is also considered to be an inflammatory mediator associated with pain, itch and inflammation in adults. CIPA results from loss-of-function mutations in the NTRK1 gene-encoding TrkA (tropomyosin-related kinase A), a receptor tyrosine kinase for NGF. Defects in NGF-TrkA signal transduction lead to the failure of survival of various NGF-dependent neurons. As a result, patients with CIPA lack NGF-dependent neurons. Recent studies have revealed that mutations in the NGFB gene-encoding NGF protein also cause congenital insensitivity to pain. Using the pathophysiology of CIPA as a foundation, this review investigates the ways in which NGF-dependent neurons contribute to interoception, homeostasis and emotional responses and, together with the brain, immune and endocrine systems, play crucial roles in pain, itch and inflammation. The NGF-TrkA system is essential for the establishment of neural networks for interoception, homeostasis and emotional responses. These networks mediate reciprocal communication between the brain and the body in humans.     

Fit for purpose? Using the fit note with patients with chronic pain: a qualitative study

Background

Staying in work may benefit patients with chronic pain, but can be difficult for GPs to negotiate with patients and their employers. The new fit note is designed to help this process, but little is known of how it is operating.

Aim

To explore GPs'' views on the fit note, with particular reference to sickness certification for patients with chronic pain.

Design and setting

Qualitative study using semi-structured interviews in eight primary care trusts in south-west England.

Method

In-depth interviews with 13 GPs.

Results

GPs reported that the rationale behind the fit note is sound and that it may help patients with chronic pain to return to work earlier. However, GPs also reported barriers to successful fit note use, including the need to preserve doctor–patient relationships, inconsistent engagement from employers, GPs'' lack of specialist occupational health knowledge, issues with fit note training, and whether a new form can achieve cultural shift.

Conclusion

While doctors agree that good work improves health outcomes, they do not think that fit notes will greatly alter sickness-certification rates without more concerted initiatives to manage the tripartite negotiation between doctor, patient, and employer.     

Next‐generation sequencing: ready for the clinics?

Next-generation sequencing (NGS) has transformed genomic research by decreasing the cost of sequencing and increasing the throughput. Now, the focus is on using NGS technology for diagnostics and therapeutics. In this review, we discuss the possible clinical applications of NGS and the potential of some of the current systems to transition to the clinic. Clinical use of NGS technologies will enable the identification of causative mutations for rare genetic disorders through whole-genome or targeted genome resequencing, rapid pathogen screening and cancer diagnosis along with the identification of appropriate therapy. Routine clinical use of NGS technologies is appealing, but mandates high accuracy, simple assays, small inexpensive instruments, flexible throughput, short run times and most importantly, easy data analysis as well as interpretation. A number of NGS systems launched recently have least some of these characteristics, namely, small instruments, flexible throughput and short run time, but still face a few challenges. Moreover, simplified data analysis tools will need to be developed to minimize the requirement of sophisticated bioinformatics support in clinics. In summary, for successful transition of NGS to clinic, a sustained collaboration between research labs, clinical practitioners and vendors offering sequencing based genetic tests is required.     

A risk‐based decision‐making framework for blood safety: what's the case for Zika?

Risk‐based decision‐making (RBDM) is a systematic approach to decision‐making that strives to minimize risk, optimize outcomes and prioritize resources for maximum good. Such is achieved by weighing all the factors that influence policy for a given threat, drawing on the best available scientific data, engaging key stakeholders, while still considering the complex interplay of ethics, social values, politics, economics, culture and historical precedent that argue for or against intervention. In the context of blood transfusion safety, attention to RBDM stems from a growing awareness that the current paradigm of ‘safety at any cost’ is unsustainable and unbalanced. By contrast, RBDM emphasizes proportionality and encourages review of decisions as new data emerge. Zika virus (ZIKV), a formerly obscure mosquito‐borne flavivirus, emerged rapidly in 2015, spurring an international public health emergency. The mandatory adoption of laboratory‐based blood donor screening for ZIKV in the United States (US) in 2016 remains contentious. Clinical cases of transfusion‐transmitted ZIKV infection have never been reported, and four years after the emergence of ZIKV in the Americas, the pandemic has waned, suggesting that the donor screening for ZIKV is high cost yet of questionable benefit. The US response to ZIKV offers an illustrative case study of the challenges surrounding intervention to protect the blood supply from emerging pathogens, and how an RBDM framework might help to guide policy. However, careful assessment (i.e. RBDM) alone does not guarantee a desirable outcome. Rather, risk‐tolerance in a given setting should not be understated.     

Branchial cyst,sensorineural deafness,congenital heart defect,and skeletal abnormalities: Branchio‐oto‐cardio‐skeletal (BOCS) syndrome?

This article describes a boy with an unusual combination of features, namely, intrauterine growth retardation, short stature, branchial cyst, sensorineural hearing loss, congenital heart defect, rib and vertebral abnormalities, micromelia, brachymesophalangia, and absence of phalanges. We suggest that these findings comprise a new entity of combined branchio‐oto and cardio‐digital developmental field abnormalities, which we termed branchio‐oto‐cardio‐skeletal syndrome. The pattern of inheritance remains uncertain. © 2002 Wiley‐Liss, Inc.     

Hypo‐Functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: Genotype‐phenotype correlation or coincidental polymorphisms?

Hearing loss with enlargement of the vestibular aqueduct (EVA) can be associated with mutations of the SLC26A4 gene encoding pendrin, a transmembrane Cl^?/I^?/HCO exchanger. Pendrin's critical transport substrates are thought to be I^? in the thyroid gland and HCO in the inner ear. We previously reported that bi‐allelic SLC26A4 mutations are associated with Pendred syndromic EVA whereas one or zero mutant alleles are associated with nonsyndromic EVA. One study proposed a correlation of nonsyndromic EVA with SLC26A4 alleles encoding pendrin with residual transport activity. Here we describe the phenotypes and SLC26A4 genotypes of 47 EVA patients ascertained since our first report of 39 patients. We sought to determine the pathogenic potential of each variant in our full cohort of 86 patients. We evaluated the trafficking of 11 missense pendrin products expressed in COS‐7 cells. Products that targeted to the plasma membrane were expressed in Xenopus oocytes for measurement of anion exchange activity. p.F335L, p.C565Y, p.L597S, p.M775T, and p.R776C had Cl^?/I^? and Cl^?/HCO exchange rate constants that ranged from 13 to 93% of wild type values. p.F335L, p.L597S, p.M775T and p.R776C are typically found as mono‐allelic variants in nonsyndromic EVA. The high normal control carrier rate for p.L597S indicates it is a coincidentally detected nonpathogenic variant in this context. We observed moderate differential effects of hypo‐functional variants upon exchange of HCO versus I^? but their magnitude does not support a causal association with nonsyndromic EVA. However, these alleles could be pathogenic in trans configuration with a mutant allele in Pendred syndrome. Hum Mutat 0, 1–10, 2009. © 2009 Wiley‐Liss, Inc.     

Interactive e‐counselling for genetics pre‐test decisions: where are we now?

In‐person genetic counselling (GC) is the model typically used to provide patients with information regarding their genetic testing options. Current and emerging demand for genetic testing may overburden the health care system and exceed the available numbers of genetic counsellors. Furthermore, GC is not always available at times and places convenient for patients. There is little evidence that the in‐person model alone is always optimal and alternatives to in‐person GC have been studied in genetics and other areas of health care. This review summarizes the published evidence between 1994 and March 2014 for interactive e‐learning and decisional support e‐tools that could be used in pre‐test GC. A total of 21 papers from 15 heterogeneous studies of interactive e‐learning tools, with or without decision aids, were reviewed. Study populations, designs, and outcomes varied widely but most used an e‐tool as an adjunct to conventional GC. Knowledge acquisition and decisional comfort were achieved and the e‐tools were generally well‐accepted by users. In a time when health care budgets are constrained and availability of GC is limited, research is needed to determine the specific circumstances in which e‐tools might replace or supplement some of the functions of genetic counsellors.     

Update on peripheral T-cell lymphomas with T-helper phenotype: Are there too many subtypes?

Follicular helper T (T_FH) cells are the providers of T-cell help to B-cells in the development of germinal centers and for the generation of most class-switched antibodies. The markers most commonly associated with T_FH activity are IL21, IL4, CD40L, BCL6, SAP, CXCR5/CXCL13, and ICOS. T-cell lymphoma genomic studies have shown that different T-cell lymphoma types express signatures typical for T_FH cells, this including angioimmunoblastic T-cell lymphoma (AITL), a related condition termed peripheral T-cell lymphoma with T_FH phenotype and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder.Angioimmunoblastic T-cell lymphoma is a well-established entity, a clinically aggressive disease with a survival of 30% OS after 5 years. Molecular and clinical studies have confirmed this as a well-established clinicopathological entity with relatively specific gene mutations, including mutations found in hematopoietic precursor cells and others.Peripheral T-cell lymphoma with T_FH phenotype is an associated disorder with histology of PTCL but a T_FH phenotype, as defined by the expression of 2–3 immunohistochemical markers. Molecular studies on this entity are showing a partial overlap with AITL.Primary cutaneous CD4+ small/medium lymphoproliferative disorder is an entirely different process that takes place in the skin, showing frank cytologic atypia, monoclonal TCR rearrangement and T_FH phenotype in the context of a clinically benign lesion.Here we review the main clinical, molecular and diagnostic features of these three lymphoproliferative processes.     

Non‐HLA genomics: does it have a role in predicting haematopoietic stem cell transplantation outcome?

Haematopoietic stem cell transplantation (HSCT) remains the only cure for many haematological neoplasms; however, the mortality rate remains high, at around 30–80%. Complications after HSCT include relapse, graft‐versus‐host disease, graft rejection and infection. High‐resolution HLA matching has improved survival in HSCT over recent years; however, GVHD still remains a serious complication. Single nucleotide polymorphisms (SNPS) within genes that are involved with an individual's capability to mount an immune response to infectious pathogens, residual leukaemia, alloantigens or genes involved in drug metabolism have been studied for their association with HSCT outcome. Indeed, over the last 15 years, several groups, including ourselves, have demonstrated that non‐HLA gene polymorphisms can be predictive of HSCT outcome. Can genetic characteristics of the patient and donor be used in the future to tailor HSCT protocols and determine GVHD prophylaxis? This review summarizes some of the recent SNP association studies in HSCT and highlights some of the disparities therein, discussing the integral problems of performing genetic association studies on diseases with complex outcomes using heterogeneous cohorts. The review will comment on recent genomewide association studies (GWAS) and discuss their relevance in this field, and it will also comment on recent meta‐analysis combining GWAS studies with other studies such as gene expression micro array data in the field of autoimmune disease and solid organ transplantation. It will mention possible novel candidate gene polymorphisms, for example SNPS in microRNAs. In addition, it will discuss some of the inherent problems associated with gene association studies including the GRIPs (genetic risk prediction studies) recommendations. In summary, this review will assess the usefulness of non‐HLA genomic studies in HSCT with regard to predicting outcome and modifying therapy.