Michael Walsh

Anaplastic (undifferentiated) thyroid cancer: improved insight and therapeutic strategy into a highly aggressive disease.

BACKGROUNDnThis review article discusses the clinical and diagnostic implications of anaplastic thyroid cancer, recognizing the aggressive nature of the disease and extensive disease progression upon diagnosis. Standard treatment strategies (surgical, chemotherapy, radiation) are discussed, comparing adjuvant and neo-adjuvant regimens and the emergence of tumour resistance with expression of multidrug resistance pumps. We question the pathological evolution of anaplasia as a de novo disease or a post malignant transformation or dedifferentiation and the therapeutic implications of p53 mutation. Future treatment options are reviewed with an emphasis on specific molecular targets responsible for the neoplastic phenotype.nnnMETHODnAn electronic search on Medline and Pubmed was performed under anaplastic thyroid carcinoma, anaplastic thyroid carcinogenesis, anaplastic thyroid carcinoma treatment reviews. Relevant papers were systematically reviewed from 1965 to present.

Anaplastic thyroid cancer, tumorigenesis and therapy.

BackgroundAnaplastic thyroid cancer (ATC) is a fatal endocrine malignancy. Current therapy fails to significantly improve survival. Recent insights into thyroid tumorigenesis, post-malignant dedifferentiation and mode of metastatic activity offer new therapeutic strategies.MethodsAn extensive literature search of Medline and Pubmed was conducted to include all published reports on ATC. Secondary articles were identified from key paper reference listings.ConclusionsSignificant progress, in the last 5xa0years, has been made outlining thyroid tumorigenesis and the progression to anaplasia. Continued identification and development of drug therapies is required to counter specific molecular targets responsible for the post-malignant dedifferentiation process and ultimately the fatal neoplastic phenotype.

Eosinophil recruitment to nasal nerves after allergen challenge in allergic rhinitis.

In allergen challenged animal models, eosinophils localize to airway nerves leading to vagally-mediated hyperreactivity. We hypothesized that in allergic rhinitis eosinophils recruited to nasal nerves resulted in neural hyperreactivity. Patients with persistent allergic rhinitis (n=12), seasonal allergic rhinitis (n=7) and controls (n=10) were studied. Inferior nasal turbinate biopsies were obtained before, 8 and 48h after allergen challenge. Eight hours after allergen challenge eosinophils localized to nerves in both rhinitis groups; this was sustained through 48h. Bradykinin challenge, with secretion collection on the contralateral side, was performed to demonstrate nasal nerve reflexes. Twenty fourhours after allergen challenge, bradykinin induced a significant increase in secretions, indicating nasal hyperreactivity. Histological studies showed that nasal nerves expressed both vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-C motif) ligand 26 (CCL-26). Hence, after allergen challenge eosinophils are recruited and retained at nerves and so may be a mechanism for neural hyperreactivity.

In vitro fertilisation and allied techniques the initial experiences of the first Irish service

SummarySince 1986 in vitro fertilisation and allied techniques have formed a part of the fertility service at St. James’s Hospital. By June 1988 using routine methodology, IVF or GIFT has been attempted at least once in 94 women with a further 17 having one repeat procedure and 4 two repeat procedures performed. Although embryos were cultured from 54% of oocytes in which fertilisation was attempted, no pregnancies were achieved during that period with IVF. Ten pregnancies had occurred during a GIFT cycle (9 at first attempt, 16%) 60% of these are on-going. Also continuing were pregnancies where ovulation induction was abandoned on day 8(1) and where conception occurred spontaneously whilst on the waiting list for the procedure (8) and in untreated cycles following the procedure (4) (16%). Seventy percent of patients who failed the first time expressed a wish to try again.

Role of sphingosine 1-phosphate receptor expression in eosinophils of patients with allergic rhinitis, and effect of topical nasal steroid treatment on this receptor expression

OBJECTIVEnRecent research has indicated that sphingosine 1-phosphate plays a role in allergy. This study examined the effect of allergen challenge on the expression of sphingosine 1-phosphate receptors on the eosinophils of allergic rhinitis patients, and the effect of steroid treatment on this expression.nnnSTUDY DESIGNnA prospective, non-randomised study.nnnMETHODSnThe study had three parts. Firstly, sphingosine 1-phosphate receptor expression on the eosinophils of allergic rhinitis patients and control patients was determined. Secondly, sphingosine 1-phosphate receptor expression was quantified pre- and post-allergen challenge, before and after a short course of fluticasone propionate; all patients underwent symptom scoring and peak nasal inspiratory flow measurement pre- and post-allergen challenge, both before and after steroid or saline treatment. Thirdly, the effect of sphingosine 1-phosphate on eosinophil migration was examined.nnnRESULTSnThe eosinophils of both allergic rhinitis patients and controls expressed sphingosine 1-phosphate1, 3, 4, and 5. Eosinophils from all allergic rhinitis patients demonstrated up-regulation in sphingosine 1-phosphate expression after allergen challenge. These changes were statistically very significant for sphingosine 1-phosphate1, 4, and 5, and moderately significant for sphingosine 1-phosphate3. Sphingosine 1-phosphate receptor expression up-regulation was abolished in the steroid-treated group after allergen challenge; however, the saline-treated group showed no change in sphingosine 1-phosphate receptor expression after allergen challenge. Peak nasal inspiratory flow scores were significantly diminished after allergen challenge prior to treatment, but not after a course of topical nasal steroids. Sphingosine 1-phosphate induced eosinophil chemotaxis was increased following allergen challenge in allergic rhinitis subjects.nnnCONCLUSIONSnLocal intranasal steroid therapy acts directly to block allergen-induced up-regulation of sphingosine 1-phosphate receptors on the peripheral eosinophils of allergic rhinitis patients, and this is coincident with post-challenge peak nasal inspiratory flow measurement improvements. These observations support the idea that such an increase in sphingosine 1-phosphate receptor expression is clinically relevant in allergic rhinitis, with potential consequences for eosinophil migration and survival.

Subjects with non-allergic non-infectious perennial rhinitis do not show nasal hyper-responsiveness to bradykinin

Symptoms in non-allergic non-infectious perennial rhinitis (NANIPER) are characteristically trigged by non-specific irritants. Hyper-responsiveness to cold dry air has been demonstrated in NANIPER. Bradykinin is a peptide involved in allergic inflammation. Neurally mediated hyper-responsiveness to bradykinin has been demonstrated in allergic rhinitis. The purpose of the present study was to investigate whether hyper-responsiveness to bradykinin is present in NANIPER. Normal subjects (nxa0=xa013) and subjects with NANIPER (nxa0=xa010) were subjected to a nasal bradykinin challenge protocol. Secretory responses were measured using filter paper disks, and congestive responses measured using acoustic rhinometry. Compared to normal subjects, with NANIPER had a greater secretory response to control challenge with Hartman’s solution. On the other hand, the normal ipsilateral secretory and congestive response to bradykinin was absent in NANIPER. Subjects with NANIPER did not demonstrate any evidence of reflex responses to bradykinin, and no evidence of nasal hyper-responsiveness to bradykinin. Hyper-responsiveness to bradykinin is absent in NANIPER. These results suggest that autonomic hyporesponsiveness rather than neural hyper-responsiveness may be an important factor in the etiology of NANIPER.

The Allergic Rhinitis and its Impact on Asthma system: a new classification of allergic rhinitis and nasal responsiveness.

OBJECTIVES AND HYPOTHESISnAllergic rhinitis has traditionally been classified into seasonal and perennial rhinitis. However, many subjects with dual sensitisation do not fit neatly into either category. Recently, the Allergic Rhinitis and its Impact on Asthma workshop has proposed a new allergic rhinitis classification, into intermittent and persistent forms. The purpose of the present study was to investigate whether the symptomatic and secretory responsiveness of allergic rhinitis sufferers correlated well with the Allergic Rhinitis and its Impact on Asthma classification, compared with the traditional classification.nnnSTUDY DESIGNnExperimental study.nnnMETHODSnForty subjects with allergic rhinitis and 13 normal controls underwent a unilateral nasal bradykinin challenge protocol. Symptom scores were recorded and secretion weights measured bilaterally using filter paper disks. The symptomatic and secretory responses of allergic subjects were analysed according to both the traditional and the Allergic Rhinitis and its Impact on Asthma classifications, and the two systems were compared.nnnRESULTSnFor both classification systems, the two groups of allergic subjects were clearly demarcated by secretory responses. However, after classification according to the traditional system, there was a lack of clear demarcation between the groups as regards symptomatic response, whereas clear demarcation of symptomatic responses was seen after using the Allergic Rhinitis and its Impact on Asthma classification.nnnCONCLUSIONSnIn allergic rhinitis subjects, the degree of nasal responsiveness was closely related to their Allergic Rhinitis and its Impact on Asthma classification. Furthermore, this classification was not compromised by the inclusion of subjects with dual sensitisation. Thus, the Allergic Rhinitis and its Impact on Asthma classification may have advantages for future research studies on allergic rhinitis.

Olfactory Derived Stem Cells Delivered in a Biphasic Conduit Promote Peripheral Nerve Repair In Vivo

Peripheral nerve injury presents significant therapeutic challenges for recovery of motor and sensory function in patients. Different clinical approaches exist but to date there has been no consensus on the most effective method of treatment. Here, we investigate a novel approach to peripheral nerve repair using olfactory derived stem (ONS) cells delivered in a biphasic collagen and laminin functionalized hyaluronic acid based nerve guidance conduit (NGC). Nerve regeneration was studied across a 10‐mm sciatic nerve gap in Sprague Dawley rats. The effect of ONS cell loading of NGCs with or without nerve growth factor (NGF) supplementation on nerve repair was compared to a cell‐free NGC across a variety of clinical, functional, electrophysiological, and morphologic parameters. Animals implanted with ONS cell loaded NGCs demonstrated improved clinical and electrophysiological outcomes compared to cell free NGC controls. The nerves regenerated across ONS cell loaded NGCs contained significantly more axons than cell‐free NGCs. A return of the nocioceptive withdrawal reflex in ONS cell treated animals indicated an advanced repair stage at a relatively early time point of 8 weeks post implantation. The addition of NGF further improved the outcomes of the repair indicating the potential beneficial effect of a combined stem cell/growth factor treatment strategy delivered on NGCs. Stem Cells Translational Medicine 2017;6:1894–1904

William Wilde: his contribution to otology.

AbstractnSir William Wilde pioneered the epidemiology of deafness. He set otology on a firm scientific basis by applying the principles established by Robert Graves and William Stokes of the Dublin School of Medicine of correlating clinical observation with post-mortem findings and utilising this information as a framework for therapeutic intervention.