Physicochemical, biological, functional and toxicological characterization of the European follow-on glatiramer acetate product as compared with Copaxone.

For more than 20 years, Copaxone (glatiramer acetate, Teva), a non-biological complex drug, has been a safe and effective treatment option for multiple sclerosis. In 2016, a follow-on glatiramer acetate product (FOGA, Synthon) was approved in the EU. Traditional bulk-based methods and high-resolution assays were employed to evaluate the physicochemical, functional, and bio-recognition attributes, as well as the in vivo toxicity profile of the active substances in Copaxone and Synthon EU FOGA lots. These tests included quality control tests applied routinely in release of Copaxone lots, as well as additional characterization assays, gene expression studies and a rat toxicity study. Even though the Synthon FOGA was designed to copy and compete with Copaxone, the active substances were found to be similar in only 7 of the tested 14 (50%) methods (similar is defined as within approved specifications or within the inherent microheterogeneity range of tested Copaxone batches, or not showing statistically significant differences). With additional methods applied, consistent compositional differences in attributes of surface charge distribution, molecular size, and spatial arrangement were observed. These marked differences were concordantly observed with higher biological activity of some of the Synthon EU FOGA lots compared with Copaxone lots, including potency and cytotoxicity activities as well as gene expression of pathways that regulate apoptosis, IL-2, and inflammation signaling. These observations raise concerns for immunogenicity differences, particularly in (repeated) substitution settings. Another orthogonal finding demonstrated increased frequency of injection-site local toxicity observations for the Synthon EU FOGA in an in vivo daily dosing rat study, thus warranting further qualification of the link between compositional and functional differences in immunogenicity, and potential impact on long-term efficacy and safety.

Eustachian tube dysfunction leading to middle-ear pathology in patients on chronic mechanical ventilation.

OBJECTIVE: This study aimed to investigate the prevalence of and risk factors for Eustachian tube dysfunction leading to middle-ear pathology in patients on chronic mechanical ventilation via tracheostomy tube. METHODS: A total of 40 patients on chronic ventilation were included in a prospective cohort study. Middle-ear status was determined by tympanometry. Tympanograms were categorised as types A, B or C; types B and C were defined as middle-ear pathology. RESULTS: In all, 57 ears of 40 patients were examined. Disease was found in at least 1 ear in 26 out of 40 patients. Middle-ear pathology was found in 25 out of 34 patients who were tube fed (via nasogastric tube or percutaneous endoscopic gastrostomy) vs 1 patient out of the 6 fed orally (p = 0.014), and in 23 out of 31 with conscious or cognitive impairment vs 3 out of 9 cognitively intact patients (p = 0.044). CONCLUSION: Middle-ear pathology is common in patients on chronic mechanical ventilation via tracheostomy tube. The highest prevalence was in those with impaired consciousness or cognition, and oral feeding appeared protective.

The behaviour of residual tumour after the intentional incomplete excision of a vestibular schwannoma: is it such a bad thing to leave some behind?

OBJECTIVES: To evaluate the biological behaviour of tumour remnants intentionally left in the surgical bed following the incomplete excision of vestibular schwannomas (VS) and to review the relation between extent of resection and preservation of facial nerve function. METHODS: A retrospective chart review of 450 patients who underwent surgery for resection of VS over 23 years (1992-2014). Of these, 50 (11%) patients had residual tumour intentionally left on/around the facial nerve (near-total or subtotal excision) to preserve facial nerve function intra-operatively. The growth of residual tumour was evaluated using serial magnetic resonance imaging scanning; pre- and postoperative facial nerve function was assessed using the House-Brackmann grading scale. SETTING: Tertiary referral neurotology unit. RESULTS: Of the 42 non-NF2 cases where the tumour was intentionally incompletely excised, 28 (67%) patients underwent subtotal resection (mean follow-up 68.5 ± 39.0 months) and 14 (33%) underwent near-total resection (mean follow-up 72.9 ± 48.3 months). Three patients (all in subtotal resection group) showed regrowth. This was not statistically different from the near-total resection group (χ2 = 0.92, P = 0.31). The mean overall growth for these cases was 0.68 mm ± 0.32 mm/year. 5 (one near total, four subtotal) of the eight NF2 patients (62.5%) were excluded from our analysis. In the non-NF2 group, poor facial nerve outcomes (House-Brackmann scores of III-IV) were seen in 2/14 and V-VI in 3/14 of the near total compared with 7/25 and 4/25 respectively in the subtotal group. CONCLUSIONS: Given that the primary surgery for the VS was only for tumours that were relatively large or grew during conservative treatment, the low rate of tumour remnant growth (7%) is reassuring. It may be appropriate to have a lower threshold for leaving tumour on the facial nerve in non-NF2 patients where complete resection may jeopardise facial nerve function.

Olfactory and cochleovestibular dysfunction after head injury in the workplace: an updated series.

OBJECTIVES: The objective of this study was to determine the incidence of olfactory dysfunction in workers following head injury in the work place, to define its relationship to the site, severity of injury and direction of force. The demographics of head injured workers were also assessed to determine whether those with olfactory loss were more likely to have sustained a cochleovestibular injury. DESIGN: Retrospective case analysis. SETTING: Tertiary referral university hospital in Toronto, Ontario. PARTICIPANTS: A total of 3438 consecutive patients referred from the Workplace Safety and Insurance Board (WSIB) in the province of Ontario who sustained a work-related head injury were assessed between 1987 and 2014. MAIN OUTCOME MEASURES: Olfactory and cochleovestibular dysfunction assessed by history, clinical examination and subjective and objective tests. RESULTS: Olfactory dysfunction (OD) was identified in 413 of 3438 patients (12.0%) of which 321 were diagnosed with anosmia and 92 with hyposmia. In our series, injuries from a fall were the commonest cause for OD and a frontal or mid-face impact was more likely to result in OD than other regions (P = 0.0002). A loss of consciousness (LOC) of any duration correlated with OD. In those with olfactory dysfunction, an associated skull fracture occurred in 37.1% of patients and a CSF leak in 4.1%, which was significantly higher compared with those without OD(<0.0001). Patients with OD had a higher incidence of cochlear and vestibular loss (19.9% and 20.6%, respectively) compared with those without OD (14.3% and 17.1%, respectively). CONCLUSIONS: Post-traumatic olfactory dysfunction is more likely to occur in patients who experienced a moderate to severe head injury, LOC and more likely to result from a frontal or mid-face blow to the skull. Cochleovestibular dysfunction is likely to occur concurrently with olfactory dysfunction.

Intratympanic therapy in Meniere's syndrome or disease: up to date evidence for clinical practice.

BACKGROUND: Meniere's syndrome or disease (MS/D) is typically characterised by episodic vertigo, aural fullness, tinnitus and fluctuating hearing loss. There are multiple options available for treatment with variation in consensus on the best intervention. OBJECTIVE: To evaluate the evidence on the efficacy of intratympanic therapies [steroids, gentamicin, antivirals and other therapies] on the frequency and severity of vertigo and other symptoms of MS/D. SEARCH STRATEGY: A literature search was performed on AMED, EMBASE, HMIC, MEDLINE, PsycINFO, BNI, CINAHL, HEALTH BUSINESS ELITE, CENTRAL and Cochrane Ear, Nose and Throat disorders group trials register using various MeSH. The search was restricted to English and human subjects, and the last date of search was December 2014. SELECTION CRITERIA: Randomised controlled trials of intratympanic therapies [steroids, gentamicin antivirals and latanoprost] versus a placebo or another treatment. RESULTS: We analysed 8 RCT's comparing intratympanic steroids, gentamicin, ganciclovir (antiviral) and latanoprost versus another form of intratympanic treatment or placebo. CONCLUSIONS: On the basis of 6 RCT's (n = 242), there is evidence to support the effectiveness of intratympanic steroids and gentamicin to control symptoms of vertigo in MS/D albeit with a risk of hearing loss with gentamicin. However, there was no consensus found on doses or treatment protocols. There was no evidence to support the use of other forms of intratympanic therapy (antivirals and latanoprost) in MS/D.

Protein tyrosine kinases in bacterial pathogens are associated with virulence and production of exopolysaccharide.

In eukaryotes, tyrosine protein phosphorylation has been studied extensively, while in bacteria, it is considered rare and is poorly defined. We demonstrate that Escherichia coli possesses a gene, etk, encoding an inner membrane protein that catalyses tyrosine autophosphorylation and phosphorylation of a synthetic co-polymer poly(Glu:Tyr). This protein tyrosine kinase (PTK) was termed Ep85 or Etk. All the E.coli strains examined possessed etk; however, only a subset of pathogenic strains expressed it. Etk is homologous to several bacterial proteins including the Ptk protein of Acinetobacter johnsonii, which is the only other known prokaryotic PTK. Other Etk homologues are AmsA of the plant pathogen Erwinia amylovora and Orf6 of the human pathogen Klebsiella pneumoniae. These proteins are involved in the production of exopolysaccharide (EPS) required for virulence. We demonstrated that like Etk, AmsA and probably also Orf6 are PTKs. Taken together, these findings suggest that tyrosine protein phosphorylation in prokaryotes is more common than was appreciated previously, and that Etk and its homologues define a distinct protein family of prokaryotic membrane-associated PTKs involved in EPS production and virulence. These prokaryotic PTKs may serve as a new target for the development of new antibiotics.