Improving End-User Trust in the Quality of Commercial Probiotic Products

In a rapidly growing global probiotic market, end-users have difficulty distinguishing between high quality and poor quality products. This ambiguity threatens the trust consumers and healthcare providers have in probiotic products. To address this problem, we recommend that companies undergo third-party evaluations to certify probiotic quality and label accuracy. In order to communicate about product quality to end-users, indication of certification on product labels is helpful, although not all manufacturers choose to use this approach. Herein we discuss: third-party certification, the process of setting standards for identity, purity, and quantification of probiotics; some emerging methodologies useful for quality assessment; and some technical challenges unique to managing quality of live microbial products. This review provides insights of an Expert Panel engaged in this process and aims to update the reader on relevant current scientific methodologies. Establishing validated methodologies for all aspects of quality assessment is an essential component of this process and can be facilitated by established organizations, such as United States Pharmacopeia. Emerging methodologies including whole genome sequencing and flow cytometry are poised to play important roles in these processes

Bilateral Visual Improvement with Unilateral Gene Therapy Injection for Leber Hereditary Optic Neuropathy

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase III clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2 ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject’s right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2 ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At Week 96, rAAV2/2 ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of 0.259 (0.068) LogMAR (+13 ETDRS letters) was observed in the sham treated eyes. Consequently, the primary endpoint, defined as the difference in the change in BCVA from baseline to Week 48 between the two treatment groups, was not met (p = 0.894, ANCOVA). At Week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye and 29 subjects (78%) had an improvement in vision in both eyes. A non-human primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina and optic nerve of the contralateral non-injected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection

Human Skin Microbiota: High Diversity of DNA Viruses Identified on the Human Skin by High Throughput Sequencing

The human skin is a complex ecosystem that hosts a heterogeneous flora. Until recently, the diversity of the cutaneous microbiota was mainly investigated for bacteria through culture based assays subsequently confirmed by molecular techniques. There are now many evidences that viruses represent a significant part of the cutaneous flora as demonstrated by the asymptomatic carriage of beta and gamma-human papillomaviruses on the healthy skin. Furthermore, it has been recently suggested that some representatives of the Polyomavirus genus might share a similar feature. In the present study, the cutaneous virome of the surface of the normal-appearing skin from five healthy individuals and one patient with Merkel cell carcinoma was investigated through a high throughput metagenomic sequencing approach in an attempt to provide a thorough description of the cutaneous flora, with a particular focus on its viral component. The results emphasize the high diversity of the viral cutaneous flora with multiple polyomaviruses, papillomaviruses and circoviruses being detected on normal-appearing skin. Moreover, this approach resulted in the identification of new Papillomavirus and Circovirus genomes and confirmed a very low level of genetic diversity within human polyomavirus species. Although viruses are generally considered as pathogen agents, our findings support the existence of a complex viral flora present at the surface of healthy-appearing human skin in various individuals. The dynamics and anatomical variations of this skin virome and its variations according to pathological conditions remain to be further studied. The potential involvement of these viruses, alone or in combination, in skin proliferative disorders and oncogenesis is another crucial issue to be elucidated

Contribution of Cerebellar Sensorimotor Adaptation to Hippocampal Spatial Memory

Complementing its primary role in motor control, cerebellar learning has also a bottom-up influence on cognitive functions, where high-level representations build up from elementary sensorimotor memories. In this paper we examine the cerebellar contribution to both procedural and declarative components of spatial cognition. To do so, we model a functional interplay between the cerebellum and the hippocampal formation during goal-oriented navigation. We reinterpret and complete existing genetic behavioural observations by means of quantitative accounts that cross-link synaptic plasticity mechanisms, single cell and population coding properties, and behavioural responses. In contrast to earlier hypotheses positing only a purely procedural impact of cerebellar adaptation deficits, our results suggest a cerebellar involvement in high-level aspects of behaviour. In particular, we propose that cerebellar learning mechanisms may influence hippocampal place fields, by contributing to the path integration process. Our simulations predict differences in place-cell discharge properties between normal mice and L7-PKCI mutant mice lacking long-term depression at cerebellar parallel fibre-Purkinje cell synapses. On the behavioural level, these results suggest that, by influencing the accuracy of hippocampal spatial codes, cerebellar deficits may impact the exploration-exploitation balance during spatial navigation

Anterior open bite correction by Le Fort 1 osteotomies with or without anterior segmentation: Which is more stable?

A retrospective cohort study was conducted to analyze the relapse rate of anterior open bite (AOB) correction comparing Le Fort I osteotomy with and without anterior segmentation. The risk factors that might contribute to relapse were also assessed. Lateral cephalograms obtained at six different times were analyzed. A total of 81 patients with AOB were recruited. Thirty-five patients underwent Le Fort I osteotomy without anterior segmentation and 46 patients underwent anterior segmentation. Le Fort I osteotomy with anterior segmentation resulted in significantly more AOB relapse when compared to that without anterior segmentation at 7 weeks postoperative (15.2% vs. 0%, P = 0.016). During the early postoperative period, factors that contributed to AOB relapse in Le Fort I osteotomy with anterior segmentation were AOB closure 4 mm and inferior positioning of the anterior segment >2 mm. Over the long term, AOB closure �4 mm and intraoral vertical ramus osteotomy as the only mandibular procedure were factors identified as causing more AOB relapse in those treated by Le Fort I osteotomy with anterior segmentation. In conclusion, Le Fort I osteotomy without anterior segmentation was found to be more stable in the surgical correction of AOB in the early and late postoperative periods

Role of the cerebellar cortex in conditioned goal-directed behavior

Learning a new goal-directed behavioral task often requires the improvement of at least two processes, including an enhanced stimulus-response association and an optimization of the execution of the motor response. The cerebellum has recently been shown to play a role in acquiring goal-directed behavior, but it is unclear to what extent it contributes to a change in the stimulus-response association and/or the optimization of the execution of the motor response.Wetherefore designed the stimulus-dependent water Y-maze conditioning task, which allows discrimination between both processes, and we subsequently subjected Purkinje cell-specific mutant mice to this new task. The mouse mutants L7-PKCi, which suffer from impaired PKC-dependent processes such as parallel fiber to Purkinje cell long-term depression (PF-PC LTD), were able to acquire the stimulus-response association, but exhibited a reduced optimization of their motor performance. These data show that PF-PC LTD is not required for learning a stimulus-response association, but they do suggest that a PKC-dependent process in cerebellar Purkinje cells is required for optimization of motor responses. Copyrigh