Should we screen extensively for cancer after unprovoked venous thrombosis?


What you need to know

  • The prevalence of occult cancer in patients with a first unprovoked venous thromboembolism seems to be lower (~4%) than previously reported (10%)

  • There is limited evidence to recommend extensive cancer screening with computed tomography in such patients

  • Consider history and physical examination, basic laboratory tests, and results from routine age-specific cancer screening to guide further testing as an alternative to extensive screening

How far to go in screening patients with an unprovoked venous thromboembolism (VTE) for an occult cancer is a clinical dilemma. Unprovoked VTE, either deep vein thrombosis or pulmonary embolism, can be the first manifestation of an undiagnosed cancer. Until recently, the literature suggested that up to 10% of such patients would be diagnosed with a cancer in the year after their diagnosis of VTE.1 However, the incidence of occult cancer in patients studied in two recent, high quality, randomised controlled trials was only about 4%.23 This drop in the proportion of people with occult cancer may require an adjustment in the clinical approach.

Fig 1⇓ outlines a conservative approach and a more detailed approach to investigating such patients. Extensive screening has become the standard of care, though it is based on limited data.

 However, high quality data from recently completed trials discussed below suggest that extensive screening strategies may not provide additional value over routine cancer screening in the frequency of cancer detection in these patients.

What is the evidence of uncertainty?

Search strategy and study selection

We searched PubMed (from inception to 31 December 2016) for randomised controlled trials and systematic reviews using the search terms “cancer screening,” “venous thromboembolism,” “unprovoked,” “meta-analysis,” and “randomized controlled trial.” We reviewed articles published in English between 2012 (publication of NICE guidelines) and 2016.

Source:BMJ

The effect of different radiological models on diagnostic accuracy and lung cancer screening performance.


Abstract

High false-positive (FP) scan rates associated with low-dose computed tomography (LDCT) lung cancer screening result in unnecessary follow-up tests and exposure to harm. The definition of a ‘positive’ scan can impact FP rates and screening performance. We explored the effect of Lung Imaging Reporting and Data System (Lung-RADS) criteria, PanCan Nodule Malignancy Probability Model and varying nodule size thresholds (≥4 mm, ≥6 mm, ≥8 mm) on diagnostic accuracy and screening performance compared with original trial definitions (National Lung Screening Trial (NLST) criteria) in a secondary analysis of a lung cancer screening cohort. We found Lung-RADS criteria and the PanCan Nodule Malignancy Probability Model could substantially improve screening performance and reduce FP scan rates compared with NLST definitions of positivity but that this needs to be balanced against possible risk of false-negative results.

source: BMJ THORAX

The Need for Predictive, Prognostic, Objective and Complementary Blood-Based Biomarkers in Osteoarthritis (OA)


Osteoarthritis (OA) has traditionally been viewed as a non-inflammatory arthropathy and has not been considered a ‘serious disease’. However, this view has radically changed in recent years, due to the complexity and heterogeneity of the patient populations, spiralling socio-economical costs and long-term impact on the quality of life of affected individuals. There is an acute need for objective and non-invasive diagnostic biomarkers in OA, markers that can stratify patient subtypes and thereby direct therapeutic treatments at an earlier disease stage (read personal health care (PHC)) (Conaghan, 2013). Increased interest in the development of new diagnostic and prognostic tests for early forms of OA may incorporate the use of blood-based biomarkers; however, both research and regulated development and approval are still needed to reach a diagnostically important significant point where a given biomarker will benefit the clinical management of the patient.

1. The OA Biomarker Landscape Today

There are currently no disease-modifying osteoarthritis drugs (DMOAD) available for treatment of OA patients (Mobasheri, 2013, Qvist et al., 2008). This may be due to the heterogeneity of the OA population, where the origin and driver of disease progression is often poorly understood. The main treatment options for OA presently are pain relief, physical therapy and nutritional supplements (nutraceuticals). However, none of these can halt or reverse disease progression. In addition, diagnosis is often subjective, due to the lack of objective, precise and accurate diagnostic devices. Thus the limited clinical diagnosis and characterization of the individual patient will adversely influence healthcare management and the recruitment of the right patient cohorts for the testing of drugs in clinical trials. There is a medical need for objective, precise and accurate in vitro diagnostic devices for clinical trial enrichment (Kraus et al., 2015, Karsdal et al., 2013).

2. What Is the Medical Need for Biomarkers?

The lack of approved DMOADs in OA drags a long tail of failed clinical drug trials. Recently the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and other regulatory agencies have published guidelines on how biomarkers should be defined. Different groups and public-private partnerships have proposed different models for classifying OA biomarkers for clinical use (Bauer et al., 2006, Kraus et al., 2011, Bay-Jensen et al., 2016a, Bay-Jensen et al., 2016b). There is a general consensus on the medical need for biomarker development which may be summarized as seven key points:
  • 1.

    Translational biomarkers, which allow better characterization of a drug in preclinical development, ensuring of selection of the most viable projects

  • 2.

    Early identification of efficacy of intervention; Go/no-go decision-making already in phase 1b/2a studies, which normally do not include efficacy measures.

  • 3.

    Phase II and Phase III trial enrichment; reduction in study size, and a particular OA phenotype tailored for a selective interventions, which will recuse length of the clinical study to allow more efficient and less costly trials

  • 4.

    Identification of patients who are fast progressors and as such in greatest need of treatment.

  • 5.

    Identification of super responders to a specific treatment; patients with high efficacy and low safety concerns

  • 6.

    Biomarkers of disease activity; as OA is not a stabile disease, there is a need for devices for identification with high disease activity and potential progression

  • 7.

    Easy accessible monitoring devices – point of care; post marketing patient care and personalized medicine

Although there are clear overlaps in the above, it is clear that no single biomarker will be the answer for all.

3. Message From the Regulators

The public attention to biomarkers is increasing, recently further emphasized by the “white house” initiate focusing on quantifiable tools for patient election and monitoring.2
2The White house, 2015. Precision Medicine Initiative | The White House [WWW Document]. White house. URL https://www.whitehouse.gov/precision-medicine (accessed 2.5.16).

On the regulatory side, the FDA issued a position document describing the need and road ahead for personalized medicine “FDA: Paving the Way for Personalized Medicine”,3

3FDA, 2013. Paving the Way for Personalized Medicine [WWW Document]. URL http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PersonalizedMedicine/UCM372421.pdf(accessed 2.5.16).

which later resulted in new guidelines to faster biomarker tool development by the guidelines “Identifying Potential Biomarkers for Qualification and Describing Contexts of Use To Address Areas Important to Drug Development”,4

4FDA, 2015. Identifying Potential Biomarkers for Qualification and Describing Contexts of Use To Address Areas Important to Drug Development; Request for Comments [WWW Document]. FDA. URL https://www.federalregister.gov/articles/2015/02/13/2015-02976/identifying-potential-biomarkers-for-qualification-and-describing-contexts-of-use-to-address-areas (accessed 2.5.16)

which are in addition to the standard guidelines for in vitro companion diagnostic device. This has led to the discussion on prospective-retrospective biomarker analysis for regulatory consideration, by the white paper from the industry pharmacogenomics working group (Patterson et al., 2011). This will greatly assist precision medicine and PHC by guiding the discussion on how to implement a “prospective-retrospective biomarker analysis”. The prospective-retrospective biomarker analysis approach is developed to “rescue” failed phase III trials. Qualified biomarkers are to be measured in certified, high-quality laboratories and analyzed using predefined statistical analysis plans to test hypotheses related to retrospective analysis of technically and biologically validated biomarkers.

According to the FDA, a prognostic in vitro diagnostic biomarker would need a 510 K or de novo approval (class II device), whereas a predictive biomarker would need ldt pre-market approval (PMA, class III device). The main separating factor is that a prognostic biomarker provides you with an estimate for progression, whereas a predictive biomarker would be used to decide the exact treatment regimen for individual patients, and would therefore have a significant impact on the patient’s life. A predictive biomarker will often become a companion diagnostic.5

5FDA, 2014. In Vitro Companion Diagnostic Devices. Guidance for Industry and Food and Drug Administration Staff.

In addition, the recent “drug development tool (DDT) box” guidelines are also allowing for regulatory assessment of tools to assist in clinical drug development, such as the fibrinogen enrichment of patients in COPD clinical studies with a more severe outcome (fast progressors), which is now classified as a DDT.

No biomarkers have yet been qualified as biomarkers for OA, however several biomarkers have been developed targeting cartilage degradation and formation (e.g. CTX-II, ARGS, PIIANP), joint inflammation (e.g.C3M, Col2-NO2), bone remodelling (e.g. alpha CTX I, osteocalcin) as well as inflammation and metabolic factors (Bay-Jensen et al., 2016a, Bay-Jensen et al., 2016b). The scientists and clinicians working in the biomarker field cannot expect a “one size fits all” solution for OA. Consequently it is important to test and validate a biomarker to a specific hypothesis. This can be done under the laboratory-developed test (LDT) (Sarata and Johnson, 2014), which is a type of in vitro diagnostic test that is designed, manufactured and used within a single laboratory.

4. How Do We Move Forward?

Different approaches, techniques and better-stratified patient samples are needed to move biomarker development towards qualification, which means that new partners need to come together and collaborate. For example development of a novel blood-based and cartilage-derived protein biomarker requires application of advanced analytical techniques such as proteomics and mass spectrometry, whereas development of the biomarker assay requires knowhow of biochemical and immunological assessment platforms. Furthermore, testing, validation and qualification requires access to high quality clinical samples from several independent retrospective or prospective cohorts. In the end a commercialisation plan needs to be established to push forwards and finance the qualification of biomarkers. Thus it is most likely that no single entity, public or private, will be able to complete these development steps alone. There is a need for i) Formation of public-private partnerships to develop, test, validate and qualify biomarkers for use in clinical trial and patient management, ii) Design of clinical studies that stratify patients and investigate trends and characteristics of specific OA cohorts and study populations, and iii) Collaboration between biotech and pharmaceutical companies to support the commercialization of biomarkers.

In summary, a great deal of collaborative work needs to be done in this area to develop more predictive, prognostic, objective and complementary biomarkers for OA management and DMOAD development.

Clinical Translation and Validation of a Predictive Biomarker for Patritumab, an Anti-human Epidermal Growth Factor Receptor 3 (HER3) Monoclonal Antibody, in Patients With Advanced Non-small Cell Lung Cancer


Highlights

  • High heregulin levels predict benefit from patritumab treatment in patients with NSCLC.

    A prospective–retrospective approach provisionally validated a predictive biomarker.

    Post hoc analyses can be used to test underlying assumptions in biomarker validation.

    The median may be a reasonable initial cutoff for a unimodal continuous biomarker.

Abstract

Background

During early clinical development, prospective identification of a predictive biomarker and validation of an assay method may not always be feasible. Dichotomizing a continuous biomarker measure to classify responders also leads to challenges. We present a case study of a prospective–retrospective approach for a continuous biomarker identified after patient enrollment but defined prospectively before the unblinding of data. An analysis of the strengths and weaknesses of this approach and the challenges encountered in its practical application are also provided.

Methods

HERALD (NCT02134015) was a double-blind, phase 2 study in patients with non-small cell lung cancer (NSCLC) randomized to erlotinib with placebo or with high or low doses of patritumab, a monoclonal antibody targeted against human epidermal growth factor receptor 3 (HER3). While the primary objective was to assess safety and progression-free survival (PFS), a secondary objective was to determine a single predictive biomarker hypothesis to identify subjects most likely to benefit from the addition of patritumab. Although not identified as the primary biomarker in the study protocol, on the basis of preclinical results from 2 independent laboratories, expression levels of the HER3 ligand heregulin (HRG) were prospectively declared the predictive biomarker before data unblinding but after subject enrollment. An assay to measure HRG mRNA was developed and validated. Other biomarkers, such as epidermal growth factor receptor (EGFR) mutation status, were also evaluated in an exploratory fashion. The cutoff value for high vs. low HRG mRNA levels was set at the median delta threshold cycle. A maximum likelihood analysis was performed to evaluate the provisional cutoff. The relationship of HRG values to PFS hazard ratios (HRs) was assessed as a measure of internal validation. Additional NSCLC samples were analyzed to characterize HRG mRNA distribution.

Results

The subgroup of patients with high HRG mRNA levels (“HRG-high”) demonstrated clinical benefit from patritumab treatment with HRs of 0.37 (P = 0.0283) and 0.29 (P = 0.0027) in the high- and low-dose patritumab arms, respectively. However, only 102 of the 215 randomized patients (47.4%) had sufficient tumor samples for HRG mRNA measurement. Maximum likelihood analysis showed that the provisional cutoff was within the optimal range. In the placebo arm, the HRG-high subgroup demonstrated worse prognosis compared with HRG-low. A continuous relationship was observed between increased HRG mRNA levels and lower HR. Additional NSCLC samples (N = 300) demonstrated a similar unimodal distribution to that observed in this study, suggesting that the defined cutoff may be applicable to future NSCLC studies.

Conclusions

The prospective–retrospective approach was successful in clinically validating a probable predictive biomarker. Post hoc in vitro studies and statistical analyses permitted further testing of the underlying assumptions. However, limitations of this analysis include the incomplete collection of adequate tumor tissue and a lack of stratification. In a phase 3 study, findings are being confirmed, and the HRG cutoff value is being further refined.

Source:http://www.ebiomedicine.com

Building the Evidence Base of Blood-Based Biomarkers for Early Detection of Cancer: A Rapid Systematic Mapping Review


 There are a large number of biomarkers with potential utility for early cancer detection from blood samples

Few biomarkers have been studied sufficiently with clinical validation to allow their use in combination for screening in the general population.

We used an iterative mapping review of 20,000 references, retrieving 3,990 relevant papers, and identified 788 markers in blood of potential use

Screening for cancer can save lives, but it is difficult to justify individual screening programmes for many cancer types. However, cancers of different types share many attributes, and markers of cancer biology found in the blood. We surveyed the literature to identify known biomarkers using a new mapping approach. With nearly 20,000 papers on the subject, we retrieved 3990 papers, and identified 788 markers in blood of potential use. Most have not been studied enough to justify their use in clinical practice. This evidence based approach should help us to develop a blood-based cancer screening test in the general population.

Abstract

Background

The Early Cancer Detection Consortium is developing a blood-test to screen the general population for early identification of cancer, and has therefore conducted a systematic mapping review to identify blood-based biomarkers that could be used for early identification of cancer.

Methods

A mapping review with a systematic approach was performed to identify biomarkers and establish their state of development. Comprehensive searches of electronic databases Medline, Embase, CINAHL, the Cochrane library and Biosis were conducted in May 2014 to obtain relevant literature on blood-based biomarkers for cancer detection in humans. Screening of retrieved titles and abstracts was performed using an iterative sifting process known as “data mining”. All blood based biomarkers, their relevant properties and characteristics, and their corresponding references were entered into an inclusive database for further scrutiny by the Consortium, and subsequent selection of biomarkers for rapid review. This systematic review is registered with PROSPERO (no. CRD42014010827).

Findings

The searches retrieved 19,724 records after duplicate removal. The data mining approach retrieved 3990 records (i.e. 20% of the original 19,724), which were considered for inclusion. A list of 814 potential blood-based biomarkers was generated from included studies. Clinical experts scrutinised the list to identify miss-classified and duplicate markers, also volunteering the names of biomarkers that may have been missed: no new markers were identified as a result. This resulted in a final list of 788 biomarkers.

Interpretation

This study is the first to systematically and comprehensively map blood biomarkers for early detection of cancer. Use of this rapid systematic mapping approach found a broad range of relevant biomarkers allowing an evidence-based approach to identification of promising biomarkers for development of a blood-based cancer screening test in the general population.

Source:http://www.ebiomedicine.com

Role of psilocybin in the treatment of depression


Abstract

Psilocybin is a naturally occurring alkaloid, pharmacologically similar to the classic hallucinogen lysergic acid diethylamide (LSD). Although primarily used as a recreational drug or an entheogen in particular cultural settings, recent population based studies have shown that it does not lead to serious physical or mental health problems or dependent use. In view of recent work demonstrating psilocybin’s potential to increase subjective sense of wellbeing and because of its novel mechanism of 5-HT2A serotonin receptor agonism, it is being explored for possible therapeutic utility in mood and anxiety disorders.

Keywords: depression, hallucinogen, psilocybin, treatment

Classical hallucinogens have been categorized into three groups: tryptamines, such as psilocin, the psychoactive metabolite of psilocybin; lysergamines (a subgroup of tryptamines), prominently lysergic acid diethylamide (LSD); and phenethylamines, such as mescaline [Geyer et al. 2009]. Psilocybin is a naturally occurring alkaloid. Though primarily considered a recreational substance, recent population-based studies have shown that it does not lead to serious physical or mental health problems, including dependence [Krebs and Johansen, 2013; Johansen and Krebs, 2015]. The psychopharmacological action of psilocybin is thought to be mediated via binding to serotonergic 5-HT2 receptors, primarily 5-HT2A receptors, although non-5-HT2 receptors are probably also involved [Tylš et al. 2014]. Downregulation of 5-HT2A receptors is purported to mediate antidepressant and antianxiety effects of antidepressants and atypical antipsychotics [Van Oekelen et al. 2003]. Because of the high binding affinity of psilocybin to the 5-HT2A receptor, its effects are thought to be mediated through modulation of 5-HT2A receptors, in addition to second messenger signalling and gene-expression effects [Gonzalez-Maeso et al. 2007].

In view of recent work demonstrating psilocybin’s potential to increase subjective sense of wellbeing [Griffiths et al. 2008] and because of its novel mechanism of 5-HT2A serotonin receptor agonism, it is being explored for therapeutic utility in mood and anxiety disorders [Vollenweider and Kometer, 2010].

A recent study made an attempt to investigate the feasibility, safety and efficacy of psilocybin in treatment-resistant unipolar depression, when administered along with psychological support [Carhart-Harris et al. 2016]. This was the first open-label study in patients with moderate to severe unipolar depression who had not responded to two or more adequate trials of antidepressants from different pharmacological classes. The authors administered 10 mg (low dose) oral psilocybin, followed 1 week later by another dose of 25 mg (high dose). Psilocybin was well tolerated by all patients, and no serious or unexpected adverse events were reported. Relative to baseline, depressive symptoms were markedly reduced at 1 week and at 3 months after treatment. This study paves the way for more rigorous trials in the future to further investigate the therapeutic potential of psilocybin in depression.

The foremost requirement for any pharmacological agent to be used as a medicinal drug is that it should be acceptably safe when administered to humans. The doses of psilocybin used in the present study have been shown to be safe previously when administered to both healthy individuals, and patients with medical and psychiatric illness. A study in 36 healthy individuals who received 30 mg of psilocybin found no sustained deleterious physiological or psychological effects [Griffiths et al. 2006]. Another study exploring the effects of psilocybin on anxiety in 12 patients with advanced-stage cancer reported no clinically significant adverse effects [Grob et al. 2011].

Second, for a psychedelic drug to be feasibly used as a pharmacologic agent in humans, its acute effects themselves should be well tolerated, and easily managed. Psilocybin has been found to have mild, pleasurable and nonthreatening effects in 110 healthy individuals in a pooled analysis of eight double-blind placebo-controlled experimental studies [Studerus et al. 2011]. This study concluded that administration of moderate doses of psilocybin in well-prepared subjects in a carefully monitored environment was associated with an acceptable level of risk.

There is a growing evidence base suggesting a neurobiological basis for the possible efficacy of psilocybin in unipolar depression. A functional magnetic resonance imaging (fMRI) study showed that the medial prefrontal cortex (mPFC) was consistently deactivated by psilocybin [Carhart-Harris et al. 2012a]. Medial PFC has been shown to be hyperactive in fMRI studies in depression, and effective treatment of depression has shown to normalize this hyperactivity [Holtzheimer and Mayberg, 2011]. Thus, the deactivation of mPFC by psilocybin is consistent with its proposed effect in depression. The fact that the magnitude of deactivation of mPFC was found to be correlated with the drug’s subjective effects further supports this assumption [Carhart-Harris et al. 2012a]. Other fMRI studies have found that psilocybin attenuates amygdala activation in response to threat-related visual stimuli [Kraehenmann et al. 2015a], and decreases threat-induced modulation of top-down connectivity from the amygdala to the primary visual cortex [Kraehenmann et al. 2015b]. Both of these mechanisms are proposed to induce positive affect states. Given that the amygdala plays a central role in the perception and generation of emotions, and given that amygdala hyperactivity in response to negative stimuli has consistently been related to negative mood states in depressed patients [DeRubeis et al. 2008], the effect of psilocybin strongly points at a therapeutic mechanism in depression. Though psychedelics have historically been used to assist psychotherapy, recently a neurobiological basis for the same is emerging. Psilocybin has been found to robustly facilitate activation of various areas of the brain, including the limbic system, in response to autobiographical memory cues [Carhart-Harris et al. 2012b]. Such facilitation of the recall of salient memories during psychotherapy may be of significance. In addition, ayahuasca, a naturally occurring hallucinogen with a pharmacological profile similar to psilocybin, has been shown to significantly reduce depressive symptoms [Osório Fde et al. 2015], and increase blood perfusion in brain areas implicated in regulation of mood [Sanches et al. 2016].

The study by Carhart-Harris and colleagues [Carhart-Harris et al. 2012b] suffered from a few methodological issues. As it was an open-label, non-placebo-controlled study, it is not possible to differentiate between pharmacological action and the placebo effect of administering psilocybin, as the placebo effect has been shown to have a significant beneficial effect on depression on its own. However, designing double-blind, controlled studies with agents such as psilocybin is difficult, given the ease with which its psychotropic actions are recognizable. Also, as 5 of the 12 participants reported previous psilocybin use, it is possible that a predisposition towards the pleasurable effects of the substance may have contributed to the improvement in symptoms, thus confounding the results. Adverse effects such as paranoia, as described by one of the participants, may also hamper the effectiveness of such drugs. In addition, patient compensation may influence outcomes in such studies, and this information is not adequately elucidated in the paper in question. Finally, the authors have declared support from one of the many private foundations which finance research into hallucinogens [Dakwar, 2016]. Since detailed information on conflicts of interest has not been provided, skepticism may arise as to the role of such foundations in study design and execution, potentially biasing the results. Such studies also face practical issues, such as procuring supplies of hallucinogens. By overcoming limitations such as unclear information on the conflicts of interest, such studies may gain more acceptance in the medical community.

Thus, although limited, the current evidence base suggests that psilocybin may prove to be a safe, feasible, and efficacious pharmacological agent for depression, at least in patients not responding to conventional therapies.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The authors declare that there is no conflict of interest.

Contributor Information

Ananya Mahapatra, Department of Psychiatry, 4th floor Academic Block, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.

Rishi Gupta, Junior Resident, Department of Psychiatry and National Drug-Dependence Treatment Centre (NDDTC), All India Institute of Medical Sciences (AIIMS), New Delhi, India.

References

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Source:https://www.ncbi.nlm.nih.gov

Syria: Health in Conflict


The Lancet and the American University of Beirut have together established the concept for a Commission on Syria: Health in Conflict. The aim of the Commission will be to describe, analyse and interrogate the calamity before us through the lens of health and wellbeing. With this Commission, we aim to examine five priority areas: health of people inside Syria; health of refugees and host communities; health systems, which includes the pillars of health professionals, delivery, infrastructure, and transition to rebuilding; challenges of the international response to the crisis particularly health-related international law violations and humanitarian aid design and delivery; and policy options and next steps, including those that can strengthen the role of global health in conflict and health more broadly. The Commission will develop concrete recommendations to address the unmet current and future health needs.

Source: Lancet

Photovoltaic retinal implant could restore functional sight, researchers say


Photovoltaic retinal implant could restore functional sight, researchers say
The wireless retinal implants convert light transmitted from special glasses into electrical current, which stimulates the retina’s bipolar cells. 

A team led by Stanford University researchers has developed a wireless retinal implant that they say could restore vision five times better than existing devices.

 Results in rat studies suggest it could provide functional vision to patients with , such as or .

A paper describing the implant was published online April 27 in Nature Medicine.

“The performance we’re observing at the moment is very encouraging,” said Georges Goetz, a lead author of the paper and graduate student in electrical engineering at Stanford. “Based on our current results, we hope that human recipients of this implant will be able to recognize objects and move about.”

Retinal degenerative diseases destroy photoreceptors—the retina’s rods and cones—but other parts of the eye usually remain healthy. The implant capitalizes on the electrical excitability of known as bipolar cells. These cells process the photoreceptors’ inputs before they reach ganglion cells, which send retinal signals to the brain. By stimulating bipolar cells, the implant takes advantage of important natural properties of the retinal neural network, which produces more refined images than the devices that skip these cells.

Made of silicon, the implant is composed of hexagonal photovoltaic pixels that convert light transmitted from special glasses worn by the recipient into electrical current. These electrical pulses then stimulate the retina’s , triggering a neural cascade that reaches the brain.

Clinical trial planned

So far, the team has tested the device only in animals, but a clinical trial is planned next year in France, in collaboration with a French company called Pixium Vision, said Daniel Palanker, PhD, professor of ophthalmology and a senior author of the paper. Initially, patients blinded by a genetic disease called retinitis pigmentosa will be included in the study.

Existing retinal prostheses are powered by extraocular devices wired to the retinal electrode array, which require complex surgeries, and provide visual acuity up to about 20/1,200. This new photovoltaic implant could be a big improvement because its small size, modularity and lack of wires enable a minimally invasive surgery. Vision tests in rats have shown it restores to an equivalent of 20/250.

Next, Palanker and his team plan to further improve acuity by developing chips with smaller pixels. To ensure the signals reach the target neurons, they plan to add a tiny prong to each electrode that will protrude into the target cell layer.

“Eventually, we hope this technology will restore vision of 20/120,” Palanker said. “And if it works that well, it will become relevant to patients with .”

 

Abstract

Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-μm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration.

Source: Nature

Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas


Highlights

  • Retinal injury activates Wnt signaling in MGs
  • Wnt-Lin28-let-7 miRNA signaling regulates MG proliferation
  • Gene transfer of β-catenin or Lin28 stimulates MG proliferation without injury
  • Cell-cycle-reactivated MGs show neurogenic potential

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Summary

In cold-blooded vertebrates such as zebrafish, Müller glial cells (MGs) readily proliferate to replenish lost retinal neurons. In mammals, however, MGs lack regenerative capability as they do not spontaneously re-enter the cell cycle unless the retina is injured. Here, we show that gene transfer of β-catenin in adult mouse retinas activates Wnt signaling and MG proliferation without retinal injury. Upstream of Wnt, deletion of GSK3β stabilizes β-catenin and activates MG proliferation. Downstream of Wnt, β-catenin binds to the Lin28 promoter and activates transcription. Deletion of Lin28 abolishes β-catenin-mediated effects on MG proliferation, and Lin28 gene transfer stimulates MG proliferation. We further demonstrate that let-7 miRNAs are critically involved in Wnt/Lin28-regulated MG proliferation. Intriguingly, a subset of cell-cycle-reactivated MGs express markers for amacrine cells. Together, these results reveal a key role of Wnt-Lin28-let7 miRNA signaling in regulating proliferation and neurogenic potential of MGs in the adult mammalian retina.

Source: Cell.com

Epileptic activity in Alzheimer’s disease: causes and clinical relevance.


Epileptic activity is frequently associated with Alzheimer’s disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer’s disease can easily go unrecognised because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer’s disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer’s disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer’s disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer’s disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid β and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer’s disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline.

Soure: Lancet