313 research outputs found
Plexin-semaphorin signalling modifies neuromuscular defects in a Drosophila model of peripheral neuropathy
Dominant mutations in GARS, encoding the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and Charcot-Marie-Tooth disease type 2D (CMT2D). This genetic disorder exemplifies a recurring paradigm in neurodegeneration, in which mutations in essential genes cause selective degeneration of the nervous system. Recent evidence suggests that the mechanism underlying CMT2D involves extracellular neomorphic binding of mutant GlyRS to neuronally-expressed proteins. Consistent with this, our previous studies indicate a non-cell autonomous mechanism, whereby mutant GlyRS is secreted and interacts with the neuromuscular junction (NMJ). In this Drosophila model for CMT2D, we have previously shown that mutant gars expression decreases viability and larval motor function, and causes a concurrent build-up of mutant GlyRS at the larval neuromuscular presynapse. Here, we report additional phenotypes that closely mimic the axonal branching defects of Drosophila plexin transmembrane receptor mutants, implying interference of plexin signaling in gars mutants. Individual dosage reduction of two Drosophila Plexins, plexin A (plexA) and B (plexB) enhances and represses the viability and larval motor defects caused by mutant GlyRS, respectively. However, we find plexB levels, but not plexA levels, modify mutant GlyRS association with the presynaptic membrane. Furthermore, increasing availability of the plexB ligand, Semaphorin-2a (Sema2a), alleviates the pathology and the build-up of mutant GlyRS, suggesting competition for plexB binding may be occurring between these two ligands. This toxic gain-of-function and subversion of neurodevelopmental processes indicate that signaling pathways governing axonal guidance could be integral to neuropathology and may underlie the non-cell autonomous CMT2D mechanism
Predictive Technique Of Security Data Breaches In Ai Powered Mobile Cloud Application Using Deep Random Forest Algorithm
With the rapid integration of artificial intelligence (AI) in mobile cloud applications, ensuring robust security mechanisms is vital to safeguard sensitive user data. The proliferation of AI technologies in mobile cloud applications has brought unprecedented efficiency and convenience, accompanied by an escalating risk of security breaches. As the threat landscape evolves, traditional security measures fall short in providing comprehensive protection. This research recognizes the critical need for a predictive approach to security data breaches in AI-powered mobile cloud applications. Existing security frameworks often lack the adaptability to detect and pre-emptively address emerging threats specific to AI-enhanced mobile cloud environments. This study employs the Deep Random Forest Algorithm, an advanced machine learning technique known for its ability to handle complex and dynamic datasets. The algorithm combines the power of deep learning with the versatility of random forest classifiers to predict security breaches in real-time. The results demonstrate the efficacy of the proposed Deep Random Forest Algorithm in predicting and mitigating security breaches in AI-powered mobile cloud applications. The model exhibits high accuracy and sensitivity, showcasing its potential to enhance the security posture of mobile cloud ecosystems
Hearing Benefit in Middle Ear Reconstructive Surgery: A Comparative Study of the Current Methods
INTRODUCTION:
Discharging ear and deafness are perpetual source of misery to
humankind. Chronic suppurative otitis media is found to be the single
major cause of conductive deafness manifesting in 66.3% of cases. The
other causes being trauma, otosclerosis, congenital malformations,
neoplastic causes etc. Auditory sensation is one of the vital sensations for
existence. Deafness upsets the tranquility of life. When such a great vital
sensation is lost, life naturally loses its charm.
In last 50 years, various researches have been carried out for repair
of ossicular chain defects alone or those associated with tympanic
membrane perforations. A number of materials have been used with
varying results. Right from Hall and Rytzer of 1957 till today, several
pioneers have revolutionized the outlook of ossiculoplasty.
Several materials have been used for ossiculoplasty. Some of the
materials are autograft/homograft ossicles, autograft/homograft cartilage,
teflon, hydroxyapatite, titanium, gold, bioglass etc.
The goal of otologists performing middle ear surgery to correct
conductive hearing loss is to improve hearing as well as to provide a
functional benefit to the patient. Unilateral conductive hearing loss is
associated with various disabilities including difficulty in sound
localization and in hearing and understanding speech.
Traditionally, otologists have reported the results of middle ear
surgery as the closure of the air - bone gap or the reduction in air
conduction thresholds. The closure of the air-bone gap refers to
improvement of the air conduction thresholds (involving conductive and
sensorineural components) to the level of the bone conduction thresholds
(sensorineural component). While these provide a measure of the
technical success of the operation, they may not always translate into real
life benefit for the patient. Hence standardization of results of treatment
should be by a method based on subjective perception which benefits
patients in real life.
Other methods have been used to evaluate the effectiveness of
middle ear surgery including questionnaires that evaluate a patient's
subjective benefit from surgery. Using questionnaires to evaluate benefit
is complicated by the fact that both surgeons and patients want to believe
that the operation has succeeded. The two most common methods found
in the otologic literature to evaluate benefit from middle ear surgery are
the Belfast 15/30 dB rule of thumb and the Glasgow benefit plot. These
methods facilitates the assessment of subjective benefit as well as
objective achievement, we have employed these two most common
methods to estimate patient benefit from middle ear surgery in our study.
AIMS AND OBJECTIVES:
1. To compare two methods of predicting the level of hearing benefit
following middle ear surgery, namely Glasgow benefit plot and
Belfast 15/30 dB rule of Thumb.
2. To correlate hearing benefit as measured by using the above
methods with patients' self assessment of his/her hearing status
3. To analyze the differences in hearing improvement by various
ossiculoplasties like incus interposition, tragal/ conchal cartilage
and autograft malleus.
4. To compare the success rates with surgery on dry and wet ears.
5. To compare success rates with cavity mastoidectomy cases versus
those without cavity.
MATERIALS AND METHODS:
Sixty patients undergoing middle ear surgery were selected at
random with no age or sex bias. Only patients with conductive hearing
loss were selected. The minimum age was 11 years and maximum age
was 48 years. Those cases requiring myringoplasty were excluded from
the study. Any allergic or septic focus was ruled out preoperatively.
Cases with bilateral ear disease were also taken up and revision
cases were also subjected to surgery on 7 occassions.
Both wet and dry ears were taken up. Patients were admitted one
day before the surgery. Mastoid shaving and local preparation were done
in the ward. All cases were operated under general anaesthesia. The types
of surgery included in the study were mastoid exploration, tympanoplasty
and ossiculoplasty. Apart from a detailed case history, patients were
assessed clinically with the help of otoscopy, tuning fork tests, pure tone
audiometry, free field hearing tests, X-ray Mastoids and CT Temporal
bone were done where applicable. A detailed questionnaire was used
(separately to be filled in by the patient and the close first relative of the
patient) pre and post operatively, to assess the level of hearing. Patients
were followed post operatively for 3 & 6 months.
RESULTS AND OBSERVATIONS:
There were 38 males and 22 females. Age range was from 11-48
years. The younger patients were more aware of their hearing loss and
consisted of 76.6 % of all the patients. The commonest disease was
CSOM - tubotympanic (14 cases) and atticoantral (46 cases).
Group 1 : Unilateral hearing impairment, asymmetric threshold
12 patients were included in this group. All had pure tone average
above 30 dB in one ear; all had interaural difference of more than 10 dB.
Preoperative self assessment of hearing loss by patients : Patients
presented with varying degrees of subjective hearing impairment, such as
diminished hearing from a distance, in group conversation, on telephone,
discharge and diminished hearing.
Post operatively: Hearing from operated and non-operated ear was
same in 6 patients (3 patients had inter aural difference of 12, 12 & 18 dB
but claimed symmetric hearing).
Group 2 : Bilateral hearing impairment, asymmetric threshold.
40 patients were included in this group and 37 patients had pure
tone averages above 30 dB in both ears. 29 patients had inter aural
difference of more than 10dB. Patients claimed significant benefit post
operatively. Hearing from operated and non-operated ear was same in 33
patients. The prediction by both methods in this group was 100%. 19
patients fell in category 'c' and claimed significant benefit.
Group 3 : Bilateral hearing impairment - symmetric threshold
8 patients were included in this group. Pure tone average was less
than 30 dB in six cases and interaural difference within 10 dB in 2 cases
and 12,12,15,16,25,28,26 dB in 6 patients. They had significant benefit
following surgery and claimed that the operated ear was the better
hearing ear.
As per audiometry, 2 patients fell in category 'c' and claimed
significant benefit. As per subjective benefit all these patients claimed
significant benefit. Comparing the same with 15/30 dB rule of thumb as
per audiometry, the overall positive predictive value was 80% and as per
subjective benefit 84%.
Applying Z test for significance of difference between the
predictive values by pure Tone Audiometry and subjective benefit in both
the methods, the difference is not significant since Z is <1.96 at 95%
confidence interval.
10 out of 12 patients (83%) in Group I had no difficulty in
localizing sound, as only one ear is actually sufficient to localize sound.
According to Browning GG (1993), minor head movement can achieve
the necessary variation in speech perception level.
In Group 3, 8 patients had bilateral symmetric hearing loss as per
pure tone audiometry. Pure tone averages in the 0.5,1,2 kHz were same in
both ears. This correlates with observations of G.G.Browning (1993),
audiometric tests do not measure all aspects of hearing; hence the ear
being operated upon should be as per patient's choice.
CONCLUSION:
1. The overall success rate of ossiculoplasty in the present study
is 80%.
2. In this study its found that Glasgow benefit plot is more
sophisticated, graphical, providing a good visual impression
whereas Belfast Rule of thumb is easy and simple to use, but, it
suffers from the disadvantages of 'all or none phenomenon' with no
place for marginal benefit.
3. Hearing improvement with Incus transposition is better followed
by tragal and conchal cartilage ossiculoplasty, Homograft Malleus
(in descending order).
4. Hearing improvement is better when minimal ossicular disruption
is present. (All present > Incus absent > M-I-> M-I-S-)
5. Hearing improvement is better when cholesteatoma is absent (when
compared to cholesteatoma cases).
6. Hearing improvement is better with dry ears.
7. Hearing improvement is better when cavity mastoidectomy was not
done (when compared to cavity mastoidectomy cases.)
8. Fresh cases do better than revision cases.
9. Cases without granulations do better than those with granulations
Progressive ataxia with oculo-palatal tremor and optic atrophy
The final publication is available at Springer via doi: 10.​1007/​s00415-013-7136-
TRESK is a key regulator of nocturnal suprachiasmatic nucleus dynamics and light adaptive responses
The suprachiasmatic nucleus (SCN) is a complex structure dependent upon multiple mechanisms to ensure rhythmic electrical activity that varies between day and night, to determine circadian adaptation and behaviours. SCN neurons are exposed to glutamate from multiple sources including from the retino-hypothalamic tract and from astrocytes. However, the mechanism preventing inappropriate post-synaptic glutamatergic effects is unexplored and unknown. Unexpectedly we discovered that TRESK, a calcium regulated two-pore potassium channel, plays a crucial role in this system. We propose that glutamate activates TRESK through NMDA and AMPA mediated calcium influx and calcineurin activation to then oppose further membrane depolarisation and rising intracellular calcium. Hence, in the absence of TRESK, glutamatergic activity is unregulated leading to membrane depolarisation, increased nocturnal SCN firing, inverted basal calcium levels and impaired sensitivity in light induced phase delays. Our data reveals TRESK plays an essential part in SCN regulatory mechanisms and light induced adaptive behaviours
Minimally Invasive In Vivo Real-Time Identification of Human Astrocytoma with Sulforhodamine 101
Abstract and poster under embargo until May 31, 2019
Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis.
In June 1999, the Association of British Neurologists (ABN) first published guidelines for the use of the licensed multiple sclerosis (MS) disease-modifying treatments (at that time β-interferon and glatiramer acetate). The guidelines were revised in 2001 and have been periodically updated since then. In 2002, following the negative assessment of these treatments by the National Institute for Health and Care Excellence (NICE), the MS risk-sharing scheme started, in which patients eligible according to the 2001 ABN guidelines were provided with treatment funded through the UK National Health Service (NHS), and monitored annually for up to 10 years.1 Recruitment to the risk-sharing scheme cohort is complete. Pending a future final evaluation, the UK Department of Health's instruction to NHS funders remains in place: that patients who fulfil the ABN criteria should continue to receive treatment funded through the NHS. The British neurological community has fully accepted the risk-sharing scheme for prescribing β-interferon and glatiramer acetate. Approximately 70 ‘treating centres’ have recruited >5000 patients between 2002 and 2005, and these have been monitored annually for 10 years; many more patients have received these treatments since 2005. The ABN published revised guidelines in 2007, and then again in 2009, following the licensing of natalizumab and mitoxantrone. This 2015 revised guideline replaces former versions. It includes all newly approved or licensed treatments for MS and represents a consensus concerning their use. These guidelines will require future revision as other treatments receive approval (eg, daclizumab and ocrelizumab): we suggest they are reviewed after an interval of no longer than 12 months. The guideline is not intended to provide a complete description of the possible complications and monitoring of disease-modifying treatments in MS; we refer prescribing neurologists to the relevant summaries of product characteristics.PostprintPeer reviewe
A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response
Microglia are increasingly implicated in brain pathology, particularly neurodegenerative disease, with many genes implicated in Alzheimer's, Parkinson's, and motor neuron disease expressed in microglia. There is, therefore, a need for authentic, efficient in vitro models to study human microglial pathological mechanisms. Microglia originate from the yolk sac as MYB-independent macrophages, migrating into the developing brain to complete differentiation. Here, we recapitulate microglial ontogeny by highly efficient differentiation of embryonic MYB-independent iPSC-derived macrophages then co-culture them with iPSC-derived cortical neurons. Co-cultures retain neuronal maturity and functionality for many weeks. Co-culture microglia express key microglia-specific markers and neurodegenerative disease-relevant genes, develop highly dynamic ramifications, and are phagocytic. Upon activation they become more ameboid, releasing multiple microglia-relevant cytokines. Importantly, co-culture microglia downregulate pathogen-response pathways, upregulate homeostatic function pathways, and promote a more anti-inflammatory and pro-remodeling cytokine response than corresponding monocultures, demonstrating that co-cultures are preferable for modeling authentic microglial physiology
TASK-3, two-pore potassium channels, contribute to circadian rhythms in the electrical properties of the suprachiasmatic nucleus and play a role in driving stable behavioural photic entrainment
Stable and entrainable physiological circadian rhythms are crucial for overall health and well-being. The suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, consists of diverse neuron types that collectively generate a circadian profile of electrical activity. However, the mechanisms underlying the regulation of endogenous neuronal excitability in the SCN remain unclear. Two-pore domain potassium channels (K2P), including TASK-3, are known to play a significant role in maintaining SCN diurnal homeostasis by inhibiting neuronal activity at night. In this study, we investigated the role of TASK-3 in SCN circadian neuronal regulation and behavioural photoentrainment using a TASK-3 global knockout mouse model. Our findings demonstrate the importance of TASK-3 in maintaining SCN hyperpolarization during the night and establishing SCN sensitivity to glutamate. Specifically, we observed that TASK-3 knockout mice lacked diurnal variation in resting membrane potential and exhibited altered glutamate sensitivity both in vivo and in vitro. Interestingly, despite these changes, the mice lacking TASK-3 were still able to maintain relatively normal circadian behaviour
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