268 research outputs found
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
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
A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases
Cerebral small vessel disease (SVD) affects the small vessels in the brain and is a leading cause of stroke and dementia. Emerging evidence supports a role of the extracellular matrix (ECM), at the interface between blood and brain, in the progression of SVD pathology, but this remains poorly characterized. To address ECM role in SVD, we developed a co-culture model of mural and endothelial cells using human induced pluripotent stem cells from patients with COL4A1/A2 SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodeling, and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cell tight junctions through paracrine actions. COL4A1/A2 models also express high levels of matrix metalloproteinases (MMPs), and inhibiting MMP activity partially rescues the ECM abnormalities and mural cell phenotypic changes. These data provide a basis for targeting MMP as a therapeutic opportunity in SVD.</p
Physical activity monitoring to assess disability progression in multiple sclerosis
Background: Clinical outcome measurement in multiple sclerosis (MS) usually requires a physical visit. Remote activity monitoring (RAM) using wearable technology provides a rational alternative, especially desirable when distance is involved or in a pandemic setting. Objective: To validate RAM in progressive MS using (1) traditional psychometric methods (2) brain atrophy. Methods: 56 people with progressive MS participated in a longitudinal study over 2.5 years. An arm-worn RAM device measured activity over six days, every six months, and incorporated triaxial accelerometry and transcutaneous physiological variable measurement. Five RAM variables were assessed: physical activity duration, step count, active energy expenditure, metabolic equivalents and a composite RAM score incorporating all four variables. Other assessments every six months included EDSS, MSFC, MSIS-29, Chalder Fatigue Scale and Beck’s Depression Inventory. Annualized brain atrophy was measured using SIENA. Results: RAM was tolerated well by people with MS; the device was worn 99.4% of the time. RAM had good convergent and divergent validity and was responsive, especially with respect to step count. Measurement of physical activity over one day was as responsive as six days. The composite RAM score positively correlated with brain volume loss. Conclusion: Remote activity monitoring is a valid and acceptable outcome measure in MS
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Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis.
IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis
Proteolytic shedding of the prion protein via activation of metallopeptidase ADAM10 reduces cellular binding and toxicity of amyloid-β oligomers
The cellular prion protein (PrPC) is a key neuronal receptor for amyloid-β oligomers (AβO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer's disease (AD). Similarly to the amyloid precursor protein (APP), PrPC is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hypothesized that ADAM10-modulated PrPC shedding would alter the cellular binding and cytotoxicity of AβO. Here, we found that in human neuroblastoma cells, activation of ADAM10 with the muscarinic agonist carbachol promotes PrPC shedding and reduces the binding of AβO to the cell surface, which could be blocked with an ADAM10 inhibitor. Conversely, siRNA-mediated ADAM10 knockdown reduced PrPC shedding and increased AβO binding, which was blocked by the PrPC-specific antibody 6D11. The retinoic acid receptor analog acitretin, which up-regulates ADAM10, also promoted PrPC shedding and decreased AβO binding in the neuroblastoma cells and in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Pretreatment with acitretin abolished activation of Fyn kinase and prevented an increase in reactive oxygen species caused by AβO binding to PrPC Besides blocking AβO binding and toxicity, acitretin also increased the non-amyloidogenic processing of APP. However, in the iPSC-derived neurons, Aβ and other amyloidogenic processing products did not exhibit a reciprocal decrease upon acitretin treatment. These results indicate that by promoting the shedding of PrPC in human neurons, ADAM10 activation prevents the binding and cytotoxicity of AβO, revealing a potential therapeutic benefit of ADAM10 activation in AD
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