Vertigo in Children and Adolescents

ScientificWorldJournal. 2012; 2012: 109624.

Published online 2012 Jan 3. doi: 10.1100/2012/109624

PMCID: PMC3259473

PMID: 22272166

Vertigo in Children and Adolescents: Characteristics and Outcome

Maayan Gruber, 1 Raanan Cohen-Kerem, 1, 2 , Margalit Kaminer, 3 and Avi Shupak 1, 2, 3 , , *

Author information Article notes Copyright and License information Disclaimer

1Department of Otolaryngology, Head and Neck Surgery, Carmel Medical Center, Haifa 34362, Israel

2The Bruce Rappaport Faculty of Medicine, Israel Institute of Technology (Technion), Haifa 32000, Israel

3Unit of Otoneurology, Lin Medical Center, Haifa 35152, Israel

*Avi Shupak: ten.vahaz-tenretni@kapuhs

Academic Editors: C. Bosetti and P. A. Schachern

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Abstract

Objectives. To describe the characteristics and outcome of vertigo in a pediatric population. Patients. All children and adolescents presenting with vertigo to a tertiary otoneurology clinic between the years 2003–2010 were included in the study. Results. Thirty-seven patients with a mean age of 14 years were evaluated. The most common etiology was migraine-associated vertigo (MAV) followed by acute labyrinthitis/neuritis and psychogenic dizziness. Ten patients (27%) had pathological findings on the otoneurological examination. Abnormal findings were documented in sixteen of the twenty-three (70%) completed electronystagmography evaluations. Twenty patients (54%) were referred to treatment by other disciplines than otology/otoneurology. A follow-up questionnaire was filled by twenty six (70%) of the study participants. While all patients diagnosed with MAV had continuous symptoms, most other patients had complete resolution. Conclusions. Various etiologies of vertigo may present with similar symptoms and signs in the pediatric patient. Yet, variable clinical courses should be anticipated, depending on the specific etiology. This is the reason why treatment and follow up should be specifically tailored for each case according to the diagnosis. Close collaboration with other medical disciplines is often required to reach the correct diagnosis and treatment while avoiding unnecessary laboratory examinations.

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1. Introduction

Vertigo is an uncommon complaint in children and adolescents. Surveys of the adult population have reported a one-year prevalence of 23% for unspecified dizziness and 5% for vestibular vertigo [1]. In comparison, a recent review of all ICD-9 codes related to vestibular and balance disorders in more than 560000 distinct pediatric patient encounters during a 4-year period revealed prevalence of only 0.4% for unspecific dizziness, 0.03% for peripheral, and 0.02% for central vestibulopathy [2].

The first reference in the modern scientific literature for pediatric vertigo was published by Harrison [3] in 1962. Despite the most significant technological achievements in the development of diagnostic tools since then, diagnosis is still based mainly upon the patient's history and physical examination. When a child or an adolescent presents with dizziness, he or she is first being evaluated by the primary physician, usually a pediatrician, and only some are diagnosed with true vertigo. Dizziness and vertigo might present a considerable pathology, and patients are often referred to additional tests or further evaluation performed by either an otolaryngologist or a neurologist [4–6].

The most important clues to the diagnosis of vertigo are obtained through a careful and pertinent clinical history. However, when a child as the patient is considered this task might be hampered due to lack of communication abilities, narrowed vocabulary, and distractibility. These difficulties sometimes lead to the erroneous impression that the presenting symptoms are secondary to lack of coordination or behavioral problems [7]. Due to these limitations meticulous physical examination and laboratory tests are important stepping stones towards the correct diagnosis. Yet, the pediatric patients' compliance may also be limited in the performance of a complete otoneurological evaluation. A further challenge is presented by the remarkable ability of most children to compensate for static vestibular deficits. Vestibular insults that often result in disequilibrium and considerable daily activities limitation in the adult would often show no evidence for such symptoms in the pediatric patient.

The differential diagnosis of childhood vertigo differs from that of adults. Several etiologies are unique to the pediatric population while [5] the occurrences of other pathologies are rather different in children and adults [8, 9].

The aim of this study was to present the etiologies of vertigo in children and adolescents and to describe its course over time.

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2. Materials and Methods

In a retrospectively designed study we have looked at a cohort of children and adolescents presenting to a tertiary otoneurology clinic with vertigo between the years 2003–2010. The study included patients younger than 18 years with normal otoscopy who had suffered at least one episode of vertigo and had no prior otoneurological evaluation.

Acute otitis media and otitis media with effusion are common causes for unsteadiness or vertigo in children [16]. However, in the present study we focused on children and adolescents presenting to the clinic with vertigo albeit normal otoscopic findings.

We have excluded patients with prior cranial or neurosurgical surgery, previous otoneurological evaluation, or documented developmental disorders.

A detailed medical history of vestibular and migraine symptoms was obtained from the patient and his parents. All patients had a complete otolaryngological and otoneurological physical examination, and audiological evaluation including pure tone, speech, and admittance audiometry. Further tests such as electronystagmography (ENG), auditory brainstem response (ABR), computerized tomography, and magnetic resonance imaging were carried out as indicated.

Follow-up was performed using a telephone-administered questionnaire completed by a parent addressing continuous or recurrent symptoms, need for further evaluation and treatment, overall wellbeing, and compliance with the recommended treatment (See the appendix).

An ethical committee approval was granted for this study.

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3. Results

A total of thirty-seven patients were included in the study. Patients' demographics and symptoms on presentation are detailed in Table 1.

Table 1

Patient's characteristics on presentation.

Total number of patients		37
Male/female		19/18
Age (years) at presentation (Mean ± SD)		14 ± 3.3
Age range (years)		6–19
Symptoms at presentation	Headache	19 (51%)
	Vomiting	11 (30%)
	Nausea	19 (51%)
	Hearing loss	8 (22%)
	Tinnitus	6 (16%)
Findings on bedside examination	Spontaneous nystagmus	10 (27%)
	Positive post-head-shaking nystagmus	6 (16%)
	Positive head-impulse test	5 (14%)
	Positional nystagmus	2 (5%)
Pathological ENG findings in the 23 completed tests		16 (70%)

Bedside examination has documented spontaneous nystagmus in ten (27%) patients, post-head-shaking nystagmus in six (16%), positive head impulse test in five (14%), and positional nystagmus in two (5%).

ENG was indicated in twenty-seven patients. Twenty-three children completed the study successfully while four did not comply with the test. Of the patients completing the ENG sixteen (70%) had pathological caloric test defined as canal paresis >25% or directional preponderance >30% according to Jongkees formula [17]. Other pathological findings included positional nystagmus in two patients, abnormal oculomotor function in one patient, and spontaneous nystagmus in one patient.

Audiological evaluation revealed high tone hearing loss in six patients (16%) and low tone hearing loss in three (8%). One patient had unilateral profound hearing loss.

Thirteen (35%) patients had a brain CT prior to their referral to our clinic. None have revealed findings that contributed to the patient's diagnosis.

Brain MRI was performed in eight (22%) patients and was positive for demyelinative changes in one.

The most common etiology for vertigo was migraine (twelve patients, 32%), followed by acute labyrinthitis/neuritis (eight patients, 22%) and psychogenic dizziness (eight patients, 22%) (Figure 1).

Figure 1

Distribution of the various etiologies for vertigo. MAV: migraine-associated vertigo, VN: vestibular neuritis, BPVC: benign paroxysmal vertigo of childhood, and SMD: space and motion discomfort.

A telephone follow-up questionnaire was completed by twenty six (70%) of the study participants 2–8 years after presentation. Follow-up drop-outs were due to failure in locating the patient in ten cases and refusal to complete the questionnaire in one case. Of the completed questionnaires nine were related to the migraine-associated vertigo (MAV), seven to the labyrinthitis/neuritis, and six to the psychogenic subgroups, respectively. All nine followed-up MAV patients had continuous vertigo complaints, in comparison to three (50%) of the psychogenic dizziness subgroup and two (29%) of the labyrinthitis/neuritis subgroup (Table 2). Four patients, all suffering from MAV, have received pharmacological treatment at the time of follow-up.

Table 2

Follow-up outcome of the three major etiology subgroups.

	Migraine-associated vertigo	Psychogenic vertigo	Vestibular neuritis or labyrinthitis
Number of patients	12	8	8
Completed questionnaire	9/12 (75%)	6/8 (75%)	7/8 (88%)
Ongoing symptoms	9/9 (100%)	3/6 (50%)	2/7 (29%)
Symptoms limit daily activities	6/9 (67%)	1/6 (17%)	1/7 (13%)
Ongoing medical follow-up due to vertigo	4/9 (44%)	1/6 (17%)	0/7 (0%)
Current pharmacological treatment	4/9 (44%)	0/6 (0%)	0/7 (0%)
Satisfied with the medical care provided	6/9 (67%)	6/6 (100%)	7/8 (88%)

Twenty-one patients and/or parents from the twenty six (81%) that were available for follow-up were satisfied with the otoneurological evaluation and management.

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4. Discussion

Vestibular disorders in the pediatric population assume higher profile in recent years as data and studies highlight its importance in general pediatric healthcare.

The main observation of this study is the diversity of etiologies that might be presented by the leading symptoms of vertigo in the pediatric population. Detailed anamnesis aiming to maximal collaboration of the patient and his caregiver combined with a comprehensive otoneurological bedside examination are essential and most of the time sufficient steps towards the correct diagnosis and recommended treatment approach.

Our experience corroborated by previous publications (Table 3) shows that the etiology of vertigo in a significant percent of patients is migraine. Migrainous headache might accompany the vertigo but often dominate the clinical picture years after the initial presentation. MAV is much more common in the pediatric when compared to the adult population. While MAV was reported in up to 35% of vertigo patients in the pediatric population it was diagnosed in only 6% of adults suffering from vertigo [18]. Recent data demonstrate the potential underdiagnosed extent of MAV in children. While approximately 10% of children meet the International Headache Society criteria for migraine headache, vestibular symptoms occur in about 25% of them [19].

Table 3

Previous studies on dizziness and vertigo in children and adolescents.

	Number of patients	Most common etiologies
		Peripheral vestibulopathy	29%
O'Reilly et al., 2011 [10]	132	MAV/BPVC	24%
		Developmental delay	11%
		Labyrinthitis/neuritis	22%
Szirmai, 2010 [9]	145	MAV	19%
		Panic or anxiety disorder	17%
		MAV	25%
Wiener-Vacher, 2008 [26]	>2000	BPVC	20%
		Trauma	10%
		Viral infections	28%
Balatsouras et al., 2007 [23]	54	MAV	20%
		BPVC	17%
		BPVC	21%
Niemensivu et al., 2007 [13]	24	MAV	17%
		Otitis media	17%
		MAV	34%
Erbek et al., 2006 [6]	50	BPVC	12%
		Psychogenic vertigo	10%
		BPVC	19%
	119	MAV	14%
Riina et al., 2005 [14]		Vestibular neuritis	12%
		Otitis media	10%
		Psychogenic vertigo	5%
	55	MAV	31%
Choung et al. 2003 [12]		BPVC	26%
		Trauma	7%
		Otitis media	15%
Bower and Cotton, 1995 [15]	34	BPVC	15%
		MAV	12%

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MAV: migraine-associated vertigo.

BPVC: benign paroxysmal vertigo of childhood.

All nine patients suffering from MAV in our cohort that have completed the follow-up questionnaire reported on persistent vestibular symptoms with significant impact on their daily activities. It is not surprising that this subgroup of patients was the least satisfied with the medical treatment they have received. Still, less than half of them used appropriate acute or prophylactic antimigraine medications. This data emphasizes the need for proactive interdisciplinary follow-up of these patients to avoid under-treatment and deterioration of their quality of life.

While vestibular neuritis and labyrinthitis are reported common etiologies for pediatric and adolescents vertigo also in other studies, the incidence of psychogenic vertigo which was found in 22% of our patients is much smaller. Psychogenic dizziness was reported only in three studies with incidence of 5–17% [7, 9, 14], while most reports did not mention it among the etiologies for vertigo in children (Table 3). It is interesting that a recent study focusing on unexplained neurological complaints in children including vertigo, dizziness, headache, and fainting has reported that over 90% of the patients had at least one psychiatric disorder [20].

Benign paroxysmal vertigo of childhood (BPVC) which was found in only three (8%) patients in the present study was a common etiology for childhood vertigo in most other reports (Table 3). BPVC is considered a centrally originated pathology in the spectrum of migraine disease, and some cases develop headaches and present with MAV later in their clinical course [21].

Differences in the study design, inclusion, and exclusion criteria might explain the discrepancies in the reported incidence of various etiologies between the present and previous works. Some of the previous studies have included patients with dizziness or vertigo while other works focused on vertigo alone [6, 9, 10, 12, 15, 22, 23]. The present study included only patients with complaints of whirling vertigo while patients with otoscopic findings of acute or chronic otitis media as well as serous otitis media were excluded. Also, children with previously known neurological deficits were not included in the study.

The value of imaging and neurophysiological laboratory tests should be carefully considered while taking into consideration potential long-term irradiation effects on one hand and the limited compliance of the child to imaging, vestibular, and evoked potential tests that require optimal cooperation on the other hand.

Our experience shows that the value of head CT in the evaluation of the dizzy child is very limited. Head CT results did not contribute to the diagnosis and treatment in any of the 13 patients who were evaluated by this imaging modality. Current standards of risk management for ionizing radiation in the pediatric population [11, 24] combined with the significantly higher sensitivity of brain MRI when posterior fossa and inner ear structures are considered support the use of MRI as the study of choice when brain imaging is indicated [25]. It is important to realize that vertigo due to posterior fossa tumor is uncommon in the pediatric and adolescent population and is found in less than 1% of cases [26]. A retrospective review of 87 children with vertigo who underwent neuroimaging demonstrated new findings in 23 patients. However, 19 of the patients had additional neurological deficits and 3 had intense headaches. The authors concluded that neuroimaging will not aid the diagnostic workup when the only presenting symptoms is vertigo [13].

ENG is an important adjunct in the otoneurologist armamentarium, but compliance with this test might be poor in the pediatric population. A recent report by Szirmai et al. described 145 patients with dizziness or vertigo [9]. Patients work-up was similar to that of our study and included ENG testing. 66% of the study participants completed the ENG test battery compared to 62% in the present study. The ENG findings were pathological in 80% in comparison to 70% in our cohort. Valente [27] in her recent update on vestibular evaluation in the pediatric patient stated that while the underlying causes of vertigo and dizziness might be diagnosed on the basis of patient history and clinical bedside testing, laboratory vestibular tests play an important role in reaching and ascertaining the final diagnosis.

We believe that ENG can contribute to the diagnostic evaluation especially when the clinical picture is obscure. It should be remembered that although compliance is a problem, collecting reliable information from a child is challenging, and objective tests might assume higher importance in these clinical scenarios. A possible alternative to the ENG is the computerized rotatory chair test [28]. The seated patient is exposed to a series of sinusoidal angular accelerations directly stimulating the horizontal semicircular canals while the resulting vestibule-ocular reflex response is recorded. When compared to the ENG calorics this test employs a significantly less provocative stimulus while accurately recording the vestibular response to multiple graded stimuli which better reflect the vestibular function. The mild nature of the stimuli and the possibility to conduct the test while seated on the parent's laps enables good compliance of the pediatric patient [29]. The high cost of the system is a significant limitation and it is not vastly available for clinical use.

While our patient's work-up protocol on presentation was similar to that of previous studies, follow-up results have not been previously reported. Meticulous follow-up is the only way to get important insights on the natural history of the various etiologies for childhood vertigo and vital information on the success of treatment and patient's compliance with health-providers recommendations. The present retrospective study is limited in the extent of successful follow-up that included only 70% of the study participants. We believe that a large prospective study which would include long-term follow-up examinations is warranted.

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Appendix

• Follow-up Questionnaire:

  • Pt. #   Initials   Date (yyyy-mm-dd)

  • □ □  □ □ □  □ □ □ □-□ □-□ □

• Questions:

  1. Is the patient under any medical follow-up regarding dizziness?

     1. Yes □   

     2. No □ 

     3. Remarks 

  2. Does the patient currently taking any pharmacological therapy?

     1. Yes □   

     2. No □ 

     3. Remarks 

  3. Did the patient take any pharmacological therapy in the past?

     1. Yes □   

     2. No □ 

     3. Remarks 

  4. If pharmacological therapy used—was it beneficial?

     1. Yes □   

     2. No □ 

     3. Remarks 

  5. Did the patient receive any physiotherapy treatments?

     1. Yes □   

     2. No □ 

     3. Remarks 

  6. If physiotherapy was conducted—was it helpful?

     1. Yes □   

     2. No □ 

     3. Remarks 

  7. To what extent is the patient satisfied from the treatment as a whole (scale of 0–10)?

  8. Does the patient still suffer from vertigo?

     1. Yes □   

     2. No □ 

     3. Remarks 

  9. If yes; does it interfere with his daily activities?

     1. Yes □   

     2. No □ 

     3. Remarks

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Vertigo in Children

https://www.nationwidechildrens.org/conditions/vertigo-in-children  

Vertigo in Children

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Vertigo (VER ti go) is the medical word for the feeling of spinning. Your child may feel like the world is moving, but there is no movement. These feelings come and go. They may last for seconds or for days. Your child may feel worse when changing positions, standing, rolling over, coughing, or sneezing. Vertigo can be caused by a problem inside the ear.

Vertigo is not contagious. You cannot get it from another person or give it to someone else.

Signs and Symptoms

You may see your child do some of the following:

Jerky eye movements

Tilting of the head

Swaying

Trouble walking straight

Pulling to one direction

Rocking

Falling

Your child may feel some of the following:

Spinning feeling

Dizziness

Nausea

Motion sickness

Headache

Sensitivity to light and noise

Ringing in the ears

Ear pain or fullness or pressure in the ears

Hearing loss

Sweating

Diagnosis

There is no specific test for diagnosing vertigo. The tests that the doctor will do will depend on your child's signs and symptoms.

Treatment

Treatment for vertigo depends upon what is causing it. Most often, vertigo goes away without treatment. This is because the brain is able to adjust to changes in the inner ear.

Treatment may include:

Physical Therapy exercises to improve balance. The physical therapist may teach your child special head and body movements

Medicine to relieve symptoms of nausea and motion sickness.

Antibiotic medicine to treat inner ear infections.

Steroid medicine to decrease swelling.

Water pills to reduce the amount of fluid in the inner ear.

When to Get Emergency Care

Sudden change in speech

Sudden change in vision

Head injury from a fall

Repeat episodes of falling

Continued vomiting

When to Call the Doctor

If your child falls a lot

If your child faints

If the symptoms of vertigo keep your child from doing everyday activities

If you have any questions about vertigo

Harm Prevention and Symptom Control

To avoid getting hurt during an episode of vertigo, your child should not drive or use machines. Activities that involve climbing or hiking should also be avoided.

To prevent the symptoms from getting worse, your child should avoid sudden movement and changes in position. It is important to change positions slowly.

Vertigo in Children (PDF) : 

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Vertigo in Children

Vertigo (Dizziness)

https://www.chop.edu/conditions-diseases/vertigo-dizziness  

     

What is vertigo (dizziness)?

Vertigo can be either a sensation of spinning, like the dizzy feeling your child gets after the merry-go-round, or it can be a perception that the world around him is spinning or tilting.

Occasionally, a child can experience vertigo when congestion from a cold or an ear infection presses on his inner ear, which is part of the vestibular system that affects balance. But when a child experiences repeated or prolonged bouts of vertigo, it usually happens in conjunction with other illnesses or conditions.

Overall, vertigo is far less common in children than it is in adults.

Vertigo can be very distressing to a child and can affect children of all ages. Until a child is old enough to express his feelings of vertigo, a parent might notice when the child has a bout and seems clumsy or nauseous, or his eyes might dart back and forth. It is important to seek treatment for vertigo, as it can be a sign of a serious illness and can lead to injuries due to the disruption in balance and coordination.

Cause

Vertigo or dizziness can occur in children either with or without an eardrum problem.

An eardrum problem causes dizziness because the body's sense of balance is located in the inner ear's vestibular system. Most eardrum problems that cause vertigo are tied to minor illnesses that, once treated, can eliminate the vertigo.

But other systems in the body can cause vertigo as well. Depending on the disorder causing the symptoms, the bouts of dizziness can be more persistent. In these cases, a change in head position is often a trigger, and your child may experience other symptoms, like nausea and darting eye movements (nystagmus), as well.

The many possible causes of vertigo include:

Middle-ear infection or middle-ear "effusion," in which a thick fluid builds up behind the eardrum, but no infection is present; in either case, your child's sense of balance, located in the inner ear, is temporarily disrupted from the fluid pressing on the inner ear

Inner ear infections, including labyrinthitis and vestibular neuritis

Concussion or other head trauma

Small bone-like particle(s) floating in the inner ear fluid, residual from a concussion or an infection

Migraines, considered a vascular disorder because blood vessels in the brain dilate and produce the throbbing headache; a "motion sickness," or intolerance, is often the form of vertigo that goes along with migraine

Benign paroxysmal positional vertigo (BPPV), which involves sudden attacks of dizziness and often rapid eye movements; in many cases, this disorder appears to be related to an early sign of chronic migraines  

Seizures

Low blood pressure

Autoimmune disorders, such as multiple sclerosis, Type 1 diabetes, and juvenile arthritis

Visual dysfunctions, such an excessive difference in prescription between the eyes or a congenital eye movement disorder

A brain tumor

Meniere's disease

Aspirin and other nonsteroidal anti-inflammatory drugs

Symptoms

Symptoms of vertigo can vary from child to child and depend on the cause and severity of the vertigo. Some common symptoms include:

Child complaining of a dizziness, which might feel like a post-merry-go-round sensation, a perception the room is spinning or tilting, or a "motion sickness," like your child is rocking on a boat and can't tolerate motion

Dizziness triggered by a change in head position — either your child turns his head or stands up from a lying down position. This vertigo usually lasts only seconds or minutes

Unusual awkwardness, clumsiness or poor balance

Complaint of ear ringing (tinnitus), ear pain or ear stuffiness

Hearing loss

Fever of more than 100 degrees

Migraine

Confusion

Collapse or blacking-out

Nausea

Vomiting

Sweating

Pale complexion

Eyes darting back and forth (nystagmus)

The desire to lie still

Loss of fine or gross motor skills

Delayed motor milestones, such as a slowness to hold his head upright, stand or walk

Testing and diagnosis

Your primary care provider will likely refer your child to a pediatric otolaryngologist (ENT specialist) because diagnosing the cause of vertigo can be challenging. Vertigo must be differentiated from other forms of dizziness, and a thorough evaluation of all possible causes may be necessary. An otolaryngologist is best able to perform the comprehensive evaluation and to know when to call on the expertise of other specialists. During the course of the evaluation, a specialist may perform tests such as:

Extensive medical history-taking with questions for both you and your child; a family history of migraine may be explored

Thorough physical exam, especially of the head and ears

Audiometry, or hearing testing

Vestibular function tests, such as in a rotational chair

Electronystagmography (ENG), which involves electrodes placed above and below your child's eyes to detect rapid eye movements (nystagmus)

Electroencephalography, a test that measures electrical activity in your child's brain

Lab (blood) tests

Imaging tests, such as CT scan, X-ray or MRI

Vestibular-ocular tests involving games and gaze fixation

Dynamic visual acuity, involving your child shaking his head "no" quickly

Coordination and gross motor skills, such as hopping, skipping and jumping with eyes open and closed

Treatment

Specific treatment depends on the cause of your child's vertigo. In many cases, vertigo can be relieved even if the underlying cause persists. An otolaryngologist from The Children's Hospital of Philadelphia will be able to discuss all of the available treatment options for your child and to customize the plan according to your child's symptoms and medical history. Possible treatments or therapies might include:

Medication, including antibiotics, decongestants or antihistamines for fluid in the ear

Motion sickness medicine

Seizure or antidepressant medication for migraine-associated vertigo

Behavioral modifications and changes in lifestyle, including an avoidance of positions or activities that can induce vertigo or put your child at risk for accidents if he has a bout of vertigo — for instance, if he skateboards or drives a car   

Physical therapy techniques, including the Epley or Semont maneuver, which can shift floating bone-like particles to an area of the inner ear where they don't cause vertigo

Outlook

Most cases of vertigo result from an infection or fluid in the ear; proper treatment of the infection makes the vertigo disappear. When migraines and BPPV are the cause, related episodes of vertigo, along with the migraines themselves, can usually be successfully managed with medication. When more serious disorders cause the vertigo, the vertigo may be controlled through various medicines or therapies, even if the underlying disorder poses treatment challenges. The key is to have your child meet with a specialist for a proper diagnosis and treatment plan.

Follow-up care

If there is an underlying disorder causing your child's vertigo, the specialist will design an individualized plan to manage your child's condition and track symptoms and progress. Temporary vertigo, resulting from an infection, can usually be resolved with a course of medication.

Why choose CHOP?

Because of the potential for vertigo to be a sign of a serious condition, it's important that a child with vertigo is seen by an experienced pediatric specialist. The otolaryngology team at The Children's Hospital of Philadelphia has the specialized training and expertise to accurately diagnose and successfully manage vertigo in children. When needed, our experts will collaborate with other subspecialists who may need to be involved in your child's diagnosis and care.

Otorhinolaryngology, Head and Neck Diseases

Cochleovestibular manifestations in Fabry disease: Importance of screening and systematic ENT evaluation Publication date: Available online 7 May 2019 Source: European Annals of Otorhinolaryngology, Head and Neck Diseases Author(s): C. Eyermann, T. Raguin, D. Rohmer, E. Noel, A. Charpiot Abstract Objectives Fabry disease (FD) is an X-linked inherited lysosomal storage disease. It is a multisystem pathology that can include ENT disorders. The aim of the present study was to investigate the cochleovestibular manifestations of FD, in order to show the importance of screening and systematic ENT evaluation. Material and methods A single-center retrospective study included 14 male and 23 female FD patients. Hearing impairment was defined as hearing loss greater than the 90th percentile for at least one frequency. Vestibular impairment was defined by lateral semicircular canal dysfunction. Age, ongoing enzyme replacement therapy (ERT) and organic (renal, cardiac and cerebrovascular) complications were used as severity markers. Results Hearing impairment was found in 62.6% of cases, mostly at high frequencies, and was associated with age, ERT, and cardiac and cerebrovascular disorder. It affected 46.7% of asymptomatic adult patients. Vestibular impairment was found in 56% of cases, associated with age; it affected two-thirds of ERT patients, more than 60% of patients with organic complications, and 50% of asymptomatic adult patients. Conclusions More than half of patients had ENT involvement. All FD patients should undergo early ENT screening for diagnostic, prognostic and therapeutic purposes. Systematic complete ENT follow-up with auditory and vestibular evaluation should be performed regularly, even for heterozygous women.

Plan S! Publication date: Available online 26 April 2019 Source: European Annals of Otorhinolaryngology, Head and Neck Diseases Author(s): O. Laccourreye, H. Maisonneuve

Skull vibration induced nystagmus in patients with superior semicircular canal dehiscence Publication date: Available online 25 April 2019 Source: European Annals of Otorhinolaryngology, Head and Neck Diseases Author(s): G. Dumas, H. Tan, L. Dumas, P. Perrin, A. Lion, S. Schmerber Abstract Objective To establish optimum stimulus frequency and location of bone conducted vibration provoking a skull vibration induced nystagmus (SVIN) in superior semi-circular canal dehiscences. Methods SVIN 3D components in 40 patients with semi-circular canal dehiscence (27 unilateral and 13 bilateral) were compared with a group of 18 patients with severe unilateral vestibular loss and a control group of 11 volunteers. Results In unilateral semi-circular canal dehiscences, SVIN torsional and horizontal components observed on vertex location in 88% beat toward the lesion side in 95%, and can be obtained up to 800 Hz (around 500 Hz being optimal). SVIN slow-phase-velocity was significantly higher on vertex stimulation at 100 and 300 Hz (P = 0.04) than on mastoids. SVIN vertical component is more often upbeating than downbeating. A SVIN was significantly more often observed in unilateral than bilateral semi-circular-canal dehiscences (P = 0.009) and with a higher slow phase velocity (P = 0.008). In severe unilateral vestibular lesions the optimal frequency was 100 Hz and SVIN beat toward the intact side. The mastoid stimulation was significantly more efficient than vertex stimulation at 60 and 100 Hz (P < 0.01). Conclusion SVIN reveals instantaneously in unilateral semi-circular canal dehiscences a characteristic nystagmus beating, for the torsional and horizontal components, toward the lesion side and with a greater sensitivity toward high frequencies on vertex stimulation. SVIN three components analysis suggests a stimulation of both superior semi-circular canal and utricle. SVIN acts as a vestibular Weber test, assessing a vestibular asymmetrical function and is a useful indicator for unilateral semi-circular canal dehiscence.

Less alcohol, more fruit and veg!–Spread the word Publication date: Available online 23 April 2019 Source: European Annals of Otorhinolaryngology, Head and Neck Diseases Author(s): F. Rubin, O. Laccourreye

Transnasal frontal intersinus septum takedown for frontal sinus pyocele Publication date: Available online 22 April 2019 Source: European Annals of Otorhinolaryngology, Head and Neck Diseases Author(s): A.J.K. Chua, D.C.W. Chin, X.Y. Huang Abstract Introduction The open frontal intersinus septum takedown (FISST) technique was first described in 1976. We describe our experience with an endoscopic transnasal approach to manage a frontal sinus pyocele arising from an obstructed frontal sinus outflow tract due to anterolateral thigh flap reconstruction of a maxillectomy defect. Case report A 40-year-old lady experienced upper eyelid swelling and purulent nasal discharge 3 weeks after undergoing a left extended medial maxillectomy with free anterolateral thigh flap reconstruction. A computed tomography (CT) scan revealed total opacification of the left frontal sinus. There was no improvement with intravenous antibiotics and she underwent a surgery, whenshe was found intraoperatively to have a frontal sinus pyocele, which was then drained. She then underwent an endoscopic transnasal FISST to ventilate the left frontal sinus via the contralateral frontal recess with good results. A CT scan performed 3 months postoperatively showed a widely patent interfrontal sinus septal window and right frontal outflow tract with no disease recurrence. Discussion The FISST is a useful technique to manage unilateral frontal sinus disease by taking advantage of the contralateral outflow tract when the ipsilateral frontal recess is obstructed.

Temporomandibular joint herniation through the foramen of Huschke with clicking tinnitus Publication date: Available online 20 April 2019 Source: European Annals of Otorhinolaryngology, Head and Neck Diseases Author(s): K.H. Lim, J.Y. Jung, J. Rhee, J. Choi Abstract Introduction The foramen of Huschke (FH) is an uncommon anatomical variation of the tympanic portion of the temporal bone. It is located on the anteroinferior aspect of the external auditory canal; extremely rarely, the soft tissues around the temporomandibular joint (TMJ) can herniate through it. Case summary We report two cases of TMJ herniation through the FH presenting with clicking tinnitus that were treated differently. Discussion The treatment of TMJ herniation depends on the presenting symptoms and the patient's willingness to undergo surgical correction. If surgical management is chosen, the bone can be obliterated using tragal cartilage and temporalis fascia.

Voice outcome indicators for unilateral vocal fold paralysis surgery: A survey among surgeons Publication date: Available online 19 April 2019 Source: European Annals of Otorhinolaryngology, Head and Neck Diseases Author(s): G. Desuter, M. Dedry, B. Schaar, J.T. van Lith-Bijl, P.P. van Benthem, E.V. Sjögren Abstract Introduction Standardization of voice outcomes indicators (VOIs) is an important issue when it comes to evaluating and comparing surgical treatments for Unilateral Vocal Fold Paralysis (UVFP). In a recent review, 11 VOIs were found to represent 80% of the VOIs cited in the literature. A survey was launched among the European laryngologists to acquire surgeons' opinions on the above mentioned preselected VOIs. Material and method The electronic survey took place between November and December 2016. Three general questions were asked about surgeon's practice setting(s) and experience. The eleven next questions concerned (a) surgeon's VOIs preference and (b) their estimates of post-operative target values, they would consider being satisfactory. Results The response rate was 16% (50 surveys). The majority of responders worked in tertiary hospitals (50%), had 15 years of experience with UVFP and performed on average 20 UVFP related procedures a year. The VOIs that were favored by the responding surgeons were, in decreasing order of importance, Voice handicap Index (VHI-30), Maximum Phonation Time (MPT), GRBAS-I, Mean Airflow Rate (MeAF), Jitter and Shimmer. There was an excellent consensus on post-operative VOI target values between survey's results and the literature data, except for three VOIs that showed somewhat divergent tendencies (absolute VHI-30, Jitter and Shimmer). Conclusions Three VOIs are favored by surgeons: VHI-30, MPT and GRBAS-I. Jitter and Shimmer, although very frequently reported and statistically valid in the literature, come last concerning surgeon's choice as VOI for UVFP treatment assessment.

Rare cause of vertigo in a child Publication date: Available online 19 April 2019 Source: European Annals of Otorhinolaryngology, Head and Neck Diseases Author(s): S. Achard, M. Parodi, F. Denoyelle

Anaplastic lymphoma and silicone in cochlear implants: Let's reassure Publication date: Available online 18 April 2019 Source: European Annals of Otorhinolaryngology, Head and Neck Diseases Author(s): M. Risoud, N.-X. Bonne, C. Vincent

Burnout! Publication date: Available online 18 April 2019 Source: European Annals of Otorhinolaryngology, Head and Neck Diseases Author(s): O. Laccourreye, Q. Lisan

Applied Microbiology and Biotechnology

Efficient synthesis of an antiviral drug intermediate using an enhanced short-chain dehydrogenase in an aqueous-organic solvent system Abstract (2R,3S)-N-tert-Butoxycarbonyl-3-amino-1-chloro-2-hydroxy-4-phenylbutane (1b) is key for the synthesis of the antiviral drug atazanavir. It can be obtained via the stereoselective bioreduction of (3S)-3-(N-Boc-amino)-1-chloro-4-phenyl-butanone (1a) with short-chain dehydrogenase/reductase (SDR). However, the stereoselective bioreduction of this hydrophobic and bulky substrate still remained a challenge because of the steric hindrance effect and low mass transfer rate. In this study, SDR isolated from Novosphingobium aromaticivorans (NaSDR) having low activity to 1a, which was engineered to enhance catalytic efficiency through active pocket iterative saturation mutagenesis (ISM). The obtained mutant (muSDR) (G141V/I195L) had 3.57 times higher kcat than the wild type (WT) towards 1a. Molecular docking analysis revealed considerable differences in the distance between the substrate and catalytic residues in WT and mutant SDR. Moreover, muSDR reduced 15 ketones with excellent enantioselectivity, indicating broad substrate acceptance. After optimization of expression and reaction conditions, the conversion was completed in a scale-up reaction (500 mL) using 50% toluene with 500 mM substrate without additional NADH. These results show that muSDR may be a valuable biocatalyst for future industrial applications.

A novel transcriptional regulator RXE1 modulates the essential transactivator XYR1 and cellulase gene expression in Trichoderma reesei Abstract XYR1 is the key transcription activator for cellulase gene expression in the model filamentous fungus Trichoderma reesei, which is widely applied in the industry due to its excellent capability of secreting a large quantity of cellulases. Despite the essential role of XYR1, the regulation of its expression in T. reesei cellulolytic response is poorly understood. In this study, we identified a transcription factor RXE1 exhibiting strong binding activity to the xyr1 promoter using yeast one-hybrid screen. RXE1 homologs exist in quite a few filamentous fungi but none of them have been assessed regarding their functional involvement in plant cell wall degradation. Knockdown of rxe1 in T. reesei using a copper-mediated RNAi system not only abrogated conidiation, but also remarkably compromised xyr1 and cellulase gene expression. The defective cellulase but not conidia production in the rxe1-knockdown strain was fully rescued by the constitutive expression of XYR1. Our study thus identified a novel transcriptional regulator controlling xyr1 and cellulase gene expression, which will contribute to elaborating the intricate network of cellulase gene regulation in T. reesei.

Harnessing yeast metabolism of aromatic amino acids for fermented beverage bioflavouring and bioproduction Abstract Aromatic amino acid metabolism in yeast is an important source of secondary compounds that influence the aroma and flavour of alcoholic beverages and foods. Examples are the higher alcohol 2-phenylethanol, and its acetate ester, 2-phenylethyl acetate, which impart desirable floral aromas in wine, beer and baker's products. Beyond this well-known influence on the organoleptic properties of alcoholic beverages and foods, there is a growing interest in understanding and modulating yeast aromatic amino acid metabolism. The tryptophan derivatives melatonin and serotonin have bioactive properties and exert positive effects on human health, and aromatic amino acids are also the precursors of products of industrial interest, such as nutraceuticals, fragrances, and opium-derived drugs. This mini-review presents current knowledge on the formation of compounds from aromatic amino acids by Saccharomyces cerevisiae, from genetic and environmental influences on their flavour impacts in alcoholic beverages to their potential as bioactive compounds, and the use of yeast as microbial factories for the production of commercially relevant aromatic compounds.

Xanthobacter-dominated biofilm as a novel source for high-value rhamnose Abstract Rhamnose is a high-value carbohydrate used in flavorings, aromatics, and pharmaceuticals. Current demand for rhamnose is filled through plant-based sources; however, microbially originated rhamnolipids have been proposed as an alternative source. A mixed microbial biofilm, cultured from a wastewater sludge, was found to comprise > 8 dry weight% rhamnose when provided volatile fatty acids as carbon source, and 24 dry weight% when given glucose. The latter rhamnose concentration is a fourfold higher production mass than the current plant-based origin and is competitive with yields from pure microbial cultures. The biofilm was characterized based on total carbohydrate production at varying nutrient levels, individual carbohydrate monomer production from varying organic acid substrates, and microbial community composition—based on 16s rRNA. Biofilm carbohydrate production was maximized at a C:N ratio of 28 (mol:mol). The production of rhamnose varied significantly based on carbon substrate; glucose had the greatest yield of rhamnose, followed by propionic acid, lactic acid, acetic acid, valeric acid, and butyric acid. Microbial community analysis indicated an abundance of organisms within the Xanthobacter genus, which is known to produce rhamnose as zeaxanthin rhamnoside. Rhamnose production was heavily correlated with ribose production (R2 = 0.96). Results suggest that mixed microbial biofilms could be a competitive source of monomeric rhamnose that may be produced from mixed organic waste streams of variable composition via volatile fatty acids and glucose.

Co-occurrence of functional modules derived from nicotine-degrading gene clusters confers additive effects in Pseudomonas sp. JY-Q Abstract Pseudomonas sp. JY-Q was isolated from nicotine-rich environment and could degrade and tolerate high-content nicotine. Its specific genetic architecture comprised duplicated homologous nicotine-degrading clusters for different functional modules on the whole pathway. Its adaptive and genomic properties caused our concern whether the duplicated homologous gene clusters confer additive effects on nicotine degradation and result in strain JY-Q strong capability. After deletion of representative genes from duplicated homologous gene clusters of upstream module Nic1, midstream module Spm, and downstream module Nic2, the nicotine degradation efficiency of the wild type and mutant strains were examined. As the first genes of clusters Nic1-1 and Nic1-2, nicA2 and nox are both involved in nicotine degradation, but nox exhibited more contribution to nicotine metabolism due to the higher transcriptional amount of nox than that of nicA2. Likewise, the sub-clusters spm1 and spm2 showed additive effect on nicotine metabolism. As two hpo-like genes of clusters Nic2-1 and Nic2-2, hpo1, and hpo2 also showed additive effect on the nicotine degrading, but hpo1 provided more contribution than hpo2. The third hpo-like gene in cluster NA (nicotinic acid degrading), nicX is not necessary for 2,5-dihydroxypyridine transformation when hpo1 and hpo2 exist. A variety of transposases and integrases observed around Nic1 and Nic2 cluster genes suggests that the duplicated genes could evolve from horizontal gene transfer (HGT)-related dissemination. This study provide an insight into a novel adaptability mechanism of strains in extreme environment such as high nicotine concentration, and potential novel targets to enhance strain synthesis/degradation ability for future applications.

Engineered biosynthesis of cyclic lipopeptide locillomycins in surrogate host Bacillus velezensis FZB42 and derivative strains enhance antibacterial activity Abstract Locillomycins are cyclic lipononapeptides assembled by a nonlinear hexamodular NRPS and have strong antibacterial activity. In this study, we genetically engineered Bacillus velezensis FZB42 as a surrogate host for the heterologous expression of the loc gene cluster for locillomycins. The fosmid N13 containing whole loc gene cluster was screened from the B. velezensis 916 genomic library. Subsequently, a spectinomycin resistance cassette, and the cassette fused with an IPTG inducible promoter Pspac, was introduced in the fosmid N13 using λ Red recombination system, respectively. The resulting fosmids, designated N13+Spec and N13+PSSpec, were used for the transformation of B. velezensis FZB42 to obtain derivative strains FZBNPLOC and FZBPSLOC. RT-PCR and qRT-PCR results revealed the efficient heterologous expression of the loc gene cluster in both derivative strains. Particularly, there was positive correlation between the derivative FZBPSLOC strain and the enhanced production of locillomycins upon addition of the inducer IPTG with the highest production of locillomycins at 15-fold more than that of B. velezensis 916. This overproduction of locillomycins was also related to the enhancement of antibacterial activity against methicillin-resistant Staphylococcus aureus, and exhibited moderate changes in its hemolytic activity. Together our findings demonstrate that the nonlinear hexamodular NRPS, encoded by the loc gene cluster from B. velezensis 916, is sufficient for the biosynthesis of cyclic lipononapeptide locillomycins in the surrogate host B. velezensis FZB42. Moreover, the FZBPSLOC strain will also be useful for further development of novel locillomycins derivatives with improved antibacterial activity.

A novel multiplex xMAP assay for generic detection of avian, fish, and ruminant DNA in feed and feedstuffs Abstract The identification of animal species in feed and feedstuffs is important for detecting contamination and fraudulent replacement of animal components that might cause health and economic problems. A novel multiplex assay, based on xMAP technology and the generic detection of closely related species, was developed for the simultaneous differential detection of avian, fish, and ruminant DNA in products. Universal primers and probes specific to avian, fish, or ruminant species were designed to target a conserved mitochondrial DNA sequence in the 12S ribosomal RNA gene (rRNA). The assay specificity was validated using samples of 27 target and 10 nontarget animal species. The limits of detection of the purified DNA were determined to be 0.2 pg/μL–0.1 ng/μL by testing the meat samples of six species and four feedstuffs. The detection sensitivity of the experimental mixtures was demonstrated to be 0.01% (weight percentage). The assay's suitability for practical application was evaluated by testing feed samples; unlabeled animal ingredients were detected in 32% of the 56 samples. The assay differentially detected the three targeted categories of animal species in less than 2 h, reflecting improvements in speed and efficiency. Based on these results, this novel multiplex xMAP assay provides a reliable and highly efficient technology for the routine detection of animal species in feed and other products for which this information is needed.

Capability of iturin from Bacillus subtilis to inhibit Candida albicans in vitro and in vivo Abstract Candida albicans is a fungal pathogen that is difficult to cure clinically. The current clinic C. albicans-inhibiting drugs are very harmful to humans. This study revealed the potential of iturin fractions from Bacillus subtilis to inhibit C. albicans in free status (MIC = 32 μg/mL) and natural biofilm in vitro. The inhibition mechanism was identified as an apoptosis pathway via the decrease of mitochondrial membrane potential, the increase of the reactive oxygen species (ROS) accumulation, and the induction of nuclear condensation. For in vivo experiments, the C. albicans infection model was constructed via intraperitoneal injection of 1 × 108C. albicans cells into mice. One day after the infection, iturin was used to treat infected mice at different concentrations alone and in combination with amphotericin B (AmB) by intraperitoneal injection. The treatment with AmB alone could cause the death of infected mice, whereas treatment with 15 mg/kg iturin per day alone led to the survival of all infected mice throughout the study. After continuously treated for 6 days, all mice were sacrificed and analyzed. As results, the combination of 15 mg/kg iturin and AmB at a ratio of 2:1 had the most efficient effect to remove the fungal burden in the kidney and cure the infected mice by reversing the symptoms caused by C. albicansinfection, such as the loss of body weight, change of immunology cells in blood and cytokines in serum, and damage of organ structure and functions. Overall, iturin had potential in the development of efficient and safe drugs to cure C. albicans infection.

L-Erythrulose production with a multideletion strain of Gluconobacter oxydans Abstract Many ketoses or organic acids can be produced by membrane-associated oxidation with Gluconobacter oxydans. In this study, the oxidation of meso-erythritol to L-erythrulose was investigated with the strain G. oxydans621HΔupp BP.8, a multideletion strain lacking the genes for eight membrane-bound dehydrogenases. First batch biotransformations with growing cells showed re-consumption of L-erythrulose by G. oxydans 621HΔuppBP.8 in contrast to resting cells. The batch biotransformation with 2.8 g L−1 resting cells of G. oxydans 621HΔupp BP.8 in a DO-controlled stirred-tank bioreactor resulted in 242 g L−1 L-erythrulose with a product yield of 99% (w/w) and a space-time yield of 10 g L−1 h−1. Reaction engineering studies showed substrate excess inhibition as well as product inhibition of G. oxydans 621HΔupp BP.8 in batch biotransformations. In order to overcome substrate inhibition, a continuous membrane bioreactor with full cell retention was applied for meso-erythritol oxidation with resting cells of G. oxydans 621HΔupp BP.8. At a mean hydraulic residence time of 2 h, a space-time yield of 27 g L−1 h−1 L-erythrulose was achieved without changing the product yield of 99% (w/w) resulting in a cell-specific product yield of up to 4.4 gP gX−1 in the steady state. The product concentration (54 g L−1 L-erythrulose) was reduced in the continuous biotransformation process compared with the batch process to avoid product inhibition.

Novel metagenome-derived ornithine lipids identified by functional screening for biosurfactants Abstract Biosurfactants are amphiphilic molecules that interact with the surfaces of liquids leading to many useful applications. Most biosurfactants have been identified from cultured microbial sources, leaving a largely untapped resource of uncultured bacteria with potentially novel biosurfactant structures. To access the uncultured bacteria, a metagenomic library was constructed in Escherichia coli from environmental DNA within an E. coli, Pseudomonas putida and Streptomyces lividans shuttle vector. Phenotypic screening of the library in E. coli and P. putida by the paraffin spray assay identified a P. putida clone with biosurfactant activity. Sequence analysis and transposon mutagenesis confirmed that an ornithine acyl-ACP N-acyltransferase was responsible for the activity. Although the fosmid was not active in E. coli, overexpression of the olsB gene could be achieved under the control of the inducible T7 promoter, resulting in lyso-ornithine lipid production and biosurfactant activity in the culture supernatants. Screening for activity in more than one host increases the range of sequences that can be identified through metagenomic, since olsB would not have been identified if only E. coli had been used as a host. The potential of lyso-ornithine lipids as a biosurfactant has not been fully explored. Here, we present several biosurfactant parameters of lyso-ornithine lipid to assess its suitability for industrial application.

Molecular Neurobiology

Blockade of Rapid Influx of Extracellular Zn 2+ into Nigral Dopaminergic Neurons Overcomes Paraquat-Induced Parkinson's Disease in Rats Abstract The herbicide paraquat (PQ) has been reported to enhance the risk of developing Parkinson's disease (PD) from epidemiological studies. PQ-induced reactive oxygen species (ROS) are linked with a selective loss of nigrostriatal dopaminergic neurons. Here, we first report a unique mechanism of nigrostriatal dopaminergic degeneration, in which rapid intracellular Zn2+ dysregulation via PQ-induced ROS production causes PD in rats. When the substantia nigra pars compacta (SNpc) of rats was perfused with PQ, extracellular concentrations of glutamate and Zn2+ were increased and decreased, respectively, in the SNpc. These changes were ameliorated by co-perfusion with Trolox, an antioxidative agent. In in vitro slice experiments, PQ rapidly increased extracellular Zn2+ influx via AMPA receptor activation. Both loss of nigrostriatal dopaminergic neurons and increase in turning behavior in response to apomorphine were markedly reduced by coinjection of PQ and intracellular Zn2+ chelator, i.e., ZnAF-2DA into the SNpc. Furthermore, loss of nigrostriatal dopaminergic neurons induced with a low dose of PQ, which did not induce any behavioral abnormality, was completely blocked by coinjection of ZnAF-2DA. The present study indicates that rapid influx of extracellular Zn2+ into dopaminergic neurons via AMPA receptor activation, which is initially induced by PQ-mediated ROS production in the SNpc, induces nigrostriatal dopaminergic degeneration, resulting in PQ-induced PD in rats. Intracellular Zn2+dysregulation in dopaminergic neurons is the cause of PQ-induced pathogenesis in the SNpc, and the block of intracellular Zn2+ toxicity leads to defending PQ-induced pathogenesis.

Absence of Mutation Enrichment for Genes Phylogenetically Conserved in the Olivocerebellar Motor Circuitry in a Cohort of Canadian Essential Tremor Cases Abstract Essential Tremor is a prevalent neurological disorder of unknown etiology. Studies suggest that genetic factors contribute to this pathology. To date, no causative mutations in a gene have been reproducibly reported. All three structures of the olivocerebellar motor circuitry have been linked to Essential Tremor. We postulated that genes enriched for their expression in the olivocerebellar circuitry would be more susceptible to harbor mutations in Essential Tremor patients. A list of 11 candidate genes, enriched for their expression in the olivocerebellar circuitry, was assessed for their variation spectrum and frequency in a cohort of Canadian Essential Tremor cases. Our results from this list of 11 candidate genes do not support an association for Essential Tremor in our cohort of Canadian cases. The heterogenic nature of ET and modest size of the cohort used in this study are two confounding factors that could explain these results.

Sprouty2—a Novel Therapeutic Target in the Nervous System? Abstract Clinical trials applying growth factors to alleviate symptoms of patients with neurological disorders have largely been unsuccessful in the past. As an alternative approach, growth factor receptors or components of their signal transduction machinery may be targeted directly. In recent years, the search for intracellular signaling integrator downstream of receptor tyrosine kinases provided valuable novel substrates. Among them are the Sprouty proteins which mainly act as inhibitors of growth factor-dependent neuronal and glial signaling pathways. In this review, we summarize the role of Sprouties in the lesioned central and peripheral nervous system with particular reference to Sprouty2 that is upregulated in various experimental models of neuronal degeneration and regeneration. Increased synthesis under pathological conditions makes Sprouty2 an attractive pharmacological target to enhance intracellular signaling activities, notably the ERK pathway, in affected neurons or activated astrocytes. Interestingly, high Sprouty2 levels are also found in malignant glioma cells. We recently demonstrated that abrogating Sprouty2 function strongly inhibits intracranial tumor growth and leads to significantly prolonged survival of glioblastoma bearing mice by induction of ERK-dependent DNA replication stress. On the contrary, knockdown of Sprouty proteins increases proliferation of activated astrocytes and, consequently, reduces secondary brain damage in neuronal lesion models such as kainic acid-induced epilepsy or endothelin-induced ischemia. Furthermore, downregulation of Sprouty2 improves nerve regeneration in the lesioned peripheral nervous system. Taken together, targeting Sprouties as intracellular inhibitors of the ERK pathway holds great promise for the treatment of various neurological disorders including gliomas. Since the protein lacks enzymatic activities, it will be difficult to develop chemical compounds capable to directly and specifically modulate Sprouty functions. However, interfering with Sprouty expression by gene therapy or siRNA treatment provides a realistic approach to evaluate the therapeutic potential of indirectly stimulating ERK activities in neurological disease.

The Expression and Cellular Localisation of Neurotrophin and Neural Guidance Molecules in Peritoneal Ectopic Lesions Abstract Endometriosis is a gynaecological disorder characterised by the presence of endometrial-like tissue outside the uterus. It affects 10–15% of women during their reproductive age. The existence of close and complex relationship between chronic pelvic pain and endometriosis are widely recognised. However, the mechanisms of pain generation in women with endometriosis remain poorly understood. Immunohistochemistry was used to assess the density of nerve fibres stained with protein gene product 9.5 (PGP9.5) and the expression of various neurotrophins including glial cell derived neurotrophic factor (GDNF), persephin, neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) and neuronal guidance molecules semaphorin 3E and Slit-2 and their receptors Plexin-D1 and Robo4 in peritoneal ectopic lesions from women with endometriosis and uninvolved peritoneum samples. Neurotrophins and neuronal guidance molecules and their receptors are synthesised in situ within peritoneal ectopic lesion which suggest their role in facilitating and maintaining the growth of nerve fibres. These molecules were found to be overall most highly expressed in the glands of endometriotic peritoneal lesions. In addition, the presence of ectopic lesions within the peritoneal cavity may affect the environment; in turn, the peritoneum altered appeared to play a role in the growth of nerve fibres and their development and maintenance in peritoneal lesions. Through exploring different neuronally active factors in and around ectopic lesions which may be contributing to pain generation, this study provides an insight and better understanding of the pain mechanisms associated with peritoneal endometriosis.

SNAP25 Gene Polymorphisms Protect Against Parkinson's Disease and Modulate Disease Severity in Patients Abstract Parkinson's disease (PD) is a α-synucleinopathy in which intracellular aggregates of α-synuclein (α-syn) result in neurodegeneration and in the impairment of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex-mediated release of neurotransmitters. SNAP25 is a SNARE complex component: its concentration is increased in the cerebrospinal fluid of PD patients and this is related to the severity of cognitive and motor symptoms. Five SNAP25 single-nucleotide polymorphisms (SNPs) that modulate gene expression and were described to play a role in neurologic conditions (rs363050, rs363039, rs363043, rs3746544, and rs1051312) were analyzed in a cohort of 412 sporadic Italian PD patients and 1103 healthy controls (HC) in order to identify possible correlation with the disease. The SNAP25 rs1051312 C allele and CC genotype confer protection against PD onset, in particular in males (p = 0.003, OR(95%CI) = 0.67(0.51–0.88)) (pc = 0.008, OR(95%CI) = 0.28(0.10–0.70)). Co-segregation analyses revealed that the rs1051312 effect was reinforced when present within the rs363043 C-rs3746544 T-rs1051312 C haplotype (p = 3.3 × 10−4, OR = 0.47, 95%CI = 0.31–0.72), once again in males. Finally, rs363039 influenced age at onset (p = 0.02) and MMSE (Mini-Mental State Examination) scores (p = 0.01). The SNAP25 SNPs analyzed herein modulate gene expression at different levels as they are involved in binding miRNA and transcription factors; this suggests a possible synergistic effect of SNAP25 SNPs in the pathogenesis of PD. A replication in a larger and independent sample will help to further explore this hypothesis.

Contribution of Serum Lipid Profiles to Outcome After Endovascular Thrombectomy for Anterior Circulation Ischemic Stroke Abstract The contribution of lipids, including low- and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively) and triglycerides (TG), to stroke outcomes is still debated. We sought to determine the impact of LDL-C concentrations on the outcome of patients with ischemic stroke in the anterior circulation who received treatment with endovascular thrombectomy (EVT). We performed a retrospective analysis of consecutive patients with acute ischemic stroke treated at a tertiary center between 2012 and 2016. Patients treated with EVT for large artery occlusion in the anterior circulation were selected. The primary endpoint was functional outcome at 3 months as measured with the modified Rankin Scale (mRS). Secondary outcome measures included hospital death and final infarct volume (FIV). Blood lipid levels were determined in a fasting state, 1 day after admission. We studied a total of 174 patients (44.8% men) with a median age of 74 years (interquartile range [IQR] 61–82) and median National Institutes of Health Stroke Scale at admission of 18 (14–22). Bridging therapy with intravenous tissue-plasminogen activator (t-PA) was administered in 122 (70.5%). The median LDL-C was 90 mg/dl (72–115). LDL-C demonstrated a U-type relationship with FIV (p = 0.036). Eighty-three (50.0%) patients had an mRS of 0–2 at 3 months. This favorable outcome was independently associated with younger age (OR 0.944, 95% CI 0.90–0.99, p = 0.012), thrombolysis in cerebral infarction 2b-3 reperfusion (OR 5.12, 95% CI 1.01–25.80, p = 0.015), smaller FIV (0.97 per cm3, 95% CI 0.97–0.99, p < 0.001), good leptomeningeal collaterals (OR 5.29, 95% CI 1.48–18.9, p = 0.011), and LDL-C more than 77 mg/dl (OR 0.179, 95% CI 0.04–0.74, p = 0.018). A higher LDL-C concentration early in the course of a stroke caused by large artery occlusion in the anterior circulation is independently associated with a favorable clinical outcome at 3 months. Further studies into the pathophysiological mechanisms underlying this observation are warranted.

Diltiazem Promotes Regenerative Axon Growth Abstract Axotomy results in permanent loss of function after brain and spinal cord injuries due to the minimal regenerative propensity of the adult central nervous system (CNS). To identify pharmacological enhancers of axon regeneration, 960 compounds were screened for cortical neuron axonal regrowth using an in vitro cortical scrape assay. Diltiazem, verapamil, and bromopride were discovered to facilitate axon regeneration in rat cortical cultures, in the presence of chondroitin sulfate proteoglycans (CSPGs). Diltiazem, an L-type calcium channel blocker (L-CCB), also promotes axon outgrowth in adult primary mouse dorsal root ganglion (DRG) and induced human sensory (iSensory) neurons.

Modeling Alzheimer's Disease by Induced Pluripotent Stem Cells Carrying APP D678H Mutation Abstract Alzheimer's disease (AD), probably caused by abnormal accumulation of β-amyloid (Aβ) and aberrant phosphorylation of tau, is the most common cause of dementia among older people. Generation of patient-specific neurons by induced pluripotent stem cell (iPSC) technology facilitates exploration of the disease features in live human neurons from AD patients. In this study, we generated iPSCs from two familial AD patients carrying a heterozygous D678H mutation in the APP gene (AD-iPSCs). The neurons derived from our AD-iPSCs demonstrated aberrant accumulation of intracellular and secreted Aβ42 and Aβ40, reduction of serine 9 phosphorylation in glycogen synthase kinase 3β (GSK3β) hyperphosphorylation of threonine 181 and serine 396 in tau protein, impaired neurite outgrowth, downregulation of synaptophysin, and increased caspase 1 activity. The comparison between neurons derived from a sibling pair of wild-type and mutated iPSCs successfully recapitulated these AD phenotypes. Treatment with indole compound NC009-1 (3-((1H-Indole-3-yl)methyl)-4-(2-nitrophenyl)but-3-en-2-one), a potential Aβ aggregation reducer, normalized the Aβ levels and GSK3β and tau phosphorylation, attenuated caspase 1 activity, and improved neurite outgrowth in AD-iPSC-derived neurons. Thus, APP D678H iPSCs-derived neurons recapitulate the cellular characteristics relevant to AD and enable exploration of the underlying pathogenesis and therapeutic strategies for AD.

Genetic Knockdown of mGluR5 in Striatal D1R-Containing Neurons Attenuates l -DOPA-Induced Dyskinesia in Aphakia Mice Abstract l-DOPA is the main pharmacological therapy for Parkinson's disease. However, long-term exposure to l-DOPA induces involuntary movements termed dyskinesia. Clinical trials show that dyskinesia is attenuated by metabotropic glutamate receptor type 5 (mGluR5) antagonists. Further, the onset of dyskinesia is delayed by nicotine and mGluR5 expression is lower in smokers than in non-smokers. However, the mechanisms by which mGluR5 modulates dyskinesia and how mGluR5 and nicotine interact have not been established. To address these issues, we studied the role of mGluR5 in D1R-containing neurons in dyskinesia and examined whether nicotine reduces dyskinesia via mGluR5. In the aphakia mouse model of Parkinson's disease, we selectively knocked down mGluR5 in D1R-containing neurons (aphakia-mGluR5KD-D1). We found that genetic downregulation of mGluR5 decreased dyskinesia in aphakia mice. Although chronic nicotine increased the therapeutic effect of l-DOPA in both aphakia and aphakia-mGluR5KD-D1 mice, it caused a robust reduction in dyskinesia only in aphakia, and not in aphakia-mGluR5KD-D1 mice. Downregulating mGluR5 or nicotine treatment after l-DOPA decreased ERK and histone 3 activation, and FosB expression. Combining nicotine and mGluR5 knockdown did not have an added antidyskinetic effect, indicating that the effect of nicotine might be mediated by downregulation of mGluR5 expression. Treatment of aphakia-mGluR5KD-D1 mice with a negative allosteric modulator did not further modify dyskinesia, suggesting that mGluR5 in non-D1R-containing neurons does not play a role in its development. In conclusion, this work suggests that mGluR5 antagonists reduce dyskinesia by mainly affecting D1R-containing neurons and that the effect of nicotine on dyskinetic signs in aphakia mice is likely via mGluR5.

Early Manifestations of Brain Aging in Mice Due to Low Dietary Folate and Mild MTHFR Deficiency Abstract Folate is an important B vitamin required for methylation reactions, nucleotide and neurotransmitter synthesis, and maintenance of homocysteine at nontoxic levels. Its metabolism is tightly linked to that of choline, a precursor to acetylcholine and membrane phospholipids. Low folate intake and genetic variants in folate metabolism, such as the methylenetetrahydrofolate reductase (MTHFR) 677 C>T polymorphism, have been suggested to impact brain function and increase the risk for cognitive decline and late-onset Alzheimer's disease. Our study aimed to assess the impact of genetic and nutritional disturbances in folate metabolism, and their potential interaction, on features of cognitive decline and brain biochemistry in a mouse model. Wild-type and Mthfr+/− mice, a model for the MTHFR 677 C>T polymorphism, were fed control or folate-deficient diets from weaning until 8 and 10 months of age. We observed short-term memory impairment measured by the novel object paradigm, altered transcriptional levels of synaptic markers and epigenetic enzymes, as well as impaired choline metabolism due to the Mthfr+/− genotype in cortex or hippocampus. We also detected changes in mRNA levels of Presenillin-1, neurotrophic factors, one-carbon metabolic and epigenetic enzymes, as well as reduced levels of S-adenosylmethionine and acetylcholine, due to the folate-deficient diet. These findings shed further insights into the mechanisms by which genetic and dietary folate metabolic disturbances increase the risk for cognitive decline and suggest that these mechanisms are distinct.

Sexuality

The Condom Abstract Since time immemorial the condom has been a tool for barrier contraception worldwide. Its role in prevention of sexually transmitted infections is remarkably significant for mankind. Its use in non-contraceptive fields is worth knowing as well. The transition of this amazing tool over the ages in form of material, texture, properties, colour etc. is not only unique but also a feat of human expertise and excellence. The commercial worth of this industry illustrates its importance in society.

Intimate Partner Violence Against Disabled Persons: Clinical and Health Impact, Intersections, Issues and Intervention Strategies Abstract One of the crimes currently affecting our society is intimate partner violence (IPV), which is regarded as a major global health issue especially affecting women. These health problems concern every citizen, but even more so for women with disabilities who are more exposed to dependence, prejudice and marginalisation. Although a greater focus has been placed on IPV against women with disabilities during the last decade, data about the incidence of violence still need to be confirmed and the way by which abuse situations are perpetuated has not been clarified, especially regarding what the practical aid for women living in this situation might be. This work highlights the clinical impact of the IPV phenomenon on women with disabilities, describes the difficulties experienced while dealing with this phenomenon and suggests the most appropriate intervention strategies. Our work found that people with disabilities are at a higher risk of facing IPV when compared to individuals without disabilities. The results unquestionably show that such acts of violence are often not even reported, partly because of sentimental, emotional and economic reasons. Finally, we point out policies and initiatives aimed at helping people with disabilities tackle the phenomenon.

Challenging Accepted Scripts of Sexual "Normality": Asexual Narratives of Non-normative Identity and Experience Abstract Sexual desire is often assumed to be natural and universally experienced by all adult human beings. The lived experiences of asexual individuals, however, are beginning to challenge this assumption. The purpose of this research is to gain a better understanding of asexual experience and identity. This study employed life story interviews with ten self-identified asexual individuals. Results show that asexuality is far more complicated than just a lack of sexual attraction. Respondents in this study arrived at an asexual identity after a discovery process, one that involved research on various sexualities. Participants report discovering an identity that "fit" through research on digital mediums, with Reddit being particularly influential. Several respondents reported trouble with their gender identity, particularly the set of sexual expectations that were hitched to their respective gender expressions. Many respondents noted that they were often assumed to be homosexual. Several participants described their "coming out" process as very similarly aligned with homosexual disclosure. Most respondents first had sexual encounters before realizing their asexual orientation. All respondents experienced relationships, community, connection and romance on their own terms, in unique and creative ways. This group of participants were by no means isolated. Indeed, all interviewees reported involvement in strong communities and many respondents experienced support from others. That said, several respondents did endure resistance, denial and pathologizing reactions from other people, including family members. The insights from this study challenge the normative ways we imagine sexuality, romance and attraction.

Littles: Affects and Aesthetics in Sexual Age-Play Abstract This article explores the experiences and practices of self-identifying female sexual age-players. Based on interviews and observation of the age players' blogged content, the article suggests that, rather than being fixed in one single position, our study participants move between a range of roles varying across their different scenes. In examining accounts of sexual play, we argue that the notion of play characterizes not only their specific routines of sexual "scening" but also sexual routines, experimentations, and experiences more expansively. Further, we argue that a focus on play as exploration of corporeal possibilities allows for conceptualizing sexual preferences and practices, such as age-play, as irreducible to distinct categories of sexual identity. The notion of play makes it possible to consider sexuality in terms of transformations in affective intensities and attachments, without pigeonholing various preferences, or acts, within a taxonomy of sexual identities. In doing so, it offers an alternative to the still prevalent categorical conceptualizations of sexuality that stigmatize people's lived experiences and diminish the explanatory power of scholarly and therapeutic narratives about human sexuality.

Relationships and Infidelity in Pornography: An Analysis of Pornography Streaming Websites Abstract Research suggests that pornography has the potential to inform sexual and romantic scripts, but no studies have examined the relational content within modern mainstream pornography. In this article, we present a content analysis of 190 sexually explicit online video clips from mainstream pornography streaming websites, coding for the relationship between participants (if any) and whether the video portrayed acts of infidelity. We also contrasted those clips with a comparison sample of 77 YouTube videos. We found that depictions of on-screen committed relationships were relatively rare in pornography (7.9% of videos) compared to YouTube (18.2%), but that infidelity was relatively common (25.3% vs. 2.6%), with pornography more likely to depict women as engaging in infidelity than men. Relational content was more likely to be included in a pornographic clip when the video portrayed a fictional narrative. These findings are consistent with past research connecting pornography consumption with open and liberal sexuality.

"There are Certain Rules that One Must Abide by": Predictors of Mortality in Slasher Films Abstract Slasher films, a popular and lucrative sub-genre of horror movie, are often thought to be characterized by violence, gratuitous sexual content and specific, repetitive tropes; however, although these tropes have been widely discussed and even parodied, there is scant research examining their validity. Thirty top-grossing slasher films (10 each for the 1980s, 1990s and 2000s) were subjected to content analysis at the level of the individual character to examine the factors associated with character deaths or survival. Characters who were shown nude on screen, who dressed in a revealing fashion, who did not engage in fight behaviors against the antagonist and who engaged in fewer types of pro-social behaviors were more likely to be killed. Several common tropes of slasher films (e.g., virgins survive, ethnic minority characters die) were not supported. The implications of these messages of which characters are depicted as "deserving" of survival are discussed in terms of gender, sexual scripts, and agency.

Ideological and Philosophical Underpinnings of Attitudes Toward Sexual Minorities in Vietnamese Society Abstract This paper examines the ideological and philosophical underpinnings of attitudes toward sexual minorities in Vietnamese society. The analysis focuses on the so-called 'Three Teachings' (Tam giáo) consisting of Confucianism, Taoism and Buddhism which are widely regarded as the most influential philosophies that shape Vietnamese culture and society. It is argued that these ideologies and philosophies engender systems of thought that resonate with how Vietnamese people think about and act toward sexual minorities. The article concludes with implications for research and practice in advancing the rights of sexual minorities in contexts bearing such influences.

Attitudes Toward Same-Sex Marriage in a Greek Sample Abstract This study examined the role of specific social variables in the prediction of negative attitudes toward same sex marriage in a Greek sample. Based on previous research, it appeared that gender, age, political ideology (conservatism), religiosity and personal contact, are useful variables to examine in predicting attitudes towards same sex marriage. The sample (N = 391) consisted of students and non-students at various departments of major Universities in Athens. The Greek version of the same sex marriage scale was used along with a brief demographics questionnaire. Correlation analysis showed that more tolerant attitudes toward same sex marriage were associated with religiosity, political self designation, gender, age and contact with LGBT individuals, indicating that those who have less tolerant attitudes toward same sex marriage tend to be men, individuals with higher levels of religiosity, older, not having a previous contact with LGBT individuals and politically conservative. Regression analysis revealed religiosity, political self designation, gender, age and personal contact with LGBT individuals to be independent predictors of attitudes toward same sex marriage.

To Tell or not to Tell? Parents' Reluctance to Talking About Conceiving Their Children Using Medically Assisted Reproduction Abstract While more and more researchers are investigating the effects of disclosing conceptions achieved through heterologous fertilization, even couples who use homologous medically-assisted reproduction (MAR) often do not tell their relatives and children how they conceived, possibly because they find it embarrassing. The present study explores the perception of stigma, and the reticence of Italian couples resorting to homologous MAR when speaking about conception. Interviews were conducted with 30 participants recruited through a fertility clinic at a public hospital in northern Italy, and through social media and snowball sampling. Content analysis was used to identify respondents' various attitudes to talking about their MAR experience. Their reluctance to tell their relatives and children about their conceiving experience may reflect, but also perpetuate the social stigma associated with in vitro fertilization. Further research and scientific dissemination campaigns are needed to emphasize the importance of normalizing and sharing these experiences within the family—addressing not only heterologous, but also homologous MAR—especially in the more traditional cultural and legal settings, such as Italy.

Risk Factors Related to Cognitive Distortions Toward Women and Moral Disengagement: A Study on Sex Offenders Abstract Violence against women is a heterogeneous phenomenon worldwide. In order to better understand this phenomenon, it is also necessary to study the offenders against women. Therefore, the present study investigates, in the light of risk factors, the individual and social characteristics (related to adolescence), the moral disengagement strategies and cognitive distortions of 120 sex offenders detained in Italian jails. We administered the semi-structured interview for data collection regarding family, social and medical histories and the manner in which the deviant act was carried out, the Moral Disengagement Scale, and the Vindictive Rape Attitude Questionnaire to investigate the presence of cognitive distortions toward women. Results show important risk factors in the genesis of moral disengagement strategies in the offenders: the use of substances and being institutionalized in their past. In addition, through a multiple regression model, we noticed how education levels represent a negative predictor of cognitive distortions towards women and the attribution of blame to a positive predictor. Theoretical and practical implications are discussed.