The consequences of vaccination with the Johne's disease vaccine, Gudair, on diagnosis of bovine tuberculosis.

The single intradermal comparative cervical tuberculin skin-test (SICCT) remains the primary surveillance tool to diagnose bovine tuberculosis (BTB) in the UK. Therefore, understanding the potential confounding influences on this test is important. This study investigated the effects of vaccination against Johne's disease (JD) on the immunodiagnosis of BTB using a Mycobacterium bovis BCG vaccination model as a surrogate of M bovis infection. Calves were vaccinated with either BCG (an attenuated live vaccine) or the JD vaccine, Gudair (a heat-inactivated suspension of Mycobacterium avium subspecies paratuberculosis), or a combination of both, and SICCT responses were measured approximately six and 12 weeks postvaccination. Animals vaccinated with Gudair only were negative to the SICCT test, thus supporting the specificity of the SICCT test following Gudair vaccination. However, while animals vaccinated with BCG-only demonstrated a bovine tuberculin-biased response as expected, covaccination with Gudair resulted in a bias towards avian tuberculin in the SICCT test. Therefore, our model demonstrates the potential of the Gudair vaccine to reduce the sensitivity of the SICCT. In addition, while we also demonstrate that Gudair vaccination can compromise the specificity of serological tests to detect JD, the specificity of defined M bovis antigens in serological or interferon gamma-based blood assays was not compromised by the vaccine.

Lack of correlation between BCG-induced tuberculin skin test sensitisation and protective immunity in cattle.

Vaccination of cattle with Mycobacterium bovis Bacille Calmette-Guérin (BCG) can provide significant protection against bovine tuberculosis (TB). However, BCG vaccination sensitises animals to respond to the tuberculin skin-test. This provides a potential operational impediment to the use of BCG as a cattle vaccine since the tuberculin skin-test is the primary surveillance tool used by many countries with 'test and slaughter' control strategies. Currently, it is also unclear what BCG-induced skin-test conversion means in respects to BCG's protective immunity. In the current study we first investigated the duration of tuberculin skin-test sensitisation in calves neonatally vaccinated with BCG. BCG vaccination induced strong skin-test responses in calves during their first 6 months. However, a rapid decay in skin-test sensitivity was observed after this time. Between 6 and 9 months this represented a reduction from 80% to 8% of calves providing a positive response in the single intradermal comparative cervical tuberculin test at standard interpretation. We next investigated the relationship between BCG induced skin-test sensitivity and retention of protective immunity. Calves were neonatally vaccinated with BCG and subsequently divided into 2 groups based on retention or loss of tuberculin skin-test responses after 6 months. In contrast to their skin-test responsiveness, these vaccinates maintained their tuberculin specific IFN-γ blood responses. Moreover, irrespective of their pre-challenge skin-test responses, following M. bovis challenge both groups of BCG vaccinated calves demonstrated comparable levels of protection, as evidenced by reduced TB-associated pathology. Therefore, we have demonstrated that following neonatal BCG vaccination of cattle, tuberculin skin-test responder frequencies waned rapidly after 6 months but importantly, loss of skin-test sensitivity did not correlate with loss of protective immunity. These findings could have implications for the practical application of BCG based cattle vaccines.

Development of a simple, sensitive, rapid test which discriminates BCG-vaccinated from Mycobacterium bovis-infected cattle.

Bovine tuberculosis (bTB) is increasing in incidence in the UK. Effective control strategies could involve vaccination; BCG, either alone or in prime-boost strategies, remains the most effective vaccine against bovine tuberculosis. However, BCG vaccination of cattle would require development of diagnostic tests able to accurately discriminate Mycobacterium bovis-infected from BCG-vaccinated animals. Herein, we demonstrate that the detection of secreted IFN-gamma following short term culture (4h) of whole blood with purified protein derived from M. bovis (PPD-B) allows such discrimination. This reflects, in part, the differential kinetics of IFN-gamma secretion in infected compared to vaccinated cattle. This is the first study to demonstrate that accurate, rapid distinction of BCG-vaccinated from M. bovis-infected cattle can be achieved in a short time period without the need for production of M. bovis-specific antigens, complex antigen mixtures or extensive laboratory procedures. We were also able to detect PPD-specific IFN-gamma release during short term culture of blood from a number of humans with active TB indicating that this test may have wider application and is potentially useful for the rapid diagnosis of disease in humans.

Isoniazid treatment of Mycobacterium bovis in cattle as a model for human tuberculosis.

Cattle infected with Mycobacterium bovis spoligotype 9 were treated with Isoniazid (INH) from three to 14 weeks post infection, rested for fourweeks to allow INH depletion and then challenged with M. bovis spoligotype 35. Post mortem examination (PME) 35 weeks after the initial infection showed partial protection against infectious challenge following INH-attenuated infection compared with the spoligotype 35 challenge controls. Antigen-specific IFN-gamma responses decreased over time with INH therapy, following a similar pattern to that observed in the treatment of M. tuberculosis infection in humans. Following cessation of therapy, specific IFN-gamma responses increased more strongly in those calves that were visibly lesioned at PME. IFN-gamma responses were also used to identify two antigens, TB10.4 and Acr2, that induced anamnestic responses in INH-treated, re-challenged calves, suggesting a role for both antigens in protective immunity. Specific IL-10 responses were observed in all calves following treatment with INH suggesting a role for IL-10 in the resolution of infection.

PET imaging of the normal human auditory system: responses to speech in quiet and in background noise.

The neural mechanisms involved in listening to sentences, and then detecting and verbalizing a specific word are poorly understood, but most likely involve complex neural networks. We used positron emission tomography to identify the areas of the human brain that are activated when young, normal hearing males and females were asked to listen to a sentence and repeat the last word from the Speech in Noise (SPIN) test. Listening conditions were (1) Quiet, (2) Speech, (3) Noise, and (4) SPIN with stimuli presented monaurally to either the left ear or the right ear. The least difficult listening task, Speech, resulted in bilateral activation of superior and middle temporal gyrus and pre-central gyrus. The Noise and SPIN conditions activated many of the same regions as Speech alone plus additional sites within the cerebellum, thalamus and superior/middle frontal gyri. Comparison of the SPIN condition versus Speech revealed additional activation in the right anterior lobe of the cerebellum and right medial frontal gyrus, near the cingulate. None of the left ear-right ear stimulus comparison revealed any significant differences except for the SPIN condition that showed greater activation in the left superior temporal gyrus for stimuli presented to the right ear. No gender differences were observed. These results demonstrate that repeating the last word in a sentence activates mainly auditory and motor areas of the brain when Speech is presented, whereas more difficult tasks, such as SPIN or multi-talker Noise, activate linguistic, attentional, cognitive, working memory, and motor planning areas.

Characteristics of patients with gaze-evoked tinnitus.

OBJECTIVE: The authors describe symptoms and population characteristics in subjects who can modulate the loudness and/or pitch of their tinnitus by eye movements. STUDY DESIGN: Data were obtained by questionnaire. SETTING: The study was conducted at a university center and a tertiary care center. PATIENTS: Respondents had the self-reported ability to modulate their tinnitus with eye movements. RESULTS: Ninety-one subjects reported having gaze-evoked tinnitus after posterior fossa surgery involving the eighth nerve. Eighty-seven of them underwent removal of a vestibular schwannoma (acoustic neuroma), two had bilateral eighth nerve tumors (one underwent bilateral tumor removal; the other unilateral tumor removal), one underwent removal of a cholesteatoma, and one underwent removal of a glomus jugulare tumor. Seventeen subjects who had never had posterior fossa surgery reported gaze-evoked tinnitus. Of those with vestibular schwannomas, tumor size ranged from small (<2 cm) to large (>4 cm). The gender distribution was 48.3% male and 51.7% female. In 77% of patients, the gaze-evoked tinnitus was localized to the surgical ear or side of head; 21.8% had bilateral tinnitus that was louder in the surgical ear or side of head. In 86 of 87 subjects, loudness of tinnitus changed with eye movement. Eye movement away from the central (eyes centered) position increased the loudness of tinnitus in all 86 subjects who responded to this question. Seventy-three of 85 (85.9%) patients indicated that pitch changed with eye movement, with pitch increasing in 64/72 (88.9%) of them. Eighty-three of 87 (95.4%) patients reported total loss of hearing in the surgical ear. Seventy of 83 (84.3%) patients reported facial nerve problems immediately after surgery, 52 of 87 (60%) reported persistent facial weakness, and 16 of 87 (18.4%) patients reported persistent double vision. In those 17 subjects with gaze-evoked tinnitus and no posterior fossa surgery, the majority of respondents (14/17, 82.4%) were male. CONCLUSIONS: Gaze-evoked tinnitus after cerebellar pontine angle surgery is more common than was previously believed. In addition, posterior fossa surgery is not a prerequisite for the development of gaze-evoked tinnitus. It is likely that gaze-evoked tinnitus is a manifestation of functional reorganization. Gaze-evoked tinnitus could result from an unmasking of brain regions that respond to multiple stimulus/response modalities, and/or from anomalous cross-modality interactions, perhaps caused by collateral sprouting.

The functional anatomy of gaze-evoked tinnitus and sustained lateral gaze.

OBJECTIVE: To identify neural sites associated with gaze-evoked tinnitus (GET), an unusual condition that may follow cerebellar-pontine angle surgery. METHODS: The authors examined eight patients with GET and used PET to map the neural sites activated by lateral gaze in them and seven age- and sex-matched control subjects. RESULTS: In patients with GET, tinnitus loudness and pitch increased with lateral gaze and, to a lesser extent, up and down gaze. Evidence for neural activity related to GET was seen in the auditory lateral pontine tegmentum or auditory cortex. GET-associated nystagmus appears to activate the cuneus and cerebellar vermis. These sites were found in addition to an extensive network that included frontal eye fields and other sites in frontal, parietal, and temporal cortex that were activated by lateral gaze in seven control subjects and the patients. The unilateral deafness in patients with GET was associated with expansion of auditory cortical areas responsive to tones delivered to the good ear. In addition to GET, unilateral deafness, end-gaze nystagmus, and facial nerve dysfunction were common. CONCLUSIONS: Patients with GET have plastic changes in multiple neural systems that allow neural activity associated with eye movement, including those associated with the neural integrator, to stimulate the auditory system. Anomalous auditory activation is enhanced by the failure of cross-modal inhibition to suppress auditory cortical activity. The time course for the development of GET suggests that it may be due to multiple mechanisms.

The functional anatomy of the normal human auditory system: responses to 0.5 and 4.0 kHz tones at varied intensities.

Most functional imaging studies of the auditory system have employed complex stimuli. We used positron emission tomography to map neural responses to 0.5 and 4.0 kHz sine-wave tones presented to the right ear at 30, 50, 70 and 90 dB HL and found activation in a complex neural network of elements traditionally associated with the auditory system as well as non-traditional sites such as the posterior cingulate cortex. Cingulate activity was maximal at low stimulus intensities, suggesting that it may function as a gain control center. In the right temporal lobe, the location of the maximal response varied with the intensity, but not with the frequency of the stimuli. In the left temporal lobe, there was evidence for tonotopic organization: a site lateral to the left primary auditory cortex was activated equally by both tones while a second site in primary auditory cortex was more responsive to the higher frequency. Infratentorial activations were contralateral to the stimulated ear and included the lateral cerebellum, the lateral pontine tegmentum, the midbrain and the medial geniculate. Contrary to predictions based on cochlear membrane mechanics, at each intensity, 4.0 kHz stimuli were more potent activators of the brain than the 0.5 kHz stimuli.

Neuroanatomy of tinnitus.

We tested the hypothesis that tinnitus was due to excessive spontaneous activity in the central auditory system by seeking cerebral blood flow (CBF) changes that paralleled changes in the loudness of tinnitus in patients able to alter the loudness of their tinnitus. We found CBF changes in the left temporal lobe in patients with right ear tinnitus, in contrast to bilateral temporal lobe activity associated with stimulation of the right ear. The tones activated more extensive portions of the brain in patients than controls. We conclude that tinnitus is not cochlear in origin and associated with plastic transformations of the central auditory system. We suggest that tinnitus arises as a consequence of these aberrant new pathways and may be the auditory system analog to phantom limb sensations in amputees.

Modulation of tinnitus by voluntary jaw movements.

OBJECTIVE: The authors describe symptoms and population characteristics in patients with tinnitus who report the ability to control the loudness of their tinnitus by performing voluntary movements. DESIGN: The authors used a questionnaire. SETTING: The study was conducted at a tertiary care center. PATIENTS: Respondents have the self-reported ability to control the loudness of their tinnitus by performing voluntary movements. RESULTS: The authors describe symptoms and population characteristics in 93 patients with tinnitus (83% men, 17% women) who report the ability to control the loudness of their tinnitus by performing voluntary movements: 85% of these report jaw movements and 9% report eye movements affect their tinnitus. In the jaw-movement group, tinnitus loudness increased in 90%. Jaw movement affected the pitch in 51% with an increase in pitch reported by 90%. Other maneuvers, such as pressure applied to the head, affected tinnitus in many subjects. Tinnitus had a major impact on the lives of the authors' respondents: 27% registered mild to moderate depression and 8% moderate to severe depression as shown by the Beck Depression Inventory. CONCLUSIONS: The ability to modulate tinnitus by performing voluntary somatosensory or motor acts is likely the result of plastic changes in the brains of these patients with the development of aberrant connections between the auditory and sensory-motor systems. The strong predominance of men in the sample suggests the presence of a gender-specific factor that mediates these changes.

The functional neuroanatomy of tinnitus: evidence for limbic system links and neural plasticity.

We used PET to map brain regions responding to changes in tinnitus loudness in four patients who could alter tinnitus loudness by performing voluntary oral facial movements (OFMs). Cerebral blood flow was measured in four patients and six controls at rest, during the OFM, and during stimulation with pure tones. OFM-induced loudness changes affected the auditory cortex contralateral to the ear in which tinnitus was perceived, whereas unilateral cochlear stimulation caused bilateral effects, suggesting a retrocochlear origin for their tinnitus. Patients, compared with controls, showed evidence for more widespread activation by the tones and aberrant links between the limbic and auditory systems. These abnormal patterns provide evidence for cortical plasticity that may account for tinnitus and associated symptoms. Although audiologic symptoms and examinations of these patients were typical, the unusual ability to modulate tinnitus loudness with an OFM suggests some caution may be warranted in generalizing these findings.

The community integration questionnaire. A comparative examination.

The community integration questionnaire (CIQ) was designed to assess home integration, social integration and productive activity in persons with acquired brain injury. The instrument consists of 15 items and can be completed by self report or with the assistance of a family member or caregiver familiar with the person's health status and social activities. Previous research has demonstrated adequate test-retest reliability and internal consistency. This study was designed to examine further, the psychometric characteristics of the CIQ and begin the process of establishing the instrument's validity. The CIQ was administered to 341 persons with traumatic brain injury (TBI) and 210 persons without TBI or any other apparent disabilities. The results indicate that the total scores are normally distributed for both persons with and without TBI. A statistically significant difference (P < 0.01) was found between subjects with TBI and those without TBI for all three subscales of the CIQ and for total scores. Data analysis also revealed that the total CIQ scores statistically differentiated among subjects with TBI living in three different settings: (1) living independently; (2) living in a supported community situation and (3) living in an institution. Intercorrelations among the three subscales (home, social and productivity) demonstrated that the CIQ provides unique information in the assessment of community integration for persons with TBI. Areas of future research necessary to expand the research and program evaluation usefulness of the CIQ are identified.

The effects of parental traumatic brain injury on the behaviour of parents and children.

Little is known about the effects of a parent's brain injury and subsequent disabilities on the children in the family. This study examines 24 families in which one parent is brain injured. In each family the children were born before the parent's injury and still lived at home at the time of interview. Reports of the uninjured parent indicate that most of the children experienced some degree of negative behavioural change after the parent's injury. In 10 of the families, significant and problematic changes occurred. Types of problems included poor relationship with the injured parent, acting-out behaviour and emotional problems. Correlates of poor outcomes for the children were: (1) injured parent's gender, (2) compromised parenting performance of the injured parent, (3) compromised parenting performance of the uninjured parent and (4) depression in the uninjured parent. This study points to the importance of recognizing traumatic brain injury as a major family stressor.

Affect intensity and cardiac arousal.

Relationships between affect intensity and basal, evoked, and perceived cardiac arousal were investigated in 3 experiments. Affect intensity was assessed using Larsen and Diener's (1987) Affect Intensity Measure (AIM). Cardiac arousal was evoked with exercise in the 1st study and with mental arithmetic in the 2nd and 3rd. Perceived cardiac arousal was measured under optimal conditions using a standard heartbeat discrimination procedure. Women as a group scored higher on the AIM. Affect intensity was unrelated to basal or evoked cardiac arousal and was negatively related to perceived cardiac arousal in all 3 studies. Data suggest that affect intensity, although unrelated to actual physiological arousal, is negatively related to the accuracy with which individuals perceive their own arousal. Results are discussed within the context of an expanded arousal-regulation model (Blascovich, 1990).