Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice.

Mitogen-activated protein kinase (MAPK) phosphatases are dual-specificity phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs. DUSP6 preferentially dephosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2) rendering them inactive. Here, we study the role of DUSP6 in CD4(+) T-cell function, differentiation, and inflammatory profile in the colon. Upon T-cell receptor (TCR) stimulation, DUSP6 knockout (Dusp6(-/-)) CD4(+) T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation, and interferon-γ production, as well as a marked decrease in survival, interleukin- 17A (IL-17A) secretion, and regulatory T-cell function. To analyze the role of DUSP6 in vivo, we employed the Il10(-/-) model of colitis and generated Il10(-/-)/Dusp6(-/-) double-knockout mice. Il10(-/-)/Dusp6(-/-) mice suffered from accelerated and exacerbated spontaneous colitis, which was prevented by ERK1/2 inhibition. ERK1/2 inhibition also augmented regulatory T-cell differentiation in vitro and in vivo in both C57Bl/6 and Dusp6(-/-) mice. In summary, DUSP6 regulates CD4(+) T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation. DUSP6 might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases, such as inflammatory bowel disease.

A role for PPARα in the medial prefrontal cortex in formalin-evoked nociceptive responding in rats.

BACKGROUND AND PURPOSE: The nuclear hormone receptor, PPARα, and its endogenous ligands, are involved in pain modulation. PPARα is expressed in the medial prefrontal cortex (mPFC), a key brain region involved in both the cognitive-affective component of pain and in descending modulation of pain. However, the role of PPARα in the mPFC in pain responding has not been investigated. Here, we investigated the effects of pharmacological modulation of PPARα in the rat mPFC on formalin-evoked nociceptive behaviour and the impact of formalin-induced nociception on components of PPARα signalling in the mPFC. EXPERIMENTAL APPROACH: The effects of intra-mPFC microinjection of a PPARα agonist (GW7647) or a PPARα antagonist (GW6471) on formalin-evoked nociceptive behaviour in rats were studied. Quantitative real-time PCR and LC-MS/MS were used to study the effects of intraplantar injection of formalin on PPARα mRNA expression and levels of endogenous ligands, respectively, in the mPFC. KEY RESULTS: Intra-mPFC administration of GW6471, but not GW7647, resulted in delayed onset of the early second phase of formalin-evoked nociceptive behaviour. Furthermore, formalin-evoked nociceptive behaviour was associated with significant reductions in mPFC levels of endogenous PPARα ligands (N-palmitoylethanolamide and N-oleoylethanolamide) and a 70% reduction in PPARα mRNA but not protein expression. CONCLUSIONS AND IMPLICATIONS: These data suggest that endogenous ligands may act at PPARα in the mPFC to play a facilitatory/permissive role in second phase formalin-evoked nociceptive behaviour in rats. LINKED ARTICLES: This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6.

Role of central preprogramming in dynamic visual acuity with vestibular loss.

OBJECTIVE: To determine the contribution of central preprogramming of eye movements to dynamic visual acuity (DVA) during head movement in patients with vestibular hypofunction. STUDY DESIGN: Prospective, clinical study. SETTING: Tertiary care, academic hospitals. PARTICIPANTS: Twenty-six healthy subjects and 20 patients with unilateral (UVL) and 7 with bilateral vestibular loss (BVL) (age range, 20-86 years). INTERVENTIONS: Diagnostic interventions, including caloric and rotational chair testing. MAIN OUTCOME MEASURE: Measurements of DVA during predictable (DVA-predictable) and unpredictable (DVA-unpredictable) head movements using a computerized test. RESULTS: There was a difference between DVA-predictable and DVA-unpredictable scores in all groups (P<.02). The difference between DVA-predictable and DVA-unpredictable scores for the BVL group was significantly greater than that for the other groups (P<.005). Age was a significant factor in DVA-unpredictable scores for the healthy subjects (P<.001) and UVL group (P<.02). Comparisons of DVA between groups were significant (P<.03), with the following exceptions: UVL group for head movements toward the unaffected side for DVA-predictable and DVA-unpredictable scores, compared with healthy subjects, and UVL group for head movements toward the affected side for DVA-predictable scores, compared with the BVL group. CONCLUSIONS: Unpredictable head movements cause a greater decrement in visual acuity than do predictable head movements. This suggests that central programming of eye movements and/or efference copy contributes to gaze stability during predictable head movements in healthy subjects and patients with vestibular hypofunction. Patients with BVL use central programming of eye movements to maintain gaze stability more than do healthy subjects or patients with UVL.

Strategies for balance rehabilitation: fall risk and treatment.

Identification of fall risk for patients with known vestibular hypofunction is important because it affects the management and the level of independence of these patients. Patients with bilateral vestibular loss, overall, have a greater incidence of falls than the general community-dwelling population over the age of 65 years. In younger patients, the incidence of falls may be related to severity of vestibular loss and to overconfidence or a lack of caution in activities. Preliminary reports suggest that vestibular rehabilitation can reduce the fall risk in patients with vestibular loss.

Phase II evaluation of bryostatin-1 in metastatic melanoma.

In this phase II study we assessed the efficacy of bryostatin-1 (NSC 339555) in metastatic melanoma patients when given intravenously either once a week at a dose of 25 microg/m2 per day over 24 h for 3 weeks or at 40 microg/m2 per day over 72 h every 2 weeks. Treatment courses were repeated every 4 weeks. Patients who had received one prior chemotherapy regimen for advanced melanoma, with or without biotherapy, were randomized to one or the other bryostatin-1 dose schedules until 12 patients were registered to each arm. Because there was one confirmed response among the 12 patients who received the 72 h dose schedule, 25 more patients were added to that arm. No prophylactic medications were given. Objective tumour measurements were used to assess the efficacy of the regimen. The National Cancer Institutes common toxicity criteria were used to grade reactions. In total, 49 patients with metastatic melanoma, none having symptomatic brain metastasis, were studied. Of these, 12 patients received the 24 h bryostatin-1 regimen, while the remaining 37 received the 72 h regimen. One patient receiving the 72 h regimen had a partial response lasting over 7 months. Muscle pain occurred in over 90% of the patients and was the dose-limiting side effect of the 72 h regimen. Grade 3/4 nausea and vomiting were more common on the 24 h regimen than on the 72 h one (35% versus 5% of patients). There was no therapy-related thrombocytopenia. Neutropenia was mild and mainly limited to patients receiving the 72 h regimen. Bryostatin-1 has limited activity against melanoma when given by 72 h intravenous infusion.

Falls in patients with vestibular deficits.

OBJECTIVE: To determine to what extent patients with vestibular hypofunction experience falls. STUDY DESIGN: Prospective clinical study. SETTING: Outpatient tertiary care facility in a university. PATIENTS: Patients with unilateral (n = 70) and bilateral (n = 45) vestibular hypofunction, confirmed on vestibular function testing, aged 24 to 89 years. INTERVENTION: None. MAIN OUTCOME MEASURE: Incidence of falls. RESULTS: There was a significant difference in the incidence of falls reported since the onset of the vestibular deficit by patients with unilateral (UVL) and bilateral (BVL) vestibular hypofunction. The incidence of falls for BVL was significantly greater than that for UVL. The incidence of falls for UVL was not different from that expected in a community-based population when age was considered. The incidence of falls for BVL was significantly greater than that reported for the general population aged 65 through 74 years (51.1% for BVL, 25% for community-dwelling individuals) but was significantly less than expected for persons aged > or =75 years (18.2% for BVL, 49% for community-dwelling individuals). The lower incidence of falls in patients with BVL aged > or =75 years may be related to the use of assistive devices and to a decrease in risky behavior. All patients with serious injury were from the UVL group, and all were >65 years old. The incidence of fall-related injuries requiring medical attention among patients with UVL was similar to that in community-dwelling individuals. CONCLUSIONS: Falls are an important consequence of bilateral vestibular hypofunction, and patients should be counseled about the increased risk of falling. Assistive devices should be considered, especially for persons aged >65 years with BVL.

The effect of the canalith repositioning maneuver on resolving postural instability in patients with benign paroxysmal positional vertigo.

OBJECTIVE: Patients with benign paroxysmal positional vertigo (BPPV) often experience postural instability as well as brief episodes of vertigo. The purpose of this study was to determine whether successful resolution of the episodic vertigo, through use of the canalith repositioning treatment, would be accompanied by improvement in postural stability. STUDY DESIGN: Prospective clinical study. SETTING: Outpatient tertiary care facility in a university. PATIENTS: Thirty-three patients with a diagnosis of the canalithiasis form of BPPV affecting the posterior canal unilaterally. All patients had complete remission of the positional vertigo after treatment. Patients with abnormal caloric or rotary chair test results were excluded from the study. INTERVENTION: The posterior canal BPPV was treated by the canalith repositioning treatment. MAIN OUTCOME MEASURES: Postural stability was assessed by computerized dynamic posturography before and 1 to 2 weeks after treatment. Six different subtests were used. RESULTS: A significant number of patients had abnormal stability, as measured with computerized dynamic posturography, before treatment. After treatment there was a significant increase in the number of subjects with normal results on the different subtests; however, not all patients had normal postural stability. Younger subjects were more likely to show improved stability. CONCLUSIONS: Treatment of BPPV using the canalith repositioning treatment results in improved postural stability in patients with BPPV. Not all patients have normal stability after treatment, however, and assessment and treatment of the balance problems may be necessary.

Vestibular rehabilitation of patients with vestibular hypofunction or with benign paroxysmal positional vertigo.

Since the initial introduction of exercises as a treatment for patients with vestibular deficits, there have been numerous clinical reports on the benefits of treatment. Clinical reports, however, are of limited use as a basis for treatment because, without a control group, they offer only interesting descriptions of the patient populations. Fortunately, several prospective, randomized studies on the treatment of patients with vestibular hypofunction or with benign paroxysmal positional vertigo have been published recently, adding to the small number of previous publications. This review will examine the information provided by those studies. Advances in the use of outcome measures, assessment of otolith function and treatment of related balance problems are also presented.

Oscillopsia and pseudonystagmus in kidney transplant patients.

PURPOSE: Modern immunosuppressants have improved the success of kidney transplantation for renal failure patients. They also may induce neurotoxic effects including tremor. We report two cases of pseudonystagmus and oscillopsia in transplant patients caused by immunosuppressant-induced head tremor and gentamicin-induced vestibulotoxicity. METHODS: Case reports. Head tremor, static visual acuity, and dynamic visual acuity were measured. Vestibular function was evaluated with ice water calorics. RESULTS: Both patients had significant head tremor and pseudonystagmus. Head stabilization improved static visual acuity. Dynamic visual acuity revealed a 4-line and 10-line loss of visual acuity, respectively. CONCLUSIONS: These findings of pseudonystagmus and oscillopsia are likely to become more prevalent as more renal failure patients receive transplants. Improvement may be seen with reduction of immunosuppressant, reduction of stimulant intake, use of medications to reduce head tremor, and vestibular rehabilitation.

[Diagnosis and therapeutic options in benign paroxysmal positional vertigo]. / Diagnóstico y opciones terapéuticas del vértigo posicional paroxístico benigno (VPPB).

Benign paroxysmal positional vertigo (BPPV) is one of the most common and treatable causes of vertigo. We examined BPPV types and the effectiveness of physical therapy in each type. BPPV is caused by a utricular statoconium that blocks the semicircular canal. Statoconia can block any of the semicircular canals, but they generally affects the posterior canal. Diagnosis is based on a typical history and characteristic eye movements elicited by the Dix-Hallpike test. Treatment involves a physical maneuver designed to mobilize the free calcium particles from the semicircular canal to the utricle. Canalith repositioning is the mainstay of treatment. The maneuver is illustrated in detail and other forms of treatment and their indications are discussed.

Computerized dynamic visual acuity test in the assessment of vestibular deficits.

OBJECTIVE: The study was designed to measure dynamic visual acuity (DVA) during head movement as an assessment of the functional impact of vestibular deficits. STUDY DESIGN: The study design was a prospective, clinical study. SETTING: The study was performed in a tertiary, ambulatory referral center. PATIENTS: Forty-two normal subjects, 29 patients with unilateral vestibular loss, and 26 patients with bilateral vestibular hypofunction who were 19-87 years of age were examined. INTERVENTION: Diagnostic intervention was performed. MAIN OUTCOME MEASURE: Main outcome measures included the reliability, sensitivity, and specificity of a computerized test that measures visual acuity during head movement in normal subjects and in patients with vestibular deficits. RESULTS: The computerized DVA test was reliable in both normal subjects (intraclass correlation coefficient [ICC] r=0.87) and in patients with vestibular deficits (ICC r=0.83). The sensitivity of the DVA test was 94.5% and the specificity was 95.2%. The positive predictive value (individuals who test positive on the DVA test who will have a vestibular deficit) was 96.3%. The negative predictive value (individuals who test negative on the DVA test who will not have a vestibular deficit) was 93%. CONCLUSIONS: The computerized DVA test is reliable and is able to distinguish among normal subjects and patients with vestibular deficits.

Role of vestibular adaptation in vestibular rehabilitation.

Recovery of gaze and postural stability in human beings with vestibular deficits is well documented. The mechanisms that contribute to this recovery form the basis for the exercises used in the rehabilitation of these patients. These mechanisms include the central preprogramming of eye movements and of postural responses, the potentiation of the cervico-ocular reflex, modification of saccadic eye movements, and the substitution of visual and somatosensory cues for the lost vestibular cues. The mechanism most successful in contributing to recovery, however, is probably adaptation of the vestibular system itself. Understanding the various compensatory mechanisms and their limitations for improving gaze and postural stability should lead to more effective treatment of these patients.

Computerized dynamic platform posturography.

Computerized dynamic platform posturography is defined in this technology assessment. The review discusses what computerized dynamic platform posturography measures, what the reliability and validity of the information are, and the uniqueness of the information provided. The clinical contribution and indications for testing are discussed. There are comments on future directions for research on computerized dynamic platform posturography and a summary and conclusion.

Advances in the treatment of vestibular disorders.

This article discusses the pathophysiology, evidence of treatment efficacy, and factors that contribute to improved treatment outcome in three different vestibular disorders. In patients with unilateral and bilateral vestibular loss, recent research suggests that customized, supervised exercises facilitate recovery of postural stability. These exercises are based on knowledge of normal vestibular function as well as on our understanding of the various compensatory mechanisms that can contribute to recovery. Recognizing the limitations of these compensatory mechanisms as substitutes for lost vestibular function is important in establishing treatment goals. Treatment of patients with benign paroxysmal positional vertigo (BPPV) is based on the identification of the specific canal involved and the anatomy of the labyrinth. Although patients with BPPV primarily experience brief episodes of vertigo, this disorder is also associated with postural instability, which may not resolve with remission of the positional vertigo.

Entamoeba invadens: characterization of cysteine proteinases.

Cysteine proteinases have a number of important functions in the life cycle of protozoan parasites. Based on our previous studies demonstrating the role of cysteine proteinases in invasion by Entamoeba histolytica, we evaluated the cysteine proteinases of E. invadens, a related protozoan which causes invasive disease of reptiles. E. invadens readily encysts in axenic culture and provides a model to investigate the role of cysteine proteinases in encystation. Broad bands of approximately 130-230, 55, and 35 kDa were detected on gelatin substrate gels and were inhibited with specific cysteine proteinase inhibitors. Maximal enzymatic activity was detected with peptide substrates containing arginine in the P2 position. A 567-bp fragment containing the active site of an E. invadens cysteine proteinase gene was amplified by PCR and had 37.7, 79.1, and 67.9% identity to the derived amino acid sequences of the acp 1, 2, and 3 genes, respectively, of E. histolytica. The PCR product hybridized with a single band of 1.1 kb on a Southern blot of EcoRI-restricted E. invadens genomic DNA. Long-term inhibition of cysteine proteinase activity during encystation resulted in significantly fewer cysts (P < 0.02); however, this effect appeared to be secondary to decreased trophozoite cell division. No difference in chitin synthase activity was detected between controls and encysting cells with inhibited cysteine proteinases, suggesting that these proteinases are not critical for activation of a zymogen form of chitin synthase. These studies demonstrate that cysteine proteinases may be critical for the survival of E. invadens, and specific inhibition may ultimately interrupt transmission.

Visual stabilization of posture in persons with central visual field loss.

PURPOSE: To determine whether people with central visual field loss (CFL) show a smaller visual contribution to posture stabilization than people with normal vision and to determine the visual factors that predict the magnitude of visual stabilization in people with central visual field loss. METHODS: Posture information was recorded in 19 subjects with CFL and in 20 subjects with normal vision. Data were collected as the subject stood in a dark environment and also as he or she viewed a stationary visual display. In both conditions, somatosensory feedback was concurrently altered. The central visual fields of the subjects with CFL were measured by static perimetry with the confocal scanning laser ophthalmoscope. Binocular visual acuity and contrast sensitivity were measured on all subjects using the ETDRS and Pelli-Robson charts, respectively. Image-displacement thresholds were measured in a subset of the subjects. RESULTS: On average, subjects with central field loss showed a smaller visual contribution to posture stabilization than subjects with normal vision. The reduction in sway caused by visual stimuli was only 29% for the subjects with CFL compared to 41% for the subjects with normal vision. Displacement thresholds accounted for 45% of the variance in the visual stabilization magnitude of the subjects with CFL. No other visual factor significantly increased the coefficient of determination. CONCLUSIONS: The visual self-motion cues generated by small body oscillations may be undetectable and, thus, unusable as cues to postural sway by people with central field loss.

The contribution of the vertical semicircular canals to high-velocity horizontal vestibulo-ocular reflex (VOR) in normal subjects and patients with unilateral vestibular nerve section.

We have examined to what extent the vertical semicircular canals contribute to the nonlinearity of the horizontal VOR imposed by the driving of primary vestibular afferents into inhibitory cutoff at high velocities of head rotation (Ewald's second law). The gain (eye velocity/head velocity) of the horizontal component of the VOR with the head pitched down 30 degrees and pitched up 30 degrees was examined during constant-velocity rotations in normal subjects and patients following unilateral vestibular nerve section. In normal subjects, VOR gain decreases as chair velocity increases from 60-300 degrees/s when the head is pitched up, but VOR gain remains constant when the head is pitched down. This finding implies that the mechanism by which the gain of the horizontal VOR gain remains constant at all velocities of rotation depends upon the pattern of labyrinthine stimulation. Following unilateral nerve section, we found that the directional preponderance (DP) in horizontal VOR depends upon whether the head is pitched up 30 (mean asymmetry = 5%) or pitched down 30 degrees (mean asymmetry = 20%). This is what is expected based on the degree to which the lateral and vertical semicircular canals sense horizontal head acceleration with the head in different degrees of pitch. Hence, following unilateral vestibular lesions, the DP of horizontal VOR gain is most easily elicited at high velocities of head rotation and with the head pitched down 30 degrees. Evidence for DP at the bedside using the "head-shaking nystagmus" technique may be optimally elicited with the head pitched down 30 degrees.

Complications of the canalith repositioning procedure.

OBJECTIVE: To describe the conversion of benign paroxysmal positional vertigo involving the posterior canal into benign paroxysmal positional vertigo involving the anterior or horizontal canals after treatment using the canalith repositioning maneuver. DESIGN: Retrospective study of outcome. SETTING: Outpatient clinic. PATIENTS: Consecutive sample of 85 patients diagnosed as having benign paroxysmal positional vertigo affecting the posterior canal. Identification of posterior canal involvement was based on the observation of the direction of the vertical component of nystagmus after the Hallpike-Dix maneuver. INTERVENTION: Canalith repositioning maneuver. MAIN OUTCOME MEASURE: Eye movements were observed about 1 week after the treatment. The direction of nystagmus elicited after movement of the patient into the Hallpike-Dix position indicated which canal was involved in the patients who had not responded to treatment. RESULTS: Of the 85 patients studied who originally had posterior canal benign paroxysmal positional vertigo, five (6%) had anterior canal (n=2) or horizontal canal (n=3) positional vertigo after undergoing this maneuver. CONCLUSION: Careful observation of the direction of the nystagmus is necessary for correct identification of which canal is involved in patients who do not respond to the initial treatment using the canalith repositioning maneuver.