Ocular Motor Fixation Deficits in Friedreich Ataxia

Friedreich ataxia (FRDA) is the most common genetic cause of ataxia with a prevalence of approximately 1 in 29,000. Ocular motor abnormalities are common in FRDA and include fixation instability, saccadic dysmetria, and vestibular dysfunction. It has not yet been determined whether aspects of spatial attention, which are closely coupled to eye movements, are similarly compromised in FRDA. This study examined attentional engagement and disengagement of eye movements in FRDA using a gap overlap task. Thirteen individuals with genetically confirmed FRDA and 12 age-matched unaffected controls participated in the experiment. The gap overlap paradigm was used to examine the effect of early (gap condition), simultaneous (null condition), or late (overlap condition) removal of a central fixation on saccadic latency to a peripheral target stimulus. Although the FRDA group showed a larger gap effect (i.e., difference in saccadic latencies between the overlap and gap condition), these participants demonstrated a greater difference in latencies in the overlap relative to the null condition, suggestive of deficits within the disengagement process of attentional orienting. We propose a role for the cerebellum in these deficits in the disengagement of spatial attention based on evidence of cerebellar connectivity with regions involved in exogenous shifts of attention. The significant correlations between saccadic latency and disease severity as measured by the Friedreich Ataxia Rating Scale further support the proposal that saccadic latency might be useful as a surrogate marker of disease severity and progression in future clinical trials in FRDA.     

Mesenchymal stem cells attenuate hypoxic pulmonary vasoconstriction by a paracrine mechanism

BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) may be an adaptive mechanism to correct ventilation-perfusion mismatch in the face of hypoxia. In chronic hypoxia, prolonged vasoconstriction may result in pulmonary hypertension and cor pulmonale. It has been shown that during chronic hypoxia, mesenchymal stem cells (MSCs) may contribute to pulmonary vascular remodeling, anti-inflammation, and vascular stability. Also, MSCs have been shown to release growth factors when stressed by hypoxia. We hypothesized that MSCs reduce HPV by a paracrine mechanism. To test this, MSCs were stressed by hypoxia in tissue culture and the cell-free media was then used to treat the pulmonary arteries subjected to HPV. METHODS: Adult male (250-350 g) Sprague Dawley rat pulmonary arteries (n = 10/group) were isolated and suspended in physiological organ baths. Human MSCs were stressed with 60-min hypoxia and conditioned media was collected. Pulmonary artery rings were treated with vehicle or MSC-conditioned (cell-free) media prior to hypoxia. Force displacement was continuously recorded. Data (mean +/- SEM) were analyzed with two-way analysis of variance with post-hoc Bonferroni test. RESULTS: Pulmonary arteries exposed to MSC-conditioned media experienced an augmented vasodilatory phase as compared to vehicle. Maximum vasodilation was 53.58 +/- 6.42% versus 39.76 +/- 4.05% for vehicle (P < 0.001). In addition, delayed, phase II vasoconstriction was significantly attenuated as compared to vehicle. Maximum phase II vasoconstriction was 28.51 +/- 12.42 versus 86.29 +/- 15.99% for vehicle (P < 0.001). CONCLUSIONS: We conclude that acute hypoxia induces HPV and that MSC-conditioned media acutely attenuates this effect. Thus, in addition to a direct contribution to vessel remodeling in chronic hypoxia, MSCs may acutely protect and attenuate hypoxic pulmonary vasoreactivity through a paracrine mechanism.     

Contribution of lumbar spine and hip movement during the palms to floor test in individuals with diagnosed hypermobility syndrome

The ability to place the hands to the floor forms part of the assessment of joint hypermobility. The test may be symptom free, or in the case of joint hypermobility syndrome, may be associated with pain in the spine, hip, and knee. The aim of this study was to identify the relative amount of movement at the lumbar spine and hip during this test in people with asymptomatic and symptomatic hypermobility compared with a control group. Thirty-six female subjects (10 asymptomatic hypermobility, 13 symptomatic hypermobility, and 13 control) ranging between 18 and 60 years of age participated in the investigation. Measurements were made by using digital photography and inclinometers. Measurement reliability was established prior to the investigation. There was a significant difference (p<0.05) between hip flexion range in the two hypermobility groups compared to the control group; there was no significant difference in lumbar spine movement between the three groups. The findings suggest that people with asymptomatic or symptomatic hypermobility perform the hand to floor test with the same relative contribution from the lumbar spine and hip joints. Both groups perform the hands to floor test and with a greater relative hip flexion range than a control group.     

The role of interleukin-18 in renal injury

Interleukin (IL)-18 is a relatively new pro-inflammatory cytokine, formerly known as interferon-gamma-inducing factor, which induces interferon-gamma production in T cells and natural killer cells. It is synthesized as a biologically inactive precursor, which requires cleavage into an active molecule by an intracellular cysteine protease similar to IL-1beta. This review examines the pro-inflammatory role of IL-18 in various types of renal injury (i.e., endotoxemia, cisplatin toxicity, allograft rejection, and ischemia-reperfusion injury) and explores the integral role of IL-12 in IL-18 function and activity.     

Glucagon receptor agonists and antagonists affect the growth of the chick eye: a role for glucagonergic regulation of emmetropization?

PURPOSE: In chicks, plus defocus retards eye growth, thickens the choroid, and activates glucagonergic amacrine cells, probably releasing glucagon. Glucagon receptor antagonists (expected to inhibit compensation to plus defocus) and agonists (expected to block myopia induction by form deprivation) were administered to eyes of chicks, to test the hypothesis that glucagon mediates the induction of changes in eye growth by plus defocus. METHODS: Seven-day-old (P7) chick eyes were injected intravitreally with peptides at concentrations of approximately 10(-9) to 10(-5) M in 20 microL (injection volume). The glucagon-receptor antagonists [des-His(1),des- Phe(6),Glu(9)]-glucagon-NH(2) (des- Phe(6)-antagonist) and [des-His(1),Glu(9)]-glucagon-NH(2) (Phe(6)-antagonist) were administered daily for 4 to 5 days to plus-defocused eyes. Agonists (porcine glucagon-[1-29] and [Lys(17,18),Glu(21)]-glucagon-NH(2)) were monocularly administered daily for 5 days to form-deprived eyes. The contralateral eye remained open and received saline. After treatment, eyes were refracted, measured, and examined for histologic changes. RESULTS: The Phe(6)-antagonist at 10(-5) M (in the syringe) inhibited changes in both refractive error and axial length compensation induced by +7-D lens wear; however, des-Phe(6)-antagonist (10(-5) M) had weak, inconsistent effects and did not antagonize the action of exogenous glucagon. Glucagon prevented ocular elongation and myopia and induced choroidal thickening in form-deprived eyes. [Lys(17,18),Glu(21)]-glucagon-NH(2) had little effect at 10(-7) M, but at 10(-6) to 10(-5) M altered rod structure and inhibited eye growth. CONCLUSIONS: Exogenous glucagon inhibited the growth of form-deprived eyes, whereas Phe(6)-antagonist inhibited compensation to plus defocus, as might be expected if glucagon is an endogenous mediator of emmetropization. The reason for the failure of des-Phe(6)-antagonist to counteract the effects of exogenous glucagon requires further investigation.     

Mediators of fibrosis and apoptosis in obstructive uropathies

Upper urinary tract obstruction, regardless of its cause, often poses a significant clinical challenge to the urologist. Renal cellular and molecular events that occur in response to upper urinary tract obstruction result in a progressive and permanent loss in renal function when left untreated. These pathologic changes include the development of renal fibrosis, tubular atrophy, interstitial inflammation, and apoptotic renal cell death. Several cytokines and growth factors have been identified as major contributors to obstruction-induced renal fibrosis and apoptotic cell death, most notably transforming growth factor-β1 (TGF-β1), angiotensin, nuclear factor-κB (NF-κB), and tumor necrosis factor-α (TNF-α). This review examines the challenges of upper urinary tract obstruction and the role of these mediators in obstruction-induced renal injury.