Krista Kinard

Molecular mapping of the binding site for a blocker of hyperpolarization-activated, cyclic nucleotide-modulated pacemaker channels.

Hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels mediate rhythmic electrical activity of neural and cardiac pacemaker cells. Drugs that block these channels slow the beating rate of the heart and are used to treat angina. Here, we characterized the effect of the HCN channel blocker, ZD7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride] on HCN2 channels that were heterologously expressed in Xenopus oocytes. A site-directed mutagenesis approach was used to identify specific residues of the mouse HCN2 channel pore that interact with ZD7288. Two residues (Ala425 and Ile432) located in the S6 transmembrane domain were found to be the primary determinants for block of HCN2 channels by ZD7288. I432A mutant HCN2 channels were ∼100-fold less sensitive to block by ZD7288. Substitution of Ile432 with more hydrophobic residues (Phe, Leu, or Val) caused only modest shifts in the IC50 for the drug. HCN1 channels have a Val (Val390) in the equivalent position of Ile432 and are less sensitive to block by ZD7288. Accordingly, mutation of this Val390 to Ile in HCN1 increased the sensitivity of these channels to drug block. Mutation of Ala425 and Ile432 also attenuated the block of HCN2 by the more potent blocker cilobradine. An HCN2 homology model based on the bacterial KcsA K+ channel predicts that the phenyl ring of ZD7288 occupies a hydrophobic cavity formed by Ala425 and Ile432 and that the charged ring aligns with the axis of the inner pore closely corresponding to the localization of K+ ions observed in the KcsA crystal structure.

Chronic migraine is associated with reduced corneal nerve fiber density and symptoms of dry eye

We used in vivo corneal confocal microscopy to investigate structural differences in the sub‐basal corneal nerve plexus in chronic migraine patients and a normal population. We used a validated questionnaire and tests of lacrimal function to determine the prevalence of dry eye in the same group of chronic migraine patients. Activation of the trigeminal system is involved in migraine. Corneal nociceptive sensation is mediated by trigeminal axons that synapse in the gasserian ganglion and the brainstem, and serve nociceptive, protective, and trophic functions. Noninvasive imaging of the corneal sub‐basal nerve plexus is possible with in vivo corneal confocal microscopy.

Molecular mapping of a site for Cd2+-induced modification of human ether-à-go-go-related gene (hERG) channel activation

Cd2+ slows the rate of activation, accelerates the rate of deactivation and shifts the half‐points of voltage‐dependent activation (V0.5,act) and inactivation (V0.5,inact) of human ether‐à‐go‐go‐related gene (hERG) K+ channels. To identify specific Cd2+‐binding sites on the hERG channel, we mutated potential Cd2+‐coordination residues located in the transmembrane domains or extracellular loops linking these domains, including five Cys, three His, nine Asp and eight Glu residues. Each residue was individually substituted with Ala and the resulting mutant channels heterologously expressed in Xenopus oocytes and their biophysical properties determined with standard two‐microelectrode voltage‐clamp technique. Cd2+ at 0.5 mm caused a +36 mV shift of V0.5,act and a +18 mV shift of V0.5,inact in wild‐type channels. Most mutant channels had a similar sensitivity to 0.5 mm Cd2+. Mutation of single Asp residues located in the S2 (D456, D460) or S3 (D509) domains reduced the Cd2+‐induced shift in V0.5,act, but not V0.5,inact. Combined mutations of two or three of these key Asp residues nearly eliminated the shift induced by 0.5 mm Cd2+. Mutation of D456, D460 and D509 also reduced the comparatively low‐affinity effects of Ca2+ and Mg2+ on V0.5,act. Extracellular Cd2+ modulates hERG channel activation by binding to a coordination site formed, at least in part, by three Asp residues.

Effect of intraocular lens glistening size on visual quality

Purpose To determine whether intraocular glistenings have an impact on light scatter and visual function. Setting John A. Moran Eye Center Laboratories, University of Utah, Salt Lake City, Utah, USA. Design Retrospective cohort study. Methods Pseudophakic patients with visual acuity no worse than 0.02 logMAR and no ocular pathology were enrolled. All had received a single‐piece high‐refractive‐index acrylic intraocular lens (IOL). All IOLs were photographed, and glistenings were analyzed for size and density. Outcome measures included logMAR corrected distance visual acuity (CDVA), mesopic 10% contrast logMAR CDVA with and without glare, and straylight determination with a straylight meter (C Quant log). Results All 79 patients had glistenings within 2 diameter groups: 6 to 25 &mgr;m and over 25 &mgr;m. Linear regression for the nonstratified group was significant for IOL glistening size versus contrast visual acuity with glare. Linear regression for the 6 to 25 &mgr;m group was significant for a measure of severity index (%area) versus the straylight meter measurements, %area/size versus straylight meter measurements, IOL age versus CDVA, IOL age versus contrast visual acuity, and IOL age versus contrast visual acuity with glare. Linear regression for the over 25 &mgr;m group was significant for IOL age versus glistening size and %area/size versus contrast visual acuity, and density versus CDVA and contrast visual acuity with glare. Conclusions Glistening %area, at a key size, correlated with random light scatter. The age of the IOL likely affects glistening size and visual parameters. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Comparison of stromal hydration techniques for clear corneal cataract incisions: conventional hydration versus anterior stromal pocket hydration.

&NA; Anterior stromal pocket hydration was compared with conventional hydration for preventing wound leak after 2.8 mm uniplanar clear corneal incisions (CCIs) in patients having routine cataract surgery. Conventional hydration involves hydration of the lateral walls of the main incision with visible whitening of the stroma. The anterior stromal pocket hydration technique involves creation of an additional supraincisional stromal pocket overlying the main incision, which is then hydrated instead of the main incision. Sixty‐six eyes of 48 patients were included in the data analysis with 33 assigned to each study group. The anterior stromal pocket hydration technique was significantly better than conventional hydration in preventing wound leak due to direct pressure on the posterior lip of the incision. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.

Comparison of Hanna and Hessburg-Barron trephine and punch systems using histological, anterior segment optical coherence tomography, and elliptical curve fitting models

Background: This study analyzes the characteristics of donor and recipient tissue preparation between the Hessburg-Barron and Hanna punch and trephine systems by using elliptical curve fitting models, light microscopy, and anterior segment optical coherence tomography (AS-OCT). Methods: Eight millimeter Hessburg-Barron and Hanna vacuum trephines and punches were used on six cadaver globes and six corneal-scleral rims, respectively. Eccentricity data were generated using measurements from photographs of the corneal buttons and were used to generate an elliptical curve fit to calculate properties of the corneal button. The trephination angle and punch angle were measured by digital protractor software from light microscopy and AS-OCT images to evaluate the consistency with which each device cuts the cornea. Results: The Hanna trephine showed a trend towards producing a more circular recipient button than the Barron trephine (ratio of major axis to minor axis), ie, 1.059 ± 0.041 versus 1.110 ± 0.027 (P = 0.147) and the Hanna punch showed a trend towards producing a more circular donor cut than the Barron punch, ie, 1.021 ± 0.022 versus 1.046 ± 0.039 (P = 0.445). The Hanna trephine was demonstrated to have a more consistent trephination angle than the Barron trephine when assessing light microscopy images, ie, ±14.39° (95% confidence interval [CI] 111.9–157.7) versus ±19.38° (95% CI 101.9–150.2, P = 0.492) and OCT images, ie, ±8.08° (95% CI 106.2–123.3) versus ±11.16° (95% CI 109.3–132.6, P = 0.306). The angle created by the Hanna punch had less variability than the Barron punch from both the light microscopy, ie, ±4.81° (95% CI 101.6–113.9) versus ±11.28° (95% CI 84.5–120.6, P = 0.295) and AS-OCT imaging, ie, ±9.96° (95% CI 95.7–116.4) versus ±14.02° (95% CI 91.8–123.7, P = 0.825). Statistical significance was not achieved. Conclusion: The Hanna trephine and punch may be more accurate and consistent in cutting corneal buttons than the Hessburg-Barron trephine and punch when evaluated using elliptical curve fitting models, light microscopy, and AS-OCT.

Neuro-ophthalmic disorders in pregnancy.

Purpose of ReviewThis review discusses evaluation and treatment of neuro-ophthalmic disorders in the pregnant patient. Recent FindingsAny neuro-ophthalmic abnormality seen in nonpregnant women can be seen in pregnant women. Pregnancy-specific complications (preeclampsia and eclampsia) cause visual symptoms and can affect the entire visual axis. SummaryAppropriate evaluation and examination is important to preserve the health and vision of the mother and prevent complications in the fetus. Evaluation should proceed in the same way for a pregnant patient as it would for a nonpregnant patient, with few exceptions. Treatment decisions may be influenced by stage of pregnancy.

Femtosecond-assisted preparation of donor tissue for Boston type 1 keratoprosthesis

We describe a technique for femtosecond laser-assisted preparation of donor tissue for Boston type 1 keratoprosthesis to provide accurate double punching of the donor tissue for optimized alignment in the visual axis. The technique was reproducibly performed in four donor corneas mounted in an artificial anterior chamber. This technique can provide optically centered donor tissue with smooth trephinated edges.

Ataxia at the Masquerade Ball.

F ive years previously, a 52-year-old man developed diplopia requiring prism glasses. This was followed by imbalance resulting in frequent backward falls as well as oscillopsia and episodic vertigo. Subsequently, he developed fatigue, dysarthria, weight loss, numbness of his right foot, and easy bruising. He had complaints of cognitive decline but formal neuropsychological testing was normal. He had had 1 previous neurology consult and brain magnetic resonance imaging (MRI) without an explanation for his symptoms. His medical history consisted of hypertension, viral pericarditis, mononucleosis, hepatitis, and treated prostate and squamous cell skin cancers. His only medications were over-the-counter supplements. His father had undiagnosed balance problems. At the time of initial evaluation, he reported progressive worsening of his balance. Visual acuity was normal as was examination of the anterior and posterior segment of each eye. His fixation was interrupted by intermittent squarewave jerks, and his eye movements were abnormal, with saccadic pursuit, slowed adducting saccades, gaze-evoked torsional-downbeat nystagmus, and minor bilateral abduction deficits with an esodeviation in both right and left gazes. He was unable to suppress his vestibular-ocular reflex. His neurologic examination showed normal cranial nerves and normal strength, but he had mild dysarthria, a widebased ataxic gait, unsteady tandem walk, appendicular dysmetria, absent ankle reflexes, and decreased peripheral sensation in his feet. His workup revealed normal nerve conduction studies, but brainstem auditory evoked responses showed delays in waves 3 and 5. Evaluation of his swallowing showed mild dysphagia with intermittent delay of pharyngeal response. MRI demonstrated only white matter disease consistent with microvascular ischemia, which was unchanged from previous studies. The following laboratory studies were normal or negative: complete blood count with differential, erythrocyte sedimentation rate, comprehensive metabolic panel, thyroid stimulating hormone, thyroxine, vitamins B1, B12, D, and E, serum protein electrophoresis/immunoelectrophoresis, mercury, arsenic, and cadmium levels, urine protein electrophoresis, antinuclear antibody (ANA) assay, Bartonella henselae, Bartonella quintana, Lyme disease, rapid plasma reagin, fluorescent treponemal antibody absorption, Mycoplasma pneumoniae, antineutrophil cytoplasmic antibodies (ANCA) titers, Toxoplasma, Anti-Ro(SSA) and Anti-La(SSB), Coxiella burnetii, acid-fast bacilli, Mycobacterium tuberculosis antibody, quantiferon gold, Tropheryma whipplei, hepatitis C virus (HCV), herpes simplex virus (HSV), anti-JC virus (JCV) antibodies, Rocky Mountain spotted fever, varicella-zoster virus (VZV), HIV-1, HIV-2, and Epstein– Barr virus. He had a low absolute CD4 count with a low CD4:CD8 ratio, normal anticardiolipin IgG but high anticardiolipin IgM, high parvovirus B19 IgG but normal IgM, and normal cerebrospinal fluid (CSF) studies except for high HSV IgG. CSF cytology revealed no malignant cells. He had an unremarkable whole-body bone scan as well as negative findings on computed tomography of chest, abdomen, and pelvis. A subsequent sleep study confirmed sleep apnea for which he was placed on continuous positive airway pressure treatment. He was also evaluated at the cerebellar ataxia clinic and diagnosed with familial spinocerebellar ataxia as the most likely etiology of his symptoms. He was offered genetic testing but declined due to cost. He was placed on acetazolamide and then memantine without improvement. Over the next 6 years, his symptoms worsened despite physical and occupational therapy. He became disabled and wheelchair bound. Due to progressive decline, he had repeat MRI of the brain.

Adalimumab and Non-Arteritic Anterior Ischaemic Optic Neuropathy: A Case Report

Abstract Sequential anterior ischaemic optic neuropathy was observed in a patient treated with a tumour necrosis factor α (TNF) inhibitor, adalimumab, for ankylosing spondylitis. He developed decreased visual acuity in the right eye after 17 months of treatment. Findings showed right optic disc oedema with haemorrhages and visual field defect. Adalimumab was discontinued and vision stabilised. After restarting adalimumab, he developed optic neuropathy in the left eye. Findings showed optic disc oedema, with haemorrhages and visual field changes in the left eye. Adalimumab may be associated with optic neuropathy; providers prescribing TNF inhibitors should be aware of optic neuropathy as a potential complication.