Daniel Barthelmes

Nocturnal periodic breathing during acclimatization at very high altitude at Mount Muztagh Ata (7,546 m)

RATIONALE Quantitative data on ventilation during acclimatization at very high altitude are scant. Therefore, we monitored nocturnal ventilation and oxygen saturation in mountaineers ascending Mt. Muztagh Ata (7,546 m). OBJECTIVES To investigate whether periodic breathing persists during prolonged stay at very high altitude. METHODS A total of 34 mountaineers (median age, 46 yr; 7 women) climbed from 3,750 m within 19-20 days to the summit at 7,546 m. During ascent, repeated nocturnal recordings of calibrated respiratory inductive plethysmography, pulse oximetry, and scores of acute mountain sickness were obtained. MEASUREMENTS AND MAIN RESULTS Nocturnal oxygen saturation decreased, whereas minute ventilation and the number of periodic breathing cycles increased with increasing altitude. At the highest camp (6,850 m), median nocturnal oxygen saturation, minute ventilation, and the number of periodic breathing cycles were 64%, 11.3 L/min, and 132.3 cycles/h. Repeated recordings within 5-8 days at 4,497 m and 5,533 m, respectively, revealed increased oxygen saturation, but no decrease in periodic breathing. The number of periodic breathing cycles was positively correlated with days of acclimatization, even when controlled for altitude, oxygen saturation, and other potential confounders, whereas symptoms of acute mountain sickness had no independent effect on periodic breathing. CONCLUSIONS Our field study provides novel data on nocturnal oxygen saturation, breathing patterns, and ventilation at very high altitude. It demonstrates that periodic breathing increases during acclimatization over 2 weeks at altitudes greater than 3,730 m, despite improved oxygen saturation consistent with a progressive increase in loop gain of the respiratory control system. Clinical trial registered with www.clinicaltrials.gov (NCT00514826).

Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m.

Investigations studying the secretion of EPO (erythropoietin) in response to acute hypoxia have produced mixed results. Further, the errors associated with the various methods used to determine EPO are not well documented. The purpose of the current study was to determine the EPO response of 17 trained male subjects to either an acute bout of normobaric hypoxia (Hy; n = 10) or normoxia (Con; n = 7). A secondary aim was to determine the error associated with the measurement of EPO. After baseline tests, the treatment group (Hy) underwent a single bout of hypoxic exposure (F(I(O(2))) approximately 0.148; 3100 m) consisting of a 90-min rest period followed by a 30-min exercise phase (50% V(O)(2max)). Venous blood samples were drawn pre (0 min) and post (120 min) each test to assess changes in plasma EPO (DeltaEPO). The control (Con) group was subjected to the same general experimental design, but placed in a normoxic environment (F(I(O(2))) approximately 0.2093). The Hy group demonstrated a mean increase in EPO [19.3 (4.4) vs. 24.1 (5.1) mU/mL], p < 0.04, post 120 min of normobaric hypoxia. The calculated technical error of measurement for EPO was 2.1 mU/mL (9.8%). It was concluded that an acute bout of hypoxia, has the capacity to elevate plasma EPO. This study also demonstrates that the increase in EPO accumulation was 2 times greater than the calculated measurement of error.

Familial Asymptomatic Macular Telangiectasia Type 2

OBJECTIVE To report findings in asymptomatic family members of patients with macular telangiectasia type 2. DESIGN Prospective, observational, cross-sectional case series. PARTICIPANTS Four patients with symptomatic macular telangiectasia type 2 (index patients) and 5 relatives, including 2 sets of monozygotic twins. METHODS Screening of family members of participants in a non-interventional natural history study of macular telangiectasia type 2. Ophthalmologic examination included best-corrected visual acuity testing, fundus biomicroscopy, fluorescein angiography (FA), optical coherence tomography (OCT), and fundus autofluorescence (FAF) imaging. MAIN OUTCOME MEASURES Evidence for macular telangiectasia type 2 in any of the imaging methods used and visual function of the family members studied. RESULTS In the first family, 2 of 3 daughters of a severely affected 68-year-old woman had features of macular telangiectasia type 2. Although one of the daughters was diagnosed by biomicroscopic examination, the second daughter was diagnosed only by subtle changes on OCT and FAF imaging. Both affected daughters were asymptomatic and were unaware that they had the condition. In the second family, clinical examination showed that the 60-year-old brother of the 75-year-old index patient obviously was affected, despite a lack of any subjective visual dysfunction. The 65-year-old monozygotic twin of the third index patient showed a slight retinal thinning within a small area temporal to the foveola in both eyes as well as minor staining on FA and a subtle monocular loss of macular pigment. The 56-year-old asymptomatic monozygotic twin of the last proband had opacification of the retina with leakage on FA in the right eye. The fellow eye was unremarkable except for an abnormal FAF signal that was present in both eyes. CONCLUSIONS Macular telangiectasia type 2 may be more common than previously assumed, but patients may not seek ophthalmic care if their visual function is normal. The study of these early, asymptomatic cases may yield valuable insights into the pathogenesis of the condition. Further research is warranted to determine whether there is an underlying, dominantly inherited genetic abnormality in macular telangiectasia type 2 of variable penetrance and expressivity.

New insights into ocular blood flow at very high altitudes

Little is known about the ocular and cerebral blood flow during exposure to increasingly hypoxic conditions at high altitudes. There is evidence that an increase in cerebral blood flow resulting from altered autoregulation constitutes a risk factor for acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) by leading to capillary overperfusion and vasogenic cerebral edema. The retina represents the only part of the central nervous system where capillary blood flow is visible and can be measured by noninvasive means. In this study we aimed to gain insights into retinal and choroidal autoregulatory properties during hypoxia and to correlate circulatory changes to symptoms of AMS and clinical signs of HACE. This observational study was performed within the scope of a high-altitude medical research expedition to Mount Muztagh Ata (7,546 m). Twenty seven participants underwent general and ophthalmic examinations up to a maximal height of 6,800 m. Examinations included fundus photography and measurements of retinal and choroidal blood flow, as well as measurement of arterial oxygen saturation and hematocrit. The initial increase in retinal blood velocity was followed by a decrease despite further ascent, whereas choroidal flow increase occurred later, at even higher altitudes. The sum of all adaptational mechanisms resulted in a stable oxygen delivery to the retina and the choroid. Parameters reflecting the retinal circulation and optic disc swelling correlated well with the occurrence of AMS-related symptoms. We demonstrate that sojourns at high altitudes trigger distinct behavior of retinal and choroidal blood flow. Increase in retinal but not in choroidal blood flow correlated with the occurrence of AMS-related symptoms.

Quantitative OCT Analysis of Idiopathic Perifoveal Telangiectasia

PURPOSE To identify and quantitate specific changes in optical coherence tomography (OCT) images of patients with type 2 idiopathic perifoveal telangiectasia (IPT). METHODS In a prospectively designed, observational, case-control study, 28 eyes of 14 consecutive patients with IPT were examined with OCT and compared with eyes of 14 unaffected control subjects. Light reflectivity profiles of raw scan data of OCT images were quantitatively analyzed for differences in distance between different retinal reflectivity layers and their respective reflectivities. Maculae were examined in four separate regions: (1) central fovea, (2) nasal perifovea, (3) temporal perifovea, and (4) outside the fovea. RESULTS Retinal thinning, shortening of the photoreceptor outer segments and loss of reflectivity of the photoreceptor ellipsoid region were found in the central foveal region as well as the nasal and temporal perifoveal regions in eyes with IPT. In addition, increased reflectivity of the outer nuclear layer was found in a sharply demarcated area of the inferotemporal perifoveal region in all affected eyes. Retinal tissue located more than 2000 mum away from the foveola was indistinguishable from that in normal eyes. CONCLUSIONS Quantitative OCT analysis shows unique and specific changes in the photoreceptors of the central macula in IPT which can be detected from first clinical presentation. These changes may be of use as an additional diagnostic tool. Correlation of the findings in the outer nuclear layer with histologic studies may help identify the nature of the reflectivity increase and define more clearly the type of damage sustained by the photoreceptors in this condition.

A new method to monitor visual field defects caused by photoreceptor degeneration by quantitative optical coherence tomography.

PURPOSE To correlate the dimension of the visual field (VF) tested by Goldman kinetic perimetry with the extent of visibility of the highly reflective layer between inner and outer segments of photoreceptors (IOS) seen in optical coherence tomography (OCT) images in patients with retinitis pigmentosa (RP). METHODS In a retrospectively designed cross-sectional study, 18 eyes of 18 patients with RP were examined with OCT and Goldmann perimetry using test target I4e and compared with 18 eyes of 18 control subjects. A-scans of raw scan data of Stratus OCT images (Carl Zeiss Meditec, AG, Oberkochen, Germany) were quantitatively analyzed for the presence of the signal generated by the highly reflective layer between the IOS in OCT images. Starting in the fovea, the distance to which this signal was detectable was measured. Visual fields were analyzed by measuring the distance from the center point to isopter I4e. OCT and visual field data were analyzed in a clockwise fashion every 30 degrees , and corresponding measures were correlated. RESULTS In corresponding alignments, the distance from the center point to isopter I4e and the distance to which the highly reflective signal from the IOS can be detected correlate significantly (r = 0.75, P < 0.0001). The greater the distance in VF, the greater the distance measured in OCT. CONCLUSIONS The authors hypothesize that the retinal structure from which the highly reflective layer between the IOS emanates is of critical importance for visual and photoreceptor function. Further research is warranted to determine whether this may be useful as an objective marker of progression of retinal degeneration in patients with RP.

The PROM1 Mutation p.R373C Causes an Autosomal Dominant Bull's Eye Maculopathy Associated with Rod, Rod–Cone, and Macular Dystrophy

PURPOSE To characterize in detail the phenotype of five unrelated families with autosomal dominant bulls eye maculopathy (BEM) due to the R373C mutation in the PROM1 gene. METHODS Forty-one individuals of five families of Caribbean (family A), British (families B, D, E), and Italian (family C) origin, segregating the R373C mutation in PROM1, were ascertained. Electrophysiological assessment, fundus autofluorescence (FAF) imaging, fundus fluorescein angiography (FFA), and optical coherence tomography (OCT) were performed in available subjects. Mutation screening of PROM1 was performed. RESULTS The R373C mutant was present heterozygously in all affected patients. The age at onset was variable and ranged between 9 and 58 years, with most of the individuals presenting with reading difficulties. Subjects commonly had a mild to moderate reduction in visual acuity except for members of family C who experienced markedly reduced central vision. The retinal phenotype was characterized by macular dystrophy, with retinal pigment epithelial mottling in younger subjects, progressing to typical BEM over time, with the development of macular atrophy in older patients. In addition, all members of family C had typical features of RP. The electrophysiological findings were variable both within and between families. CONCLUSIONS Mutations in PROM1 have been described to cause a severe form of autosomal recessive RP in two families of Indian and Pakistani descent. The results of this study have demonstrated that a distinct redundant PROM1 mutation (R373C) can also produce an autosomal dominant, fully penetrant retinopathy, characterized by BEM with little inter- and intrafamilial variability, and retinal dystrophy with variable rod or rod-cone dysfunction and marked intra- and interfamilial variability, ranging from isolated maculopathy without generalized photoreceptor dysfunction to maculopathy associated with very severe rod-cone dysfunction.

High Incidence of Optic Disc Swelling at Very High Altitudes

OBJECTIVES To determine the incidence of optic disc swelling as a possible indicator of cerebral edema in a large group of healthy mountaineers exposed to very high altitudes and to correlate these findings with various clinical and environmental factors and occurrence of acute mountain sickness and high-altitude cerebral edema. METHODS This multidisciplinary, prospective, observational cohort study was performed in 2005 within the scope of a medical research expedition to Muztagh Ata (7546 m [24,751 ft]) in Western Xinjiang Province, China. Twenty-seven healthy mountaineers aged 26 to 62 years participated. Medical examinations were performed in Switzerland 1 month before and 4 1/2 months after the expedition. Ophthalmologic examinations were performed at 4 high camps (maximum elevation, 6865 m [22,517 ft]). Optic disc status was documented using digital photography. Further assessments included arterial oxygen saturation and cerebral acute mountain sickness scores. RESULTS Sixteen of 27 study subjects (59%) exhibited optic disc swelling during their stay at high altitudes, with complete regression on return to lowlands. Significant correlation was noted between optic disc swelling and lower arterial oxygen saturation (odds ratio, 0.86 per percentage of arterial oxygen saturation; 95% confidence interval, 0.81-0.92; P < .001), younger age (odds ratio, 0.95 per year; 95% confidence interval, 0.90-0.99; P = .03), and higher cerebral acute mountain sickness scores (odds ratio, 2.32 per 0.1 point; 95% confidence interval, 1.48-3.63; P < .001). CONCLUSION Optic disc swelling occurs frequently in high-altitude climbers and is correlated with peripheral oxygen saturation and symptoms of acute mountain sickness. It is most likely the result of hypoxia-induced brain volume increase.

Therapeutic strategy to rescue mutation-induced exon skipping in rhodopsin by adaptation of U1 snRNA

Retinitis pigmentosa (RP) is a degenerative retinopathy leading to visual impairment in more than 1.5 million patients worldwide. Splice site (SS) mutations cause various diseases including RP. Most exonic donor splice‐site (DS) mutations are reported at the last nucleotide of an exon and over 95% of them are predicted to result in missplicing. A novel human mutation at the last nucleotide of exon 4 in rhodopsin (RHO, c.936G>A) is shown to generate two misspliced transcripts in COS 7 cells and retinal explants. One of these transcripts skips exon 4 whereas the other activates a cryptic DS. Both are predicted to result in truncated RHO, explaining the pathogenic mechanism underlying the patients RP phenotype. U1 snRNA‐mediated DS recognition is a key step in the splicing process. As a therapeutic strategy, U1 snRNAs were adapted to the novel RHO mutation and tested for its potential to reverse missplicing. The rescue efficiency for misspliced transcripts of RHO was examined by quantitative RT‐PCR. Using mutation‐adapted U1 snRNA, we observed significantly reduced exon skipping that reached wild‐type levels. Nevertheless, activation of the cryptic splice site (CS) was still detected. To test the feasibility of the strategy for mutations that only cause exon skipping, we inactivated the CS. Indeed, adapted U1 snRNA was able to rescue almost 90% of misspliced transcripts. This study shows that modified U1 snRNAs constitute a promising therapeutic strategy to treat DS mutations. Our findings have implications for various diseases caused by similar mutations. Hum Mutat 0, 1–10, 2008,

Efficient capture of high-quality data on outcomes of treatment for macular diseases: The fight retinal blindness! project

Purpose: To describe the development of a web-based high-quality data collection tool to track the outcomes of treatment of macular disease in routine practice. Methods: Testing of a larger data collection tool established which fields a clinician would reliably fill out. The program, which was developed using freely available software, consists of modules interacting with a core system. The module for neovascular age-related macular degeneration is described here. Results: Data for initial visits can be entered within 30 seconds, 15 seconds for follow-up visits. Fifteen centers from Australia, New Zealand, and Switzerland are currently contributing data. Finalized data from 2,052 eyes of 1,693 participants dating from January 2006 were analyzed. Median (25th and 75th percentiles) visual acuity at the index visit was 55 (41, 68) logarithm of the minimum angle of resolution letters with the following lesion types: minimally classic 17.2%, predominantly classic 24.6%, occult 52.0%, idiopathic polypoidal choroidal vasculopathy 1.2%, and retinal angiomatous proliferation 3.2%. Conclusion: This software tool will facilitate the collection of large amounts of data on the routine use of treatments of neovascular age-related macular degeneration. This will allow us to analyze important potentially modifiable variables, such as the effect of different treatment patterns on visual outcomes, and to evaluate new treatments as they are introduced into practice.