Demosthenes G. Papamatheakis

Phacoemulsification and goniosynechialysis in the management of unresponsive primary angle closure.

Purpose:To evaluate the effectiveness of phacoemulsification and goniosynechialysis (PEGS) in managing acute and subacute primary angle closure unresponsive to conventional therapy. Materials and Methods:Retrospective series of patients of six glaucoma-trained surgeons with primary angle closure that did not respond to medical management, Nd:YAG laser peripheral iridotomy, or argon laser peripheral iridoplasty. Results:A total of twenty-one patients with an average age of 65.6 years were included. Underlying mechanism of angle closure included pupillary block (n = 18) and plateau iris (n = 3). Average intraocular pressure (IOP) immediately prior to PEGS was 40.7 mm Hg, and mean follow-up time after PEGS was 11.7 months. PEGS decreased mean IOP by 25 mm Hg (62%), and mean number of medications from 3.8 pre-surgery to 1.7 post-surgery (55%). Mean LogMar visual acuity improved after PEGS, from 0.64 to 0.44 (Paired t test t = 4.120 P = 0.001). Subsequent trabeculectomy was necessary in one case (5%). Conclusions:Phacoemulsification with goniosynechialysis may be an effective treatment option for primary angle closure unresponsive to conventional therapy.

Relationship between travoprost and central corneal thickness in ocular hypertension and open-angle glaucoma.

Purpose: To evaluate whether treatment with travoprost, an F2a prostaglandin analog, affects central corneal thickness (CCT) and whether intraocular pressure (IOP) response to the medication is related to baseline CCT. Methods: This was a prospective, interventional, nonrandomized, nonconsecutive, clinical trial. In this multicenter study, 379 total patients, 220 with newly or previously diagnosed open-angle glaucoma (OAG), 141 with ocular hypertension (OHT), and 18 unspecified, were recruited from 15 Canadian sites. IOP and CCT assessments were performed at baseline and 6 weeks after treatment with travoprost. Patients on IOP-lowering therapy at the time of enrollment were washed out for 4 weeks before baseline examinations. IOP was measured with Goldmann tonometers and CCT with Accutome IV pachymeters. Statistical analysis was performed with S-PLUS software. Results: Posttherapy mean IOP decreased by 6.31 mm Hg or 24.4% (P < 0.001), and regression analysis indicated relatively greater IOP reduction in patients with higher pretherapy IOP (slope = 0.64; 95% CI, 0.54-0.76). Mean CCT decreased by 6.9 μm (P < 0.001). IOP reduction was not related to CCT reduction (slope = 0.253; 95% CI, −0.232 to 0.739; P = 0.305). Percent IOP decrease was not related to baseline CCT (slope = −0.02; 95% CI, -0.06 to 00.02; P = 0.33) in the total study sample. When OHT and OAG groups were considered separately, the OAG patients had less percent IOP decrease with thicker baseline CCT (slope = −0.067; 95% CI, −0.13 to −0.004; P = 0.037). Conclusions: Treatment with travoprost decreased IOP significantly and was associated with CCT thinning, which had little or no effect on actual IOP decrease. In the OAG group, IOP decrease was found to be statistically smaller in patients with thicker corneas.

Early biomarker activity in severe sepsis and septic shock and a contemporary review of immunotherapy trials: not a time to give up, but to give it earlier.

ABSTRACT Improving time to diagnosis and intervention has positively impacted outcomes in acute myocardial infarction, stroke, and trauma through elucidating the early pathogenesis of those diseases. This insight may partly explain the futility of time-insensitive immunotherapy trials for severe sepsis and septic shock. The aim of this study was to examine the early natural history of circulatory biomarker activity in sepsis, relative to previous animal and human outcome trials. We conducted a literature search using PubMed, MEDLINE, and Google Scholar to identify outcome trials targeting biomarkers with emphasis on the timing of therapy. These findings were compared with the biomarker activity observed over the first 72 h of hospital presentation in a cohort of severe sepsis and septic shock patients. Biomarker levels in animal and human research models are elevated within 30 min after exposure to an inflammatory septic stimulus. Consistent with these findings, the biomarker cascade is activated at the most proximal point of hospital presentation in our patient cohort. These circulatory biomarkers overlap; some have bimodal patterns and generally peak between 3 and 36 h while diminishing over the subsequent 72 h of observation. When this is taken into account, prior outcome immunotherapy trials have generally enrolled patients after peak circulatory biomarker concentrations. In previous immunotherapy sepsis trials, intervention was delayed after the optimal window of peak biomarker activity. As a result, future studies need to recalibrate the timing of enrollment and administration of immunotherapy agents that still may hold great promise for this deadly disease.

Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs

Exposure to chronic hypoxia during gestation predisposes infants to neonatal pulmonary hypertension, but the underlying mechanisms remain unclear. Here, we test the hypothesis that moderate continuous hypoxia during gestation causes changes in the rho-kinase pathway that persist in the newborn period, altering vessel tone and responsiveness. Lambs kept at 3,801 m above sea level during gestation and the first 2 wk of life were compared with those with gestation at low altitude. In vitro studies of isolated pulmonary arterial rings found a more forceful contraction in response to KCl and 5-HT in high-altitude compared with low-altitude lambs. There was no difference between the effects of blockers of various pathways of extracellular Ca(2+) entry in low- and high-altitude arteries. In contrast, inhibition of rho-kinase resulted in significantly greater attenuation of 5-HT constriction in high-altitude compared with low-altitude arteries. High-altitude lambs had higher baseline pulmonary artery pressures and greater elevations in pulmonary artery pressure during 15 min of acute hypoxia compared with low-altitude lambs. Despite evidence for an increased role for rho-kinase in high-altitude arteries, in vivo studies found no significant difference between the effects of rho-kinase inhibition on hypoxic pulmonary vasoconstriction in intact high-altitude and low-altitude lambs. We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin.

Long-Term Maternal Hypoxia The Role of Extracellular Ca2+ Entry During Serotonin-Mediated Contractility in Fetal Ovine Pulmonary Arteries

Antenatal maternal long-term hypoxia (LTH) can alter serotonin (5-HT) and calcium (Ca2+) signaling in fetal pulmonary arteries (PAs) and is associated with persistent pulmonary hypertension of the newborn (PPHN). In humans, the antenatal maternal hypoxia can be secondary to smoking, anemia, and chronic obstructive pulmonary disorders. However, the mechanisms of antenatal maternal hypoxia-related PPHN are unresolved. Because both LTH and 5-HT are associated with PPHN, we tested the hypothesis that antenatal maternal LTH can increase 5-HT-mediated PA contraction and associated extracellular Ca2+ influx through L-type Ca2+ channels (CaL), nonselective cation channels (NSCCs), and reverse-mode sodium–calcium exchanger (NCX) in the near-term fetus. We performed wire myography and confocal-Ca2+ imaging approaches on fetal lamb PA (∼140 days of gestation) from normoxic ewes or those acclimatized to high-altitude LTH (3801 m) for ∼110 days. Long-term hypoxia reduced the potency but not the efficacy of 5-HT-induced PA contraction. Ketanserin (100 nmol/L), a 5-HT2A antagonist, shifted 5-HT potency irrespective of LTH, while GR-55562 (1 µmol/L), a 5-HT1B/D inhibitor, antagonized 5-HT-induced contraction in normoxic fetuses only. Various inhibitors for CaL, NSCC, and reverse-mode NCX were used in contraction studies. Contraction was reliant on extracellular Ca2+ regardless of maternal hypoxia, NSCC was more important to contraction than CaL, and reverse-mode NCX had little or no role in contraction. Long-term hypoxia also attenuated the effects of 2-APB and flufenamic acid and reduced Ca2+ responses observed by imaging studies. Overall, LTH reduced 5HT1B/D function and increased NSCC-related Ca2+-dependent contraction in ovine fetuses, which may compromise pulmonary vascular function in the newborn.

Antenatal hypoxia and pulmonary vascular function and remodeling.

This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression.

Racial variability of glaucoma risk factors between African Caribbeans and Caucasians in a Canadian urban screening population.

BACKGROUND The significance of race in the development and progression of glaucoma remains controversial, although in most cases the evidence shows greater prevalence and progression of the disease in African American populations. The purpose of this study was to determine the impact of the African Caribbean race on the variability of risk factors for glaucoma in an urban Canadian screening population. STUDY DESIGN Population-based, cross-sectional study. PARTICIPANTS Participants with high risk for development of open-angle glaucoma. METHODS Participants underwent confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph),frequency-doubling technology (FDT) perimetry, and complete ophthalmic examination during a high-risk glaucoma screening clinic. Statistical analysis was performed comparing the data gathered from these tests in the different racial groups. Students t tests as well as Pearsons c2 tests were done. RESULTS Racial breakdown included 64 African Caribbeans (22%) and 224 Caucasians (78%). Racial groups had similar female/male ratios, but Caucasians were significantly older (66 [SD 12] years) than African Caribbeans (56 [SD12] years) ( p = 0.001). African Caribbeans had significantly higher intraocular pressure (IOP) ( p < 0.001); thinner central corneal thickness (CCT) ( p < 0.001); greater cup/disc ratio ( p = 0.016), disc area ( p < 0.001), cup area ( p = 0.002), and cup/disc area ratio ( p = 0.009); and smaller rim/disc area ratio ( p = 0.009). The latter optic disc parameter differences were not statistically different when corrected for disc area differences. CONCLUSIONS In this study, African Caribbeans in a Canadian urban setting were associated with increased risk factors for open-angle glaucoma development, including higher IOP and thinner CCT. The larger cup/disc and cup/disc area ratios of the African Caribbean group were directly correlated to disc area differences between the 2 groups.

Schistosomiasis-associated pulmonary hypertension

Schistosomiasis, a parasite-borne disease, is highly prevalent in Africa and Asia; it is estimated that close to 20 million people worldwide have a severe form of the disease. The chronic form can affect the gastrointestinal system and lead to hepatosplenic disease, and it may cause cardiopulmonary complications, including pulmonary hypertension. The exact pathogenesis of schistosomiasis-associated pulmonary hypertension (Sch-PH) remains unclear, although several mechanisms, including parasitic arterial embolization, pulmonary arteriopathy, and portopulmonary hypertension–like pathophysiology, have been suggested. The immunopathology of the disease is also unclear, although there are similarities with the immunology of idiopathic pulmonary arterial hypertension (PAH). Finally, the treatment of Sch-PH has not been well studied. There is some evidence on treating the underlying infection, with unclear effect on Sch-PH, and advanced PAH therapies are now being suggested, but more studies are needed to confirm their efficacy.

Prenatal programming of pulmonary hypertension induced by chronic hypoxia or ductal ligation in sheep

Pulmonary hypertension of the newborn is caused by a spectrum of functional and structural abnormalities of the cardiopulmonary circuit. The existence of multiple etiologies and an incomplete understanding of the mechanisms of disease progression have hindered the development of effective therapies. Animal models offer a means of gaining a better understanding of the fundamental basis of the disease. To that effect, a number of experimental animal models are being used to generate pulmonary hypertension in the fetus and newborn. In this review, we compare the mechanisms associated with pulmonary hypertension caused by two such models: in utero ligation of the ductus arteriosus and chronic perinatal hypoxia in sheep fetuses and newborns. In this manner, we make direct comparisons between ductal ligation and chronic hypoxia with respect to the associated mechanisms of disease, since multiple studies have been performed with both models in a single species. We present evidence that the mechanisms associated with pulmonary hypertension are dependent on the type of stress to which the fetus is subjected. Such an analysis allows for a more thorough evaluation of the disease etiology, which can help focus clinical treatments. The final part of the review provides a clinical appraisal of current treatment strategies and lays the foundation for developing individualized therapies that depend on the causative factors.

Depolarization-dependent contraction increase after birth and preservation following long-term hypoxia in sheep pulmonary arteries

Membrane depolarization is critical to pulmonary arterial (PA) contraction. Both L-type Ca2+ channels (CaL) and Rho-kinase are important signaling components of this process and mitochondrial and non-mitochondrial generated superoxides can be part of the signaling process. Maturation and long-term hypoxia (LTH) each can modify depolarization-dependent contraction and the role of superoxides. By the use of wire myography, we tested the hypothesis that maturation and LTH increase pulmonary arterial reactivity to high-K+-induced membrane depolarization through enhancements in the importance of CaL and Rho-kinase-dependent pathways. The data show that maturation, but not LTH, increases contraction to 125 mM KCl (high-K+) without altering the EC50. High-K+-dependent contraction was inhibited to a similar extent in fetal and adult PA by multiple CaL blockers, including 10 μM diltiazem, 10 μM verapamil, and 10 μM nifedipine. Postnatal maturation increased the role for 10 μM nifedipine-sensitive CaL, and decreased that for 10 μM Y-27632-sensitive Rho-kinase. In all groups, the combination of nifedipine and Y-27632 effectively inhibited high-K+ contraction. Tempol (3 mM) but not 100 μM apocynin slightly reduced contraction in arteries from fetal hypoxic and adult normoxic and hypoxic sheep, indicating a limited role for non-mitochondrial derived superoxide to high-K+-induced contraction. Western immunoblot for alpha smooth muscle actin indicated small increases in relative abundance in the adult. The data suggest that while CaL therapies more effectively vasodilate PA in adults and rho-kinase therapies are more effective in newborns, combination therapies would provide greater efficacy in both young and mature patients regardless of normoxic or hypoxic conditions.