Photodynamic therapy for macular choroidal osteoma

Purpose: To report a case of macular choroidal osteoma treated with photodynamic therapy. Observations: A 34-years old woman with decreased visual acuity in her left eye came to our observation for assessment of an amelanotic choroidal tumor in the left eye. On the basis of ophthalmoscopic and echographic features the tumor was diagnosed as choroidal osteoma. Imaging examination revealed subretinal fluid involving the foveal area associated with alterations of outer neuroepithelial layers and photoreceptors without evidence of choroidal neovascularization. Foveal sparing standard fluence rate photodynamic therapy was performed. After treatment, subretinal fluid reabsorption and visual acuity recovery was noted with progressive restoration of foveal architecture. Due to the relapse of fluid and visual impairment, 1 year after treatment, a second PDT session was made using the same parameters and protocol of treatment. Despite a complete subretinal fluid reabsorption and visual acuity recovery the second treatment was complicated by the development of subretinal fibrosis. Conclusions: PDT is effective to induce subretinal fluid reabsorption and visual recovery in choroidal osteoma located in the macular area. However, the risk of possible complications related to the treatment have to be considered.

Early hours in the development of high-altitude pulmonary edema: time course and mechanisms

Clinically evident high-altitude pulmonary edema (HAPE) is characterized by severe cyanosis, dyspnea, cough, and difficulty with physical exertion. This usually occurs within 1–2 days of ascent often with the additional stresses of any exercise and hypoventilation of sleep. The earliest events in evolving HAPE progress through clinically silent and then minimally recognized problems. The most important of these events involves an exaggerated elevation of pulmonary artery (PA) pressure in response to the ambient hypoxia. Hypoxic pulmonary vasoconstriction (HPV) is a rapid response with several phases. The first phase in both resistance arterioles and venules occurs within 5–10 min. This is followed by a second phase that further raises PA pressure by another 100% over the next 2–8 h. Combined with vasoconstriction and likely an unevenness in the regional strength of HPV, pressures in some microvascular regions with lesser arterial constriction rise to a level that initiates greater filtration of fluid into the interstitium. As pressures continue to rise local lymphatic clearance rates are exceeded and interstitial fluid begins to accumulate. Beyond elevation of transmural pressure gradients there is a dynamic noninjurious relaxation of microvascular and epithelial cell-cell contacts and an increase in transcellular vesicular transport which accelerate leakage. At some point with further pressure elevation, damage occurs with breaks of the barrier and bleeding into the alveolar space, a late-stage situation termed capillary stress failure. Earlier before there is fluid accumulation, alveolar hypoxia and hyperventilation-induced hypocapnia reduce the capacity of the alveolar epithelium to reabsorb sodium and water back into the interstitial space. More modest ascent which slows the rate of rise in PA pressure and allows for adaptive remodeling of the microvasculature, drugs which lower PA pressure, and those that can enhance fluid reabsorption will all forestall the deleterious early rise of microvascular pressures and diminished active alveolar fluid reabsorption that precede and underlie the development of HAPE.

Regulation of fluid reabsorption in rat or mouse proximal renal tubules by asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase 1

Nitric oxide prevents hypertension yet enhances proximal tubule Na+ reabsorption. Nitric oxide synthase is inhibited by asymmetric dimethylarginine (ADMA) that is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) whose type 1 isoform is expressed abundantly in the proximal tubule (PT). We hypothesize that ADMA metabolized by DDAH-1 inhibits fluid reabsorbtion (Jv) by the proximal tubule. S2 segments of the PT were microperfused between blocks in vivo to assess Jv in anesthetized rats. Compared with vehicle, microperfusion of ADMA or Nω-nitro-l-arginine methyl ester (l-NAME) in the proximal tubule reduced Jv dose dependently. At 10−4 mol/l both reduced Jv by ~40% (vehicle: 3.2 ± 0.7 vs. ADMA: 2.1 ± 0.5, P < 0.01 vs. l-NAME: 1.9 ± 0.4 nl·min−1·mm−1, P < 0.01; n = 10). Selective inhibition of DDAH-1 in rats with intravenous L-257 (60 mg/kg) given 2 h before and L-257 (10−5 mol/l) perfused in the proximal tubule for 5 min reduced Jv by 32 ± 4% (vehicle: 3.2 ± 0.5 vs. L-257: 2.2 ± 0.5 nl·min−1·mm−1; P < 0.01) and increased plasma ADMA by ≈50% (vehicle: 0.46 ± 0.03 vs. L-257: 0.67 ± 0.03 µmol/l, P < 0.0001) without changing plasma symmetric dimethylarginine. Compared with nontargeted control small-interference RNA, knock down of DDAH-1 in mice by 60% with targeted small-interference RNAs (siRNA) reduced Jv by 29 ± 5% (nontargeted siRNA: 2.8 ± 0.20 vs. DDAH-1 knockdown: 1.9 ± 0.31 nl·min−1·mm−1, P < 0.05). In conclusion, fluid reabsorption in the proximal tubule is reduced by tubular ADMA or by blocking its metabolism by DDAH-1. L-257 is a novel regulator of proximal tubule fluid reabsorption.

Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility

Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.

Abstract P269: Sodium Transporter Profile in Mice Lacking AT1A Receptors in the Renal Proximal Tubule

We have reported that mice lacking AT1A receptors (KO) in renal proximal tubule (PT) have 10 mmHg lower baseline BP and less PT fluid reabsorption than wild type (WT). We tested the hypothesis that the lower BP is associated with less abundant renal Na transporters or regulators. Homogenates of renal cortex and medulla (n=6/group) were prepared and 1 and 1/2 protein amounts of each subjected to immunoblot analysis with specific antibodies and quantitated. Results for cortex and medulla, displayed as mean +/- SEM, normalized to mean abundance of WT=1 (*p <0.05), are summarized in figures. In KO vs. WT abundance of PT NHE3, the associated motor myosin VI, the paracellular NaCl transporter claudin 2, and the Na-HCO3 transporter NBCe1 are lower in KO; in the thick ascending limb (TAL) NKCC2 and its associated kinase SPAK are less abundant, and there is a tendency for lower DCT NCC and CCD ENaC in KO. The results support our hypothesis and suggest that KO of PT AT1R reduces transport routes not only in the PT but beyond the PT, in spite of increased volume flow from PT and lower BP.

Intracranial Hypertension as an Acute Complication of Aseptic Meningoencephalitis with Leptomeningeal Contrast Enhancement on FLAIR MRI

We report a case of a 19-year-old woman who developed intracranial hypertension as an unusual clinical complication of severe aseptic meningoencephalitis probably due to a diminished cerebrospinal fluid reabsorption capacity or leptomeningeal transudation as a consequence of blood-brain barrier dysfunction. These severe inflammatory changes were accompanied by prominent leptomeningeal contrast enhancement best visualized on fluid-attenuated inversion recovery magnetic resonance imaging. In such a prolonged course, a continuous lumbar drainage might be a temporary option to provide rapid symptom relief to the patient.