Pharmacokinetics of genistein distribution in blood and retinas of diabetic and non-diabetic rats.

Genistein, a natural tyrosine kinase inhibitor, may act as an intraocular antiangiogenic agent. Its therapeutical use, however, is limited by its nonlinear pharmacokinetics. We aimed to determine genistein's kinetics and retinal tissue distributions in normal and diabetic rats. We developed an isocratic, reverse-phase C18 HPLC system to measure genistein concentration in blood and retinas of streptozotocin (65 mg/kg IV)-diabetic and non-diabetic rats receiving two types of genistein-rich diet (150 and 300 mg/kg) for ten days. Genistein's decay exhibited a two-compartmental open model. Half-lives of distribution and elimination were 2.09 and 71.79 min, with no difference between groups. Genistein steady-state concentration in blood for 150 and 300 mg/kg diet did not differ between diabetic (0.259 ± 0.07 and 0.26 ± 0.06 µg/ml) and non-diabetic rats (0.192 ± 0.05 and 0.183 ± 0.09 µg/ml). In retina, genistein concentration was significantly higher in diabetic rats (1.05 ± 0.47 and 0.997 ± 0.47 µg/gm wt. vs. 0.087 ± 0.11 and 0.314 ± 0.18 µg/gm wt., p < 0.05). The study determined that increasing genistein dose did not change its bioavailability, perhaps due to the poor aqueous solubility. The retina's increased genistein could be due to increased permeability of blood-retinal barrier that occurs early in diabetes.

¿Mejora la aproximación físico-química de Stewart-Fencl la valoración del equilibrio ácido-base en pacientes estables en hemodiafiltración? / Does Stewart-Fencl approach improve the evaluation of acidbase status in stable patients on hemodiafiltration?

Introducción: la evaluación del equilibrio ácido-base se basa en la ecuación de Henderson-Hasselbach. En 1983, P. Stewart desarrolló un análisis cuantitativo del equilibrio ácido-base en el que muestra un sistema con unas variables independientes entre las que se incluyen pCO2, diferencia iónica fuerte medida (SIDm), es decir, la diferencia entre la suma de cationes fuertes (Na+, K+, Ca++, Mg++) y la suma de aniones fuertes (Cl–, lactato) y la concentración total de todos los aniones débiles no volátiles (ATot), cuyos principales representantes son el fósforo inorgánico (P–) y la albúmina (Albúm.–). El objetivo de este estudio es evaluar desde ambas perspectivas el equilibrio ácido-base en pacientes en hemodiafiltración (HDF) crónica. Material y métodos: se estudian 35 pacientes (24 hombres y 11 mujeres, con una edad media de 67,2 ± 15,7 años y con un peso seco de 72,8 ± 19,2 kg. La duración media de la hemodiálisis (HD) fue de 253,6 ± 40,5 minutos. Se analizan los parámetros gasométricos (pH, pCO2, HCO3–y exceso de bases) y Na+, K+, Cl–, Ca++, Mg++ y lactato. Se calcularon la SIDm, la SIDe mediante la fórmula de Figge (1.000 x 2,46–11 x pCO2 /[10 – pH] + Albúm. g/dl x [0,123 x pH –0,631] + P en mmol/l x [0,309 x pH –0,469)] y gap del SID (SIDm-SIDe). Resultados: el pH pre-HD fue de 7,36 ± 0,08 y el pH post-HD de 7,44 ± 0,08 (p <0,001). No se apreciaron diferencias significativas entre pCO2 pre y post-HD. El HCO3 – y el exceso de bases se incrementaron durante la sesión (p <0,001). La SIDm descendió de manera significativa de 46,2 ± 2,9 preHD a 45 ± 2,3 post-HD (p <0,05). Por el contrario, la SIDe se elevó de 38,5 ± 3,8 a 42,9 ± 3,1 (p <0,001). El anion gap descendió de 18,6 ± 3,8 pre-HD a 12,8 ± 2,8 Eq/l post-HD (p <0,001) y el gap del SID de 7,6 ± 3 a 2,1 ± 2 (p <0,001). Se apreció una correlación entre el anion gap y el gap-SID tanto antes como después de la HDF. Asimismo, se apreció una correlación significativa entre el ?? exceso de bases y ?? del gap-SID. Conclusión: en conclusión, la aproximación físico-química de Stewart-Fencl no mejora la valoración del equilibrio ácido-base en pacientes en HDF crónica. En presencia de normocloremia la SIDm no refleja el proceso alcalinizante de la sesión de hemodiálisis. Bajo esta perspectiva, la sesión de hemodiálisis se concibe como una retirada de aniones inorgánicos no metabolizables, en especial el sulfato. El espacio dejado por estos aniones es reemplazado por OH–y secundariamente por HCO3–. La única ventaja vendría dada por una mejor valoración de los aniones no medidos mediante el gap del SID, sin el efecto de la albúmina y el fosfato (AU)

Introduction: The traditional evaluation of acid-base status relies on the Henderson-Hasselbach equation. In 1983, an alternative approach, based on physical and chemical principles was proposed by P. Stewart. In this approach, plasma pH is determined by 3 independent variables: pCO2, Strong Ion Difference (SIDm), which is the difference between the strong cations (Na+, K+, Ca++, Mg++) and the strong anions (Cl–, lactate) and total plasma concentration of nonvolatile weak acids (ATot), mainly inorganic phosphate and albumin. Bicarbonate is considered a dependent variable. The aim of this study was to evaluate the acid-base status using both perspectives, physical chemical and traditional approach. Material and methods: we studied 35 patients (24 male; 11 female) on hemodiafiltration, mean age was 67.2 ± 15.7, 8 ± 19.2 kg. We analyzed plasma chemistry including pH, pCO2, HCO3–, base excess and Na+, K+, Cl–, Ca++, Mg++, lactate and SIDm. The SID estimated (SIDe) was calculated by Figge’s formula (1,000 x 2.46–11 x pCO2/[10 – pH] + Album g/dl x [0.123 x pH –0.631] + P in mmol/l0 x [0.309 x pH –0.469]) and Gap of the SID as the difference SIDm-SIDe. Results: pH preHD was 7.36 ± 0.08 and pH post-HD 7.44 ± 0.08 (p <0.001). There was no significant differences between pCO2 pre- and post-HD. HCO3– and base excess increased during the session (p <0.001). SIDm decreased from 46.2 ± 2.9 pre-HD to 45 ± 2.3 mEq/l post-HD (p <0.05). On the opposite, SIDe increased from 38.5 ± 3.8 to 429 ± 3.1 mEq/l (p <0.001). The Gap Anion descended from 18.6 ± 3.8 pre-HD to 12.8 ± 2.8 mEq/l post-HD (p <0.001) and the Gap of the SID 7.6 ± 3 to 2.1 ± 2 (p <0.001). Anion Gap correlated with the Gap-SID so much pre-HDF as pos-HDF. ?? Base excess correlated only with ?? of the Gap SID. Conclusion: Stewart-Fencl’s approach does not improve characterization of acid-base status in patients on chronic HDF. In presence of normocloremia the SIDm does not reflect the alkalinizing process of the session of hemodialysis. According this approach, hemodialysis therapy can be viewed as a withdrawal of inorganic anions, especially the sulphate. These anions are replaced by OH– and secondarily for HCO3–. The approach only improves the evaluation of unmeasured anions by the Gap of the SID, without the effect of albumin and phosphate (AU)

[Does Stewart-Fencl improve the evaluation of acid-base status in stable patients on hemodiafiltration?]. / ¿Mejora la aproximación físico-química de Stewart-Fencl la valoración del equilibrio ácido-base en pacientes estables en hemodiafiltración?

INTRODUCTION: The traditional evaluation of acid-base status relies on the Henderson-Hasselbach equation. In 1983, an alternative approach, based on physical and chemical principles was proposed by P. Stewart. In this approach, plasma pH is determined by 3 independent variables: pCO2, Strong Ion Difference (SIDm), which is the difference between the strong cations (Na +, K +, Ca ++, Mg ++) and the strong anions (Cl-, lactate) and total plasma concentration of nonvolatile weak acids (ATot), mainly inorganic phosphate and albumin. Bicarbonate is considered a dependent variable. The aim of this study was to evaluate the acid-base status using both perspectives, physical chemical and traditional approach. MATERIAL AND METHODS: We studied 35 patients (24 M; 11F) on hemodiafiltration, mean age was 67,2+/-15,7, 8+/-19,2 kg. We analyzed plasma chemistry including pH, pCO2, HCO3-, base excess and Na+, K+, Cl-, Ca++, Mg++, lactate and SIDm. The SID estimated (SIDe) was calculated by Figge's formula (1000 x 2.46E-11 x pCO2 / (10-pH) + Album gr/dl x (0.123 x pH-0.631) + P in mmol/l x (0.309 x pH-0.469) and Gap of the SID as the difference SIDm-SIDe. RESULTS: pH preHD was 7,36+/-0,08 and pH posHD 7,44+/-0,08 (p < 0.001). There was no significant differences between pCO2 pre and pos-HD. HCO3 - and base excess increased during the session (p < 0.001). SIDm decreased from 46,2+/-2,9 preHD to 45+/-2,3 mEq/l postHD (p < 0.05). On the opposite, SIDe increased from 38,5+/-3,8 to 42,9+/-3,1 mEq/l (p < 0.001). The Gap Anion descended from 18,6+/-3,8 preHD to 12,8+/-2,8 mEq/l mEq/l postHD (p < 0.001) and the Gap of the SID 7,6+/-3 to 2,1+/-2 (p < 0.001). Anion Gap correlated with the Gap-SID so much pre-HDF as pos-HDF. Delta Base excess correlated only with Delta of the Gap SID. CONCLUSION: Stewart-Fencl's approach does not improve characterization of acid-base status in patients on chronic HDF. In presence of normocloremia the SIDm does not reflect the alkalinizing process of the session of hemodialysis. According this approach, hemodialysis therapy can be viewed as a withdrawal of inorganic anions, especially the sulphate. These anions are replaced by OH - and secondarily for HCO3-. The approach only improves the evaluation of unmeasured anions by the Gap of the SID, without the effect of albumin and phosphate.

Repeated pancreatitis in peritoneal dialysis patient

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Fracaso renal agudo recurrente y reversible en un paciente afecto de hematuria y púrpura de Schönlein-Henoch / No disponible

La purpura de Schönlein-Henoch es una vasculitis de pequeño vaso caracterizada por el depósito de inmunocomplejos, principalmente IgA y C3. Es un trastorno multisistémico que afecta predominantemente la piel, las articulaciones, el tracto gastro-intestinal y los riñones. A nivel renal la expresión clínica varía desde una microhematuria aislada transitoria, hasta el cuadro de nefropatía rápidamente progresiva. El fracaso renal agudo es raro y suele verse asociado a episodios de hematuria macroscópica. Estos episodios suelen cursar con daño y obstrucción tubular por cilindros eritrocitarios. En este caso clínico describimos un paciente que sufrió dos episodios de fracaso renal agudo reversibles precedidos por brotes de hematuria macroscópica y que precisaron hemodiálisis durante cuatro y seis meses respectivamente (AU)

Sumary Henoch- Schönelin purpura (HSP) is a small vessel vasculitis characterized by deposition of inmune complexes, mainlyIg A and C3. It is a multisystem disorder affecting predominantly the skin, joints, gastrointestinal tract and kidneys. Clinical expression of nephritis ranges from transient isolated microscopic hematuria to rapidly progressive nephropathy. Acute renal failure is rare and is associated with episodes of macroscopic hematuria. These episodes are frequently associated with tubular damage and tubular obstruction by erythrocyte casts. We describe a patient with two episodes of acute renal failure after the onset of gross hematuria. Both episodes were reversible after six and four months respectively on hemodialysis (AU)

Switching from three times a week to short daily online hemodiafiltration: effects on acid-base balance.

AIMS: This study examines the effect of a change from the standard 4-5 hours 3 times a week of online hemodiafiltration (OL-HDF) to 2-2.5 hours daily (6 times a week) OL-HDF, on acid-base balance, and attempts assess the modifications of acid-base parameters, ionic concentration, and electrical charges of albumin and phosphate available for diffusion and convection mechanisms across the membrane and subsequent infusion. METHODS: In 18 patients on online HDF, blood gas, electrolytes (Na, K, Cl), lactate, phosphate, albumin, apparent strong ion difference (SIDa), effective strong ion difference (SIDe), strong ion gap (SIG), anion gap (AG), and bicarbonate and pH time-averaged concentration (TAC) and time-averaged deviation (TAD) variables were evaluated at baseline, and 1, 3, 6, 9, and 12 months after patients were switched to daily OL-HDF. Additionally, in 12 patients, the same parameters measured simultaneously at dialyzer inlet, outlet, and after reinfusion were studied. RESULTS: Throughout the study, weekly single-pool Kt/V, equilibrated Kt/V, and TAC urea remained constant. However, standard Kt/V increased and TAD urea decreased on daily OL-HDF. There were no statistical differences during the time span of 12 months in pH, cations (Na, K), anions (Cl, HCO3(-) AG, and lactate), or SIDa, SIDe, and SIG pre-HDF; while pH and HCO3(-) TAD decreased from 0.02 and 1.02 +/- 0.74 mEq/L, to 0.01 and 0.64 +/- 0.52 mEq/L, respectively (p<0.01). Net albumin charge and AG increased significantly at dialyzer outlet and decreased after reinfusion. CONCLUSIONS: We did not observe changes in the acid-base balance in patients who switched from 3 times a week to short daily OL-HDF. The main benefit observed was a lower pH and bicarbonate TAD. This shows a better physiology for daily OL-HDF.

Restoration of visual responses following transplantation of intact retinal sheets in rd mice.

PURPOSE: To correlate the functional outcomes with histologic findings following transplantation of fetal retinal sheets in rd mice, and to investigate the mechanisms of visual function restoration. METHODS: Twenty-one postnatal day 31-38 rd/rd (C3H/HeJ) mice were transplanted in one eye with retinal sheets (1.0 x 0.4 mm) obtained from embryonic day (E) 17 enhanced-green-fluorescent protein (eGFP) mice. Five mice underwent sham surgery without insertion of tissue. Four to five weeks after transplantation, visual responses to a light flash were recorded across the superior colliculus (SC) in seven eyes of seven transplanted mice that had clear corneas and lenses, and in all five sham surgery mice. Following the SC recording, the eyes were enucleated and processed for immunohistochemistry and examined using confocal microscopy. RESULTS: In three out of the seven eyes (43%), positive responses were recorded in the SC in an area topographically corresponding to the placement of the transplant in the host retina. No responses were recorded in the untreated eyes of 5-week-old and 9-week-old rd/rd mice, and in the 9-week-old sham surgery mice. In contrast, visual responses were recorded over the entire SC in normal eyes. The response onset latencies of the 3 transplanted mice with responses were similar to those of normal control mice. The organization of the graft did not appear to correlate as expected with the electrophysiology results, as eyes with well-organized, laminated grafts showed no response whereas the three light-responsive eyes had rosetted or disorganized grafts. All three light-responsive eyes demonstrated much higher levels of recoverin immunoreactivity in the host retina overlying the graft compared with untreated age-matched rd/rd mice. CONCLUSION: Restoration of the SC visual response does not appear to depend on a well-organized transplant in the rd mouse. Increased recoverin-staining in the host retina in light-responsive animals suggested that host cone rescue was the likely mechanism of vision restoration in this transplant model.

Visual task performance in blind humans with retinal prosthetic implants.

A prototype electronic retinal prosthesis has been tested in three subjects. The system features an implanted retinal stimulator and an external system for image acquisition, processing, and telemetry. The subjects in general performed better than chance on psychophysical tests involving object detection, object counting, object discrimination, and direction of movement.

Visual and electrical evoked response recorded from subdural electrodes implanted above the visual cortex in normal dogs under two methods of anesthesia.

Sensitive methods are required to record electrical evoked potentials over the visual cortex to evaluate the efficacy and safety of a retinal prosthesis before it can be implanted on the retinal surface of patients afflicted by outer retinal diseases. This study was designed to examine subdural electrodes as a mean to evaluate cortical evoked potentials in response to light and electrical stimulation of the retina in three dogs under two methods of anesthesia-halothane and propofol. Results showed that subdural electrodes could be stabilized over the visual cortex for several (3-5) months, and that they were 6.95 times more sensitive than subdermal electrodes in recording cortical visual evoked potentials (VEPs) and 4.31 times more sensitive in recording cortical electrical evoked potentials under both methods of anesthesia. The waveforms' shape changed for each electrode in the subdural array during 6/6 (100%) and 20/38 (52%) multi-channel recording sessions under halothane and propofol, respectively. This change could point to a cortical retinotopic organization versus hierarchical organization of different cortical areas for a given retinal stimulus. In summary, subdural electrodes show promising results for recording visual and electrical evoked responses (EERs) and thus for evaluation of the retinal prosthesis.

Morphometric analysis of the macula in eyes with geographic atrophy due to age-related macular degeneration.

PURPOSE: To evaluate the extent of neural cell death in eyes with geographic atrophy (GA). METHODS: Ten eyes with GA and five age-matched control eyes were selected for morphometric analysis. The nuclei of the ganglion cell, inner nuclear, and outer nuclear layers were counted in contiguous 100-microm segments from 1,500 microm nasal to 1,500 microm temporal to the fovea. RESULTS: The outer nuclear layer was most severely attenuated in eyes with GA, demonstrating a 76.9% reduction relative to control eyes (P < 0.0001). A significant loss of ganglion cells (by 30.7%) was also observed (P = 0.0008). There was no significant difference in the inner nuclear layer cells (P = 0.30). Among the GA eyes, the nuclei in all three layers were significantly reduced in segments in which the retinal pigment epithelium was completely absent (P

Morphometric analysis of the macula in eyes with disciform age-related macular degeneration.

PURPOSE: To evaluate the extent of neural cell death in eyes with disciform age-related macular degeneration. METHODS: Six eyes with disciform degeneration at various stages and five age-matched control eyes were selected for morphometric analysis using digitized light microscopic images. Disciform scars were classified as subneurosensory retinal, subretinal pigment epithelial, or combined lesions. The nuclei of the ganglion cell, inner nuclear, and outer nuclear layers were counted in contiguous 100 microm segments spanning a distance from 1,500 microm nasal to 1,500 microm temporal to the fovea. RESULTS: The outer nuclear layer was most severely attenuated in eyes with disciform scars, demonstrating a 69.4% reduction in cell number relative to control eyes. A loss in retinal ganglion cells (by 7.3%) and an increase in inner nuclear layer cells (by 10%) were observed, but these changes were not significant. Photoreceptor loss was most pronounced when the disciform scar was not covered by the retinal pigment epithelium. CONCLUSION: The nuclei of the outer nuclear layer are significantly attenuated in eyes with disciform age-related macular degeneration, while the ganglion cell and inner nuclear layers are relatively preserved. These findings suggest that replacement of outer nuclear function, by either retinal transplantation or implantation of the intraocular retinal prosthesis, might be a feasible therapeutic option for patients with this condition.

Diplopia after limited macular translocation surgery.

PURPOSE: Full macular translocation surgery relocates the fovea away from choroidal neovascularization, inducing significant postoperative torsional diplopia. In "limited macular translocation," a saline-induced retinal detachment is followed by scleral imbrication with mattress sutures and spontaneous retinal reattachment. In this study, diplopia was characterized in patients treated with limited macular translocation. METHODS: Two surgeons performed retinal translocation surgery on 250 patients over an 18-month time span. The extent and direction of the retinal translocation, and the amount and location of scleral imbrication, were recorded. All patients complaining of diplopia were referred for ocular motility evaluation and treatment. RESULTS: Thirteen (5.2%) patients complained of occasional or constant diplopia. Imbricating sutures were placed supero-temporally in all cases. Inferior foveal translocation ranged from 200 to 2115 microm (median, 1750 microm). Visual acuity ranged from 20/40 to 20/400 in the operated eye. Prism-and-cover testing underestimated the strabismus when compared with subjective testing. In 3 patients, there was no shift on alternate-cover testing despite binocular diplopia. Excyclotorsion ranged from 0 degrees to 16 degrees. Diplopia resolved in 10 cases with prism; 3 required an occlusive filter for distortion or aniseikonia. One patient underwent successful strabismus surgery to eliminate dependence on prism glasses. CONCLUSIONS: Limited macular translocation only rarely produces symptomatic diplopia. Suprisingly, traditional prism-and-cover testing does not reliably quantify the misalignment. This may result from the combination of a persistent macular scotoma and a repositioned fovea relative to the peripheral retina. Prism therapy is generally satisfactory in the absence of retinal distortion or aniseikonia.

Normalization of retinal vascular permeability in experimental diabetes with genistein.

PURPOSE: To study the effects of genistein, a tyrosine kinase inhibitor, on retinal vascular permeability in an experimental diabetic rat model. METHODS: Seventy-two rats were equally divided into four groups: (1) nondiabetic control group, (2) diabetic control group, (3) diabetic rats receiving 150 mg genistein/kg food, and (4) diabetic rats receiving 300 mg genistein/kg food. Diabetes was induced by streptozotocin injection in the three diabetic groups. Rats were fed diets with or without genistein and followed for 6 months. Retinal vascular permeability was assessed by measuring radiolabeled sucrose leakage into the retina and by Western blot analysis for total retinal albumin. Retinal phosphotyrosine levels and proliferating cell nuclear antigen (PCNA) were also evaluated by Western blot analysis. RESULTS: Diabetic control rats had markedly increased retinal vascular leakage of radiolabeled sucrose compared with nondiabetic control rats. Diabetic rats receiving oral genistein had significantly less retinal vascular leakage of radiolabeled sucrose than diabetic control rats in a dose-response fashion. Diabetic control rats had increased levels of phosphotyrosine, retinal albumin, and PCNA by Western blot analysis compared with nondiabetic control rats. Rats receiving 300 mg of genistein had decreased retinal albumin by Western blot analysis. Western blot analysis demonstrated a dose-response decrease in retinal phosphotyrosine levels and PCNA in genistein-treated diabetic rats compared with diabetic control rats. CONCLUSIONS: Long-term oral administration of genistein significantly inhibits retinal vascular leakage in experimentally induced diabetic rats. Tyrosine kinase inhibition may be a useful pharmacological approach for the treatment of diabetic-induced retinal vascular leakage.

Effective nasal limited macular translocation.

PURPOSE: To describe a case of effective foveal displacement toward the optic disk (nasal limited macular translocation) in a patient with a large subfoveal choroidal neovascularization secondary to age-related macular degeneration. METHODS: Case report. RESULTS: A 77-year-old white man presented with decreased vision of 20/400 due to subfoveal predominantly occult CNV secondary to age-related macular degeneration in the left eye. The CNV, measuring 9 Macular Photocoagulation Study disk areas in size, was centered temporally relative to the fovea with a minimum desired translocation of 650 microm for nasal macular translocation. The patient underwent nasal LMT with punctate retinotomy and temporal chorioscleral infolding, followed by postoperative head-positioning on his right side. Effective LMT was achieved with a postoperative nasal foveal displacement of 1400 microm. The entire CNV was ablated with laser photocoagulation postoperatively. His vision improved to 20/40 6 months postoperatively. CONCLUSION: Nasal LMT is feasible and may be considered in patients with subfoveal CNV centered temporally relative to the fovea.