Novel Photosensitizers Trigger Rapid Death of Malignant Human Cells and Rodent Tumor Transplants via Lipid Photodamage and Membrane Permeabilization

BACKGROUND: Apoptotic cascades may frequently be impaired in tumor cells; therefore, the approaches to circumvent these obstacles emerge as important therapeutic modalities. METHODOLOGY/PRINCIPAL FINDINGS: Our novel derivatives of chlorin e(6), that is, its amide (compound 2) and boronated amide (compound 5) evoked no dark toxicity and demonstrated a significantly higher photosensitizing efficacy than chlorin e(6) against transplanted aggressive tumors such as B16 melanoma and M-1 sarcoma. Compound 5 showed superior therapeutic potency. Illumination with red light of mammalian tumor cells loaded with 0.1 µM of 5 caused rapid (within the initial minutes) necrosis as determined by propidium iodide staining. The laser confocal microscopy-assisted analysis of cell death revealed the following order of events: prior to illumination, 5 accumulated in Golgi cysternae, endoplasmic reticulum and in some (but not all) lysosomes. In response to light, the reactive oxygen species burst was concomitant with the drop of mitochondrial transmembrane electric potential, the dramatic changes of mitochondrial shape and the loss of integrity of mitochondria and lysosomes. Within 3-4 min post illumination, the plasma membrane became permeable for propidium iodide. Compounds 2 and 5 were one order of magnitude more potent than chlorin e(6) in photodamage of artificial liposomes monitored in a dye release assay. The latter effect depended on the content of non-saturated lipids; in liposomes consisting of saturated lipids no photodamage was detectable. The increased therapeutic efficacy of 5 compared with 2 was attributed to a striking difference in the ability of these photosensitizers to permeate through hydrophobic membrane interior as evidenced by measurements of voltage jump-induced relaxation of transmembrane current on planar lipid bilayers. CONCLUSIONS/SIGNIFICANCE: The multimembrane photodestruction and cell necrosis induced by photoactivation of 2 and 5 are directly associated with membrane permeabilization caused by lipid photodamage

Challenges in Diagnosis and Management of Previously Embolized Spinal Dural Arteriovenous Fistulae

Given the growing prevalence of initial endovascular treatment for type 1 spinal dural arteriovenous fistulae (dAVF), there are an increasing number of patients presenting with progressive symptoms related to recurrent previously embolized spinal dAVF. This study's goal was to identify demographic, clinical, and radiographic variables among patients who have failed embolization of type I spinal dAVF.A retrospective review of 24 consecutive surgeries for type I spinal dAVF performed by the senior author (A.D.L.) identified 5 patients who underwent open surgery for failed embolization. These 5 cases were reviewed for location of fistula, time from embolization to recurrence, preoperative functional status, fistulous point encountered at surgery, and clinical outcome of the patient at 3-month follow-up. A representative example case is reviewed in detail.The median age at time of recurrence was 63 years (range 51–73 years). The median timing of embolization to recurrence of neurologic symptoms was 5 months (range 1–54) and to surgery 7 months (range 2–60 months). The level of the spinal dAVF was most frequently at T12–L1 (n = 3). Spinal magnetic resonance arteriography led to localization of the spinal dAVF in 2 patients and spinal catheter angiogram in 3 cases. All patients had definitive radiographic cure of the dAVF at last clinical follow-up.The increased use of endovascular treatment of spinal dAVF has led to the treatment of refractory cases with a greater degree of surgical complexity. Open surgical ligation continues to provide the most definitive treatment outcomes for this complex spinal vascular entity

Early atherosclerosis aggravates the effect of renal artery stenosis on the swine kidney

Atherosclerotic renal artery stenosis (ARAS) is increasingly identified in patients with end-stage renal disease. Renal function in ARAS patients deteriorates more frequently than in nonatherosclerotic renal artery stenosis (RAS). This study was designed to test the hypothesis that atherosclerosis modifies the relationship between single-kidney hemodynamics and function and the severity of stenosis. The degree of unilateral RAS in domestic pigs (4 normal, 26 RAS, and 22 ARAS) was correlated with renal function and hemodynamics evaluated by 64-slice multidetector computerized tomography before and after endothelium-dependent challenge with ACh. The degree of stenosis and increase in mean arterial pressure were similar in RAS and ARAS. Stenotic single-kidney volume, blood flow, glomerular filtration rate, and cortical perfusion were lower than normal in both RAS and ARAS, but only in RAS correlated inversely with increasing degree of stenosis (r = −0.62, r = −0.49, r = −0.51, and r = −0.46, respectively, P < 0.05 for all). Basal tubular fluid concentration capacity and stenotic cortical perfusion response to ACh were both blunted only in ARAS. This study shows that atherosclerosis modulates the impact of a stenosis in the renal artery on stenotic kidney hemodynamics, function, and tubular dynamics. These observations underscore the direct intrarenal effect of atherogenic factors on the kidneys

Autonomic cerebral vascular response to sildenafil in diabetic patient

<p>Abstract</p> <p>Background</p> <p>Erectile dysfunction is a common problem in type 2 diabetic patients who are at higher risk of cerebrovascular events, and it's recorded with sildenafil, a drug which is primarily used for erectile dysfunction.</p> <p>Objectives</p> <p>We tested the hypothesis whether or not sildenafil modulates cerebrovascular reactivity (CVR) in patients with type 2 diabetes mellitus.</p> <p>Methods</p> <p>A total of 35 male participants were enrolled; eighteen with type 2 diabetes mellitus matched with seventeen normal individuals. Transcranial Doppler Ultrasonographic examination (TCD) was performed for all participants to insonate the middle cerebral artery (MCA) through a trans-temporal window. CVR was assessed by using breath holding (BH)-hyperventilation (HV) test, before and after oral 50 mg sildenafil; recordings were analyzed by using SPSS program version 12.</p> <p>Results</p> <p>In normal individuals, sildenafil did not result in statistically significant change in breath holding index (BHI) from 0.91 ± 0.11 to 0.81 ± 0.09 and full range of vasodilatation (FVD) from (59.4% ± 6.3%) to (53.7% ± 4.9%). In diabetic patients, giving sildenafil resulted in significant increase in BHI (from 0.74 ± 0.14 to 1.03 ± 0.14) and FVD (from 60.2% ± 4.96% to 74% ± 4.8%), (p < 0.05).</p> <p>Conclusion</p> <p>Sildenafil significantly improves CVR in type 2 diabetic patients but not in normal subjects.</p

Correlates of protection for booster doses of the SARS-CoV-2 vaccine BNT162b2

Abstract Vaccination, especially with multiple doses, provides substantial population-level protection against COVID-19, but emerging variants of concern (VOC) and waning immunity represent significant risks at the individual level. Here we identify correlates of protection (COP) in a multicenter prospective study following 607 healthy individuals who received three doses of the Pfizer-BNT162b2 vaccine approximately six months prior to enrollment. We compared 242 individuals who received a fourth dose to 365 who did not. Within 90 days of enrollment, 239 individuals contracted COVID-19, 45% of the 3-dose group and 30% of the four-dose group. The fourth dose elicited a significant rise in antibody binding and neutralizing titers against multiple VOCs reducing the risk of symptomatic infection by 37% [95%CI, 15%-54%]. However, a group of individuals, characterized by low baseline titers of binding antibodies, remained susceptible to infection despite significantly increased neutralizing antibody titers upon boosting. A combination of reduced IgG levels to RBD mutants and reduced VOC-recognizing IgA antibodies represented the strongest COP in both the 3-dose group (HR = 6.34, p = 0.008) and four-dose group (HR = 8.14, p = 0.018). We validated our findings in an independent second cohort. In summary combination IgA and IgG baseline binding antibody levels may identify individuals most at risk from future infections

Espectroscopia multivoxel com tempo de eco curto: a razão colina/N-acetil-aspartato e a graduação dos astrocitomas cerebrais Multivoxel spectroscopy with short echo time: choline/N-acetyl-aspartate ratio and the grading of cerebral astrocytomas

Avaliou-se a relação colina/N-acetil-aspartato (Co/NAA), obtida pela espectroscopia multivoxel com tempo de eco (TE) curto, na graduação histológica dos astrocitomas encefálicos (graus I, II e III-IV), comparando com o parênquima cerebral normal. Observou-se aumento significativo (p<0,05) das relações médias de Co/NAA nos três grupos de astrocitomas estudados em relação ao tecido normal, havendo tendência de elevação com o aumento da graduação, sem significância estatística, que correspondeu a: 0,53±0,24 no grupo controle, 1,19±0,49 no grau I, 1,58±0,65 no grau II e 5,13±8,12 no grupo de alto grau (graus III-IV). Houve aumento da relação Co/NAA em 4/5 (80%) dos pacientes com grau I, 5/6 (83%) com grau II e 10/20 (50%) com graus III e IV. Concluiu-se que a espectroscopia multivoxel com TE curto pode ser usada na discriminação entre o parênquima normal e o tecido neoplásico. Entretanto, nem todo tecido neoplásico estudado apresentou aumento da relação Co/NAA, principalmente o grupo com maior malignidade.<br>The choline/N-acetyl-aspartate (Cho/NAA) ratio, obtained by the multivoxel spectroscopy with short echo time (TE), was evaluated, in the histological grading of the brain astrocytomas (grades I, II and III-IV) in comparison with the normal cerebral parenchyma. A significant increase (p<0.05) in the average ratios of Cho/NAA was observed in the three astrocytoma groups studied in relation to normal tissue, having a tendency to increase with the increase in grading, without any statistic significance, which corresponded to: 0.53±0.24 in the control group, 1.19±0.49 in grade I, 1.58±0.65 in grade II and 5.13±8.12 in the high grade group (grades III-IV), with variation in the values encountered. There was an increase in the Cho/NAA ratio in 4/5 (80%) in grade I, 5/6 (83%) in grade II and 10/20 (50%) in grades III and IV. We conclude that multivoxel spectroscopy with short TE can be used in discriminating between normal parenchyma and neoplasm tissue. However, not all neoplasm tissue studied presented an increase in Cho/NAA, especially in the group with higher grade of malignancy