N-hydroxy-pyrroline modification of verapamil exhibits antioxidant protection of the heart against ischemia/reperfusion-induced cardiac dysfunction without compromising its calcium antagonistic activity

Any clinical intervention (e.g., coronary angioplasty, thrombolysis) used to reintroduce blood flow to an ischemic region of the myocardium is accompanied by a complex enzymatic cascade of reactions resulting in severe injury to the heart, termed myocardial ischemia/reperfusion (I/R) injury. In this study, we evaluated the ability of H-3010 (1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (2-(3,4-dimethoxyphenyl)-5-([2-(3,4-dimethoxyphenyl)ethyl]-methylamino)-2-isopropylpentyl)-amide), a pyrroline modification of verapamil (2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethylmethyl-amino]-2-(1-methylethyl)pentanenitrile), to protect the heart against I/R-mediated injury. Isolated perfused rat hearts pretreated with verapamil and H-3010 were subjected to 30 min of global no-flow ischemia followed by 45 min of reperfusion. The recovery (expressed as a percentage of preischemic baseline) in contractile function (left ventricular developed pressure) of hearts subjected to I/R was significantly higher in hearts treated with H-3010 at 5 microM (51.0 +/- 6.4%) as well as at 50 microM (75.1 +/- 7.4%) as compared with verapamil at 5 microM (32.2 +/- 3.7%) or untreated control hearts (18.1 +/- 2.8%). Creatine kinase release was significantly attenuated in hearts treated with H-3010 (45.7 +/- 4.5 U/liter) as compared with untreated controls (131.5 +/- 6.4 U/liter). Similar trends were also observed for lactate dehydrogenase release as well. A marked reduction in percent area of infarction was observed in the H-3010 group (11.7 +/- 1.6%) compared with verapamil (25.1 +/- 2.9%) and control (41.3 +/- 1.9%) groups. Additional in vitro studies showed a marked decrease in reactive oxygen species generation with H-3010. In conclusion, our data clearly demonstrated that the verapamil derivative, H-3010, significantly decreased I/R-induced cardiac dysfunction. This can be attributed to the combined benefits of the pyrroline moiety (antioxidant) and the parent verapamil component (antiarrhythmic) in the protection of the heart from I/R-induced injury.     

Cardioprotection by sulfaphenazole, a cytochrome p450 inhibitor: mitigation of ischemia-reperfusion injury by scavenging of reactive oxygen species

Cytochrome P450 (P450) enzymes play a significant role in promoting myocardial ischemia-reperfusion (I/R) injury. CYP2C9, an isoform of P450, is known to generate superoxide radicals in the reperfused heart. Sulfaphenazole (SPZ), a CYP2C9 inhibitor, has been shown to decrease I/R injury; however, the mechanism of cardioprotection by SPZ is not well elucidated. The objective of this study was to test whether SPZ mitigates myocardial I/R injury by scavenging reactive oxygen species (ROS). Isolated rat hearts were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Hearts were perfused with SPZ and/or N(omega)-nitro-L-arginine methylester (L-NAME). Coronary flow (CF), left-ventricular developed pressure (LVDP), and rate-pressure product (RPP) were monitored. Superoxide and nitric oxide (NO) generation in the reperfused tissue was determined using fluorescence methods. Myocardial infarct size was measured using triphenyltetrazolium chloride staining. The SPZ-treated group showed a significant recovery of cardiac function compared with the untreated I/R group (CF, 53 versus 45%; LVDP, 48 versus 22%; RPP, 51 versus 20%). The infarct size was significantly reduced in the SPZ-treated group (15%) compared with the I/R control (42%). Coadministration of L-NAME with SPZ significantly attenuated the beneficial effects of SPZ. In addition, SPZ treatment showed significantly decreased superoxide levels and enhanced NO bioavailability in the reperfused heart. In conclusion, the protective effect of SPZ against I/R-mediated myocardial damage appears to be due to a reduction in the superoxide level caused by its inhibition of CYP2C9, as well as scavenging of oxygen free radicals generated in the reperfused heart.     

Clinical presentation and outcome of retinoblastoma based on age at presentation: a review of 1450 children

To compare the clinical presentation and outcomes of retinoblastoma (RB) based on age at presentation. Retrospective comparative study of 1940 eyes of 1450 children with RB. Presentation of RB with enlarged eyeball and eyelid swelling (2% and < 1% in ≤ 1 year, 4% and 2% in > 1–2 years, 7% and 2% in > 2–3 years, and 12% and 4% in > 3 years; p < 0.0001 and p = 0.05, respectively) is more common with increasing age. Based on the 8th edition of American Joint Committee Classification, T1 is more common in children younger than 1 year (27%), while T4 is more common in children > 3 years of age (20%) (p < 0.0001). Kaplan–Meier (KM) estimate at 1 and 5 years for globe salvage was 64% and 58% in children ≤ 1 year of age versus 30% and 20% in children > 3 years, respectively [Hazard ratio (HR) = 2.48; p < 0.0001], and KM estimate at 1 and 5 years for life salvage was 99% and 97% in children ≤ 1 year of age versus 89% and 78% in children older than 3 years, respectively (HR = 7.65; p < 0.0001). Uncommon clinical features of RB including enlarged eyeball and eyelid swelling are more common with increasing age. Younger age at presentation with RB is associated with better prognosis including higher chances of life and globe salvage.     

Commentary on the management of total laryngectomy patients during the COVID‐19 pandemic

The coronavirus disease‐2019 (COVID‐19) pandemic has rapidly spread across the world, placing unprecedented strain on the health care system. Health care resources including hospital beds, ICUs, as well as personal protective equipment are becoming increasingly rationed and scare commodities. In this environment, the laryngectomee (patient having previously undergone a total laryngectomy) continues to represent a unique patient with unique needs. Given their surgically altered airway, they pose a challenge to manage for the otolaryngologist within the current COVID‐19 pandemic. In this brief report, we present special considerations and best practice recommendations in the management of total laryngectomy patients. We also discuss recommendations for laryngectomy patients and minimizing community exposures.     

Acute changes in ganglion cell layer thickness in ischemic optic neuropathy compared to optic neuritis using optical coherence tomography

AIM:To elucidate the changes of different ganglion cell layer(GCL)thinning patterns between the optic neuritis(ON)and non-arteritic anterior ischemic optic neuropathy(NAION).METHODS:A prospective,observational study was conducted to evaluate the timing of GCL changes between acute ON and NAION using optical coherence tomography.RESULTS:Thinning on optical coherence tomography in the NAION group occurs as early as 11 d after symptomatic onset of vision loss and follows an altitudinal pattern.The mean superior-inferior GCL thickness difference in the NAION cohort was clinically significant at 5.7μm in the NAION cohort compared to controls of 0.8μm(P=0.032),but not significant in the ON group compared to controls with both groups measuring 1.1μm.Global thinning was significant for the ON group compared to controls at 7.2μm(P=0.011)but not the NAION group compared to controls at 1.35μm.CONCLUSION:These findings suggest that future treatments for NAION should be given early,and possibly before 11 d in order to prevent GCL and irreversible vision loss.     

Robotic Kidney Transplantation with Regional Hypothermia: A Step-by-step Description of the Vattikuti Urology Institute–Medanta Technique (IDEAL Phase 2a)

Background

We recently reported on preclinical and feasibility studies (Innovation, Development, Exploration, Assessment, Long-term study [IDEAL] phase 0–1) of the development of robotic kidney transplantation (RKT) with regional hypothermia. This paper presents the IDEAL phase 2a studies of technique development.

Objectives

To describe the technique of RKT with regional hypothermia developed at two tertiary care institutions (Vattikuti Urology Institute and Medanta Hospital). We report on the safety profile and early graft function in these patients.

Design, setting, and participants

This is a prospective study of 50 consecutive patients who underwent live-donor RKT at Medanta Hospital following a 3-yr planning/simulation phase at the Vattikuti Urology Institute. Demographic details, and perioperative and postoperative outcomes are reported for the initial 25 recipients who have completed a minimum 6-mo follow-up.

Surgical procedure

Positioning and port placement were similar to that used for robotic radical prostatectomy. Allograft cooling was achieved by ice slush delivered through a GelPOINT device. The accompanying video details the operative technique.

Outcome measurements and statistical analysis

The primary outcome was posttransplant graft function. Secondary outcomes included technical success or failure and complication rates.

Results and limitations

Fifty patients underwent RKT successfully, 7 in the phase 1 and 43 in the phase 2 stages of the study. For the initial 25 patients, mean console, warm ischemia, arterial, and venous anastomotic times were 135, 2.4, 12, and 13.4 min, respectively. All grafts were cooled to 18–20°C with no change in core body temperature. All grafts functioned immediately posttransplant and the mean serum creatinine level at discharge was 1.3 mg/dl (range: 0.8–3.1 mg/dl). No patient developed anastomotic leaks, wound complications, or wound infections. At 6-mo of follow-up, no patient had developed a lymphocele detected on CT scanning. Two patients underwent re-exploration, and one patient died of congestive heart failure (1.5 mo posttransplant).

Conclusions

RKT with regional hypothermia is safe and reproducible when performed by a team skilled in robotic surgery.

Patient summary

RKT is safe and effective when performed by surgeons experienced in robotic techniques.     

Can There be a Place for Intraoperative Salvaged Blood in Spine Tumor Surgery?

Background

Intraoperative cell salvage (IOCS) has been used in musculoskeletal surgery extensively. However, it has never found its place in musculoskeletal oncologic surgery. We have conducted the first-ever study to evaluate the feasibility of IOCS in combination with a leucocyte-depletion filter (LDF) in metastatic spine tumor surgery. This was to pave the path for use of IOCS-LDF in musculoskeletal oncologic surgery.

Methods

Patients with a known primary epithelial tumor, who were offered surgery for metastatic spinal disease, were recruited. Blood samples were collected at three different stages during the surgery: from the operative field before IOCS processing, after IOCS processing, and after IOCS-LDF processing. Three separate samples (5 mL each) were taken at each stage. Samples were examined using immunohistochemical monoclonal antibodies to identify tumor cells of epithelial origin.

Results

Of 30 patients in the study, 6 were excluded for not fulfilling the inclusion criteria, leaving 24 patients. Malignant tumor cells were detected in the samples from the operative field before IOCS processing in eight patients and in the samples from the transfusion bag after IOCS processing in three patients. No viable malignant cell was detectable in any of the blood samples after passage through both IOCS and LDF.

Conclusions

The findings support the notion that the IOCS-LDF combination works effectively in eliminating tumor cells from salvaged blood, so this technique can be applied successfully in spine tumor surgery. This concept can then further be extended to whole musculoskeletal tumor surgery and other oncologic surgeries with further appropriate clinical studies.     

Colonoscopic Perforation Management by Laparoendoscopy: An Algorithm

Background and Objectives:

The role of laparoscopy in the management of iatrogenic colonoscopic injuries has increased with surgeons becoming facile with minimally invasive methods. However, with a limited number of reported cases of successful laparoscopic repair, the exact role of this modality is still being defined. Drawing from previous literature and our own experiences, we have formulated a simple algorithm that has helped us treat colonoscopic perforations.

Methods:

A retrospective review was undertaken of patients treated for colonoscopic perforations since the algorithm''s introduction. For each patient, initial clinical assessment, management, and postoperative recovery were carefully documented. A Medline search was performed, incorporating the following search words: colonoscopy, perforation, and laparoscopy. Twenty-three articles involving 106 patients were identified and reviewed.

Results:

Between May 2009 and August 2012, 7 consecutive patients with colonoscopic perforations were managed by 2 surgeons using the algorithm. There were no complications and no deaths, with a mean length of stay of 4.43 days (range, 2–7 days). Of the 7 patients, 6 required surgery. A single patient was managed conservatively and later underwent an elective colon resection.

Conclusions:

Traditionally, laparotomy was the preferred method for treating colonoscopic perforations. Our initial experience reinforces previous views that laparoendoscopic surgery is a safe and effective alternative to traditional surgery for managing this complication. We have formulated a simple algorithm that we have found helpful for surgeons considering a laparoscopic approach to managing this condition.