1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking.

Targeting the VEGFR-2 signaling pathway is an inveterate approach toward combating pancreatic and hepatocellular cancers. Based on Sunitinib, the FDA-approved VEGFR-2 inhibitor, novel indolin-2-one-triazole hybrids were designed and synthesized as anti-hepatocellular and anti-pancreatic cancer agents with VEGFR-2 inhibitory activity. All the targeted compounds were assessed for their anti-cancer activity, revealing IC50 values extending from 0.17 to 4.29 µM for PANC1 and 0.58 to 4.49 µM for HepG2 cell lines. An extensive SAR study was conducted to explore the effect of different substituents along with N-alkylation. The potent anti-cancer analogs 11d, 11e, 11g, 11k and 14c were evaluated for their VEGFR-2 inhibitory actions, where their IC50 values ranged from 16.3 to 119.6 nM compared to Sorafenib, which revealed an IC50 of 29.7 nM, having compound 11d as the most active analog. An in silico ADME study was performed to confirm the drug-likeness of the synthesized compounds. Finally, molecular docking simulation was conducted for the most potent VEGFR-2 inhibitor (11d), demonstrating the strong binding with the vital amino acid residues of the VEGFR-2 ATP binding site.

The emergence of carbapenemase blaNDM genotype among carbapenem-resistant Enterobacteriaceae isolates from Egyptian cancer patients.

Carbapenem resistance among Enterobacteriaceae is a major concern that is increasingly reported worldwide. The objective of this study is to determine the incidence of carbapenem resistance as well as to investigate for carbapenemase-encoding genes among Enterobacteriaceae clinical isolates from cancer patients at different cancer institutes in Egypt. This determination was a cross-sectional study with a total of 135 clinical isolates collected over a period of 1 year. All isolates were sub-cultured on ChromID agar and subjected to phenotypic and molecular detection of carbapenemases. Most of the Enterobacteriaceae isolates were MDR with high resistance rates against tested antimicrobials. Overall, the results of PCR assays revealed that 89.62% (121/135) of isolates harbored one or more of the carbapenemase-encoding genes, while phenotypic assays revealed the production of carbapenemases in 68.88% (93/135) of isolates. BlastN analysis against the non-redundant genome sequences available in the GenBank database revealed that the blaNDM-1 gene was the most prevalent genotype of carbapenemases in 93/135 (68.88%), followed by blaOXA-48 44/135 (32.59%), blaOXA-23 42/135 (31.11%), and blaKPC-2 2/135 (1.48%). Klebsiella pneumoniae isolates harbored the highest number of carbapenemase-encoding genes 34/121 (28.09%). The high prevalence of carbapenemases and/or their encoding genes among MDR Enterobacteriaceae bacteria in Egypt is alarming, thus, the management of serious infections caused by Enterobacteriaceae, particularly in cancer patients will be challenging to clinicians. Carbapenemase blaNDM genotype is emerging in cancer healthcare settings in Egypt, which could be the cause of the current increase in carbapenemase-producing Enterobacteriaceae.

[Oral anticoagulation : Current overview and perioperative management in ophthalmic surgery]. / Orale Antikoagulation : Aktuelle Übersicht und perioperatives Management in der Ophthalmochirurgie.

Antithrombotic treatment with oral anticoagulants and antiplatelet agents can increase the risk for perioperative bleeding. In contrast to other surgical fields, the optimal perioperative management in ophthalmic surgery has not yet been exactly defined and, thus, is not standardized. In this contribution, we provide an overview of currently available oral anticoagulants and discuss potential strategies for the management of these agents in different ophthalmic surgical procedures.

[Management of anticoagulants in ophthalmic surgery-a survey among ophthalmic surgeons in Germany]. / Umgang mit gerinnungshemmenden Substanzen in der Ophthalmochirurgie ­ eine Umfrage unter Ophthalmochirurgen in Deutschland.

INTRODUCTION: As our population ages and comorbidities rise, ophthalmic surgeons are increasingly faced with patients on anticoagulant therapy or with clotting disorders. The ophthalmic surgeon has to weigh the perioperative risk of haemorrhage when anticoagulation continues against the risk of thromboembolism caused by discontinuation or changing the patient's medication (bridging, switching, cessation). There are currently no guidelines or recommendations. METHODS: A survey was sent to the DOG (German Ophthalmologic Society) divisions and associated surgical organizations to determine the status quo. A questionnaire was sent out and filled out by the different groups of specialists. RESULTS: All four divisions of the DOG and four associated organizations returned completed questionnaires. Surgical interventions were listed that are carried out during anticoagulant therapy without exceptions, as well as interventions that were classified to require medical adjustment. Although the assessments varied, general consensus was achieved regarding interventions not requiring adjustments due to anticoagulants (i. e., intravitreal injection, cataract surgery, laser and corneal operations, simple muscle surgery), and those interventions requiring adjustments in medications (glaucoma operations, complex retina surgery, eye socket surgery, complex surgery of the lid). CONCLUSION: Main result of this survey was the specification of serious bleeding complications which are permanent vision loss and re-operation. They could serve as endpoint parameters for essential future investigations. Nevertheless, this survey makes clear that the decision about an adjustment of anticoagulant medication in ophthalmic surgery is currently made individually and not based on established standards.

Factors Influencing Surveillance for Hepatocellular Carcinoma in Patients with Liver Cirrhosis.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide, and a rising cause of cancer mortality in the U.S. Liver cirrhosis is the major risk factor for HCC. Surveillance of persons with cirrhosis facilitates early detection and improves outcomes. We assessed the surveillance rate for HCC within a major academic health system and identified factors influencing surveillance. PATIENTS AND METHODS: We examined the surveillance rate for HCC using liver ultrasound, CT, or MRI, and factors influencing surveillance in a cohort of 369 Minnesota residents with cirrhosis seen at the Mayo Clinic between 2007 and 2009. RESULTS: Ninety-three percent of cirrhosis patients received at least one surveillance study, but only 14% received the recommended uninterrupted semiannual surveillance. Thirty percent received ≥75% of recommended surveillance, and 59% received ≥50% of recommended surveillance. Factors increasing surveillance included gastroenterology or hepatology specialist visits (p < 0.0001), advanced liver disease as assessed by hepatic encephalopathy (p = 0.0008), and comorbid illness as assessed by diabetes mellitus (p = 0.02). Age, sex, race, residence, cirrhosis etiology, or number of primary care visits did not significantly affect the rate of surveillance. CONCLUSIONS: While the rate of surveillance in a major academic health system was higher than reported in other studies, surveillance was heavily dependent on visits to a subspecialist. This suggests a major and urgent national need to improve identification of individuals at risk for HCC in the primary care setting and the initiation and maintenance of surveillance by primary care practitioners.

Early pulmonary arterial hypertension immediately after closure of a ventricular or complete atrioventricular septal defect beyond 6months of age.

BACKGROUND: Pulmonary arterial hypertension (PAH) is virtually absent after closure of ventricular septal defect (VSD) in the first six months of life. However the prevalence of PAH in patients, who underwent VSD closure later, is not clear. The aim of this study was to analyse the prevalence of PAH after a successful VSD closure after the age of 6months and whether there are risk factors for developing PAH. METHODS: Echocardiographic and right heart catheter data of patients with VSD or complete atrioventricular septal defect, who underwent VSD closure after the age of 6months in our institution between 01/2005 and 06/2014, were retrospectively analyzed. PAH was defined as mean pulmonary arterial pressure (mPAP) of ≥25mmHg or tricuspid regurgitation jet velocity of ≥3.5m/s. RESULTS: In 228 patients (median age at shunt closure 4.0years, range 0.5-69) and 174 complete follow-up data (median follow-up 3.7years, range 0.5-39.4), 9 patients needed pulmonary vasodilator therapy after shunt closure, 4 of them temporarily for up to 79months. Three patients are still on vasodilator treatment 1, 2.6 and 6years after surgery, other two were lost to follow-up. Another 6 patients with preoperatively borderline hemodynamics due to elevated mPAP and pulmonary vascular resistance, recovered well without signs of postoperative PAH. CONCLUSION: With the current practice for safe late VSD closure, PAH is very rare at least in the first years of follow-up. In most patients with perioperative PAH, this condition appears to be transient and shows good response on pulmonary vasodilator treatment.

[Platelet aggregation inhibitors and anticoagulants during ophthalmic interventions]. / Thrombozytenaggregationshemmer und Antikoagulantien bei augenchirurgischen Eingriffen.

In ophthalmology many patients undergo surgical treatment who need to take anticoagulant medication due to cardiovascular diseases. The proper handling of these drugs requires both correct assessment of the risk of thromboembolism as well as the rating of the risk of surgery-related hemorrhages. While there are established recommendations for estimation of the risk of thromboembolism based on a large body of prospective randomized trials, data regarding the evaluation of the related complications secondary to ophthalmic surgery are limited. In comparison to other surgical procedures, most interventions in ophthalmic surgery tend to have a relatively low risk of bleeding; therefore, in general there is no need to convert or discontinue anticoagulant drugs in patients undergoing opthalmic surgery. The sparse data available justifying the abrupt termination of anticoagulation are contrary to the approach currently widely distributed in clinical practice. This overview covers the relevant knowledge of the perioperative use of anticoagulant drugs. In addition, the data on the risk of hemorrhage in ophthalmological procedures are presented and discussed.

Carbon dioxide laser plus topical 5-fluorouracil: a new combination therapeutic modality for acral vitiligo.

BACKGROUND: Acral vitiligo (AV) is resistant to treatment. AIM: To evaluate efficacy and safety of combining carbon dioxide (CO2) laser and 5-fluorouracil (5FU) in treating AV. METHODS: This study included 68 adult patients with AV. After randomly assigning patients into 3 groups, patients in group I were treated using 5FU, group II were treated using CO2 laser, and group III were treated using CO2 laser followed by 5FU for a maximum period of 5 months. The lesions were then evaluated both qualitatively and quantitatively. RESULTS: Almost half (49.8%) of the lesions in group III achieved G4, and 6.1% of lesions achieved G3 re-pigmentation. This response was statistically significantly higher than that in the other two groups. This was not achieved in periungual areas in the hands and feet. The pain was tolerable during sessions or at sites of 5FU application. Transient hyperpigmentation, brownish spot on nail plates, itching, and infection were temporary side effects; however, Koebnerization was not detected. CONCLUSION: We concluded that prior use of CO2 laser skin ablation, followed by 5FU application for AV is a safe and tolerable technique that improves the outcome and increases patient compliance.

Does ocriplasmin affect the RPE-photoreceptor adhesion in macular holes?

BACKGROUND: To evaluate the anatomical outcome of patients after vitrectomy due to persisting symptomatic vitreomacular traction (VMT), including full-thickness macular holes (FTMHs) of less than 400 µm, after ocriplasmin treatment. METHODS: Retrospective, single centre, consecutive interventional case series. Patients were treated with a single intravitreal injection of ocriplasmin (Jetrea, Thrombogenics Inc, USA, Alcon/Novartis EU). MAIN OUTCOME MEASURES: resolution of VMT, closure of FTMH and anatomical outcome of vitrectomy after unsuccessful treatment with ocriplasmin. RESULTS: Five patients were treated with ocriplasmin injection. VMT persisted in all but one case. Four patients underwent pars-plana vitrectomy (PPV) for treatment of persistent VMT and FTMH (n=2, size of macular hole <400 µm) in spectral-domain optical coherence tomography (SD-OCT). FTMHs were closed in both cases within the first week postoperatively. After PPV, in three eyes newly developed subretinal fluid was detected, which persisted up to several months postoperatively. CONCLUSIONS: Data on ocriplasmin remain controversial. We report on four cases with resolution of VMT following PPV after unsuccessful ocriplasmin treatment. Newly developed subretinal fluid has been described after ocriplasmin treatment, predominantly in cases with resolution of VMT. We also detected this newly developed subretinal fluid after vitrectomy, which persisted for several weeks up to 7 months in two cases with FTMHs. This may be attributable to loosening of the photoreceptor complex due to enzyme activity of ocriplasmin. Long-term effects of ocriplasmin are still to be evaluated using SD-OCT.

Severe hypophosphatemia induced after first cycle of the ESHAP protocol for Hodgkin's lymphoma: a case report.

The effect of the ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) salvage protocol on serum electrolytes has been previously reported by individual observational studies. The most commonly described electrolyte affected by the ESHAP protocol is magnesium. In addition, hypophosphatemia has been studied and reported as a complication of cisplatin therapy, although it is usually asymptomatic. This is a case report of a 51-year-old woman with relapsed Hodgkin's lymphoma who developed severe hypophosphatemia following administration of the first cycle of the ESHAP protocol. The patient started to develop gradually decreasing phosphate levels 2 weeks after receiving chemotherapy, which needed to be corrected by phosphate supplementation. This case report raises concern regarding hypophosphatemia as a possible side effect of the ESHAP protocol and points to a need for close monitoring, taking into consideration vitamin D levels, urinary phosphate excretion, parathyroid hormone levels, and arterial blood gas analysis to rule out other contributing factors. Health care providers should be made aware of this possible toxicity. Critical monitoring of phosphate levels and considering supplementation is warranted with the ESHAP protocol, especially when it is used in combination with granulocyte colony-stimulating factor and diuretics, to prevent such possible hypophosphatemia. Further investigations may be required to confirm and evaluate the significance of this type of toxicity.

[Correction factors for central corneal thickness in Goldmann applanation tonometry]. / Hornhautdickenabhängige Korrekturfaktoren bei der Goldmann-Applanationstonometrie.

BACKGROUND: For many years researchers have discussed which corneal parameters can influence the measurement of intraocular pressure (IOP). As a substantial parameter, the central corneal thickness (CCT) is assumed; however, different measuring methods - including Goldmann applanation tonometry (GAT), dynamic contour tonometry (DCT), and corneal compensated pressure measured with the ocular response analyzer (IOPcc) - may lead to a completely different dependence on corneal thickness. METHOD: In a study approved by the ethics commission, the anterior chamber of 92 eyes of cataract patients and 85 eyes of glaucoma patients with very different CCT measurements was cannulized before surgery (cataract operation or trabeculectomy), and the IOP values were measured simultaneously with a pressure absorber and with GAT (Perkins tonometer) at different pressure values. RESULTS: The individual measurements exhibited an extraordinarily wide dispersion. In both groups, weak correlations of the difference between GAT and IOP values with the CCT were found (correction factors of 0.95 mmHg/100 microm CCT at pressure level 20 mmHg, 1.2 mmHg/100 microm CCT at pressure level 30 mmHg, and 1.7 mmHg/100 microm CCT at pressure level 40 mmHg). CONCLUSIONS: Measurement of CCT is valuable for prognostic assessment of glaucoma, but not for correction factors for corneal thickness.

[The effect of cataract and vitreoretinal surgery on central corneal thickness and corneal hysteresis]. / Einfluss der Katarakt- und Glaskörperchirurgie auf die Hornhautdicke und die Corneale Hysterese.

INTRODUCTION: Intraocular irrigating solutions remain for several hours beyond the actual time of surgery in the eye. The irrigating solution ought to resemble biochemically aqueous humor and vitreous and offer protection for sensitive structures of the eye, such as the corneal endothelium. Impairment of the corneal endothelium may lead to corneal oedema and biomechanical alterations of the cornea. PATIENTS AND METHODS: 54 eyes after pars-plana vitrectomy (PPV) in elective macular surgery were evaluated by measuring corneal thickness (CCT) using ultrasound pachymetry (20 MHz) and corneal hysteresis (CH) using the ocular response analyser (Reichert Ophthalmic Instruments, Buffalo, NY, USA). Measurements were performed not earlier than 2 weeks prior to surgery and 1 to 3 days after surgery. Results were compared to a control group (n = 39) and to 101 eyes after clear cornea cataract extraction (KAT). RESULTS: The two groups (PPV and KAT) did not differ with respect to age (p = 0.555). Corneal thickness has increased significantly in both groups (p

Processing and storage effects on monomeric anthocyanins, percent polymeric color, and antioxidant capacity of processed black raspberry products.

This study evaluated the effects of processing and 6 mo of storage on total monomeric anthocyanins, percent polymeric color, and antioxidant capacity of black raspberries that were individually quick-frozen (IQF), canned-in-syrup, canned-in-water, pureed, and juiced (clarified and nonclarified). Total monomeric anthocyanins, percent polymeric color, and ORAC(FL) were determined 1 d postprocessing and after 1, 3, and 6 mo of storage. Thermal processing resulted in marked losses in total anthocyanins ranging from 37% in puree to 69% to 73% in nonclarified and clarified juices, respectively, but only the juices showed substantial losses (38% to 41%) in ORAC(FL). Storage at 25 degrees C of all thermally processed products resulted in dramatic losses in total anthocyanins ranging from 49% in canned-in-syrup to 75% in clarified juices. This coincided with marked increases in percent polymeric color values of these products over the 6-mo storage. ORAC(FL) values showed little change during storage, indicating that the formation of polymers compensated for the loss of antioxidant capacity due to anthocyanin degradation. Total anthocyanins and ORACFL of IQF berries were well retained during long-term storage at -20 degrees C.

[Rate of reopening of macular holes following cataract operation]. / Wiedereröffnungsrate von Makulaforamina nach Kataraktoperation.

BACKGROUND: We set up this retrospective study to examine how different the functional and morphological results are following pars plana vitrectomy (ppV) for idiopathic macular holes in phakic eyes with later cataract surgery and in pseudophakic eyes, and to what extent cataract surgery can induce reopening of idiopathic macular holes after ppV. METHODS: A total of 189 eyes were vitrectomized because of idiopathic macular hole (37 pseudophakic, 152 phakic); 120 (22 pseudophakic, 98 phakic) of these eyes were examined at follow-up of an average of 19 months after vitrectomy. Cataract surgery was performed in 65 of the phakic eyes in this period. The functional and morphological results recorded for these 22 pseudophakic and 65 phakic eyes were evaluated. RESULTS: In the pseudophakic eyes preoperative visual acuity was 0.14, increasing to 0.20 postoperatively (p=0.16); in 1 case (4.5%) the macular hole was not closed at the time of the follow-up examination. Cataract extraction was performed in 65 of the phakic eyes an average of 10 months after ppV. The initial VA was 0.19 before ppV and increased to 0.37 (p<0.01) after cataract surgery; in 4 cases (6.2%) the macular hole was not closed by the time of the follow-up examination, but in each case this had already been noted when the cataract extraction was done. Reopening did not occur after cataract extraction in any of these cases. CONCLUSION: With a rate of 5.7% for reopening or persistence of macular holes, our results are comparable to those recorded in other studies. Cataract surgery following ppV does not influence the reopening rate of macular holes.

[Bilateral serous detachment of the neurosensory retina and retinal pigment epithelium with rip of the peripheral pigment epithelium]. / Bilaterale seröse Abhebung der neurosensorischen Retina und des retinalen Pigmentepithels mit Riss des peripheren Pigmentepithels.

HISTORY: A 52-year-old patient with atypical plasmocytoma presented with a bilateral serous detachment of the retina as well as a huge detachment of the pigment epithelium (PE) in the periphery. Shortly thereafter the PE ruptured. In the left eye this led to substantial central macular fibrosis. DIAGNOSIS: The clinically healthy patient showed a nephrotic syndrome; neither typical monoclonality was detectable nor was erythropoiesis or myelopoiesis reduced. THERAPY: To avoid further reduction of VA pars plana vitrectomy (ppV) with silicone oil tamponade and laser coagulation was performed. Clinical findings were reduced significantly and VA was stabilized for 2.5 years. DISCUSSION: PE detachments and serous retinal detachments in patients with nephrotic syndrome are only mentioned in a few cases. However, a peripheral rupture of the PE to this extent seems to be very rare. Early ppV with silicone oil and laser coagulation may prevent further macular fibrosis.

Myocardial scars determined by delayed-enhancement magnetic resonance imaging and positron emission tomography are not common in right ventricles with systemic function in long-term follow up.

OBJECTIVE: To test the hypothesis that myocardial scars are common in patients with systemic right ventricles. METHODS: 27 consecutive patients with systemic right ventricle were studied with delayed-enhancement magnetic resonance imaging and positron emission tomography. Of the 27 patients, 18 had had an atrial switch operation a mean of 21.8 (SD 4.5) years previously and were 23.4 (SD 5.3) years old. Nine patients without previous heart surgery had congenitally corrected transposition of the great arteries and were 35.3 (SD 15.6) years old. RESULTS: Only one patient had a subendocardial scar identified by delayed-enhancement magnetic resonance imaging. Positron emission tomography identified no myocardial scars. CONCLUSIONS: This study shows that the hypothesis that myocardial scars are common in patients with systemic right ventricles is not correct.

[Anatomical and functional results after elective macular surgery]. / Anatomische und funktionelle Ergebnisse nach elektiver Makulachirurgie.

PURPOSE: The purpose of this paper is to assess the anatomical and functional results after macular surgery in a large group of patients. METHODS: Between June 1995 and December 2001, 381 eyes underwent vitreous surgery for macular pucker (n=244) or macular holes (n=137) with a standard pars plana vitrectomy (PPV) with induction of posterior vitreous separation, membrane peeling, peeling of the internal limiting membrane (no ICG staining was used), and gas instillation (SF(6)). RESULTS: A second surgical intervention due to vision-threatening complications after PPV had to be performed in 8 of 381=2.1%. In the macular pucker group, metamorphopsias improved in 46.6% and the median of visual acuity (VA) improved from preoperative 0.3 to postoperative 0.5. Hole closure of macular holes was obtained in 92.2%; the median of VA improved in this group from preoperative 0.2 to postoperative 0.4. CONCLUSION: In our group a second vitreoretinal procedure due to vision-threatening complications had to be performed in 2.1%. Compared to the spontaneous course, PPV for macular pucker or macular hole has a very positive influence on functional parameters.

Oxidative study of patients with total body irradiation: effects of amifostine treatment.

In patients undergoing bone marrow transplant (BMT), reactive oxygen species (ROS) are released as a consequence of the events related to the preparative regimen. Total body irradiation (TBI), which is known to generate ROS, is a routine preconditioning procedure prior to BMT. Several studies have demonstrated that amifostine protects normal tissues. In the present report, we investigated the oxidative state of plasma and erythrocytes in 21 patients with hematological malignancies undergoing TBI. The dose fraction was 160 cGy, twice daily (eight sessions). For ROS detection, we used electron spin resonance spectroscopy and spin-trapping technique. In all, 15 patients received amifostine prior to the irradiation and six did not. No free radical signal was detected in the plasma samples spectrum of 15 amifostine-treated patients, and five of six samples of nontreated patients showed ROS signal. Only two of 15 treated patients had mucositis degree higher than 2, whereas five of six nontreated patients suffered this complication. The average hospitalization days in treated and nontreated patients were 23.5 and 29.7, respectively. This work represents an original observation; we found by direct measurements of free radicals that ROS are released during TBI, and confirmed the amifostine radical scavenger activity.

[Vitreoretinal secondary procedures following elective macular surgery]. / Vitreoretinale Zweiteingriffe nach elektiver Makulachirurgie.

OBJECTIVE: The spectrum of reoperations after macular surgery was investigated retrospectively in a large group of patients. All secondary surgical procedures except for cataract surgery were considered. METHODS: Between July 1995 and June 2001 353 eyes underwent macular surgery (218 due to macular pucker, 135 due to macular hole) with a pars-plana vitrectomy (PPV), creation of vitreous detachment, membrane peeling and SF(6)/air-instillation. The vitrectomies were performed by 4 different surgeons. In all patients a preoperative circular peripheral cryoretinopexy was performed 3-4 weeks before macular surgery. The follow-up was 20.9 months on average. The number of revitrectomies as well as the postoperative retinal detachment rate were investigated. RESULTS: In 33 cases (9.3%) a second vitrectomy had to be performed due to an unsatisfying postoperative macular finding: 17/218 (7.8%) after macular pucker surgery with a recurrent pucker and 16/135 (11.8%) after macular hole surgery with persistent or recurrent macular hole. In 7/353 (2.0%) a postoperative rhegmatogenous retinal detachment was observed and in 2/353 (0.6%) a postoperative endophthalmitis had to be treated. CONCLUSION: In 9.3% of our patients a second PPV due to an unsatisfying macular finding became necessary. The rate of postoperative retinal detachment of 2.0% is considerably lower than in most other studies. Therefore, a possible prophylactic effect of the preoperative circular peripheral cryoretinopexy is suggested to reduce the risk of postoperative retinal detachment.