Efficacy of a hinged pupil expansion device in small pupil cataract surgery

Purpose:To evaluate the efficacy and safety of a hinged pupil expansion device (PED) in eyes with small pupils undergoing phacoemulsification.Methods:In this prospective, multicenter, interventional case series of 57 eyes with suboptimal pharmacologic pupil dilation (<5 mm diameter), a hinged PED (I-Ring, Beaver-Visitec International, Waltham, MA) was applied to facilitate surgical visualization during cataract surgery. The pupil diameters (PD) were measured at different stages of the procedure and at the 1-month follow-up visit. Rate of successful intraoperative PED deployment, pupil size, and shape were assessed.Results:The mean patient age was 70.5 ± 12.1 years. The I-Ring PED was successfully applied in all eyes. The mean PD at various stages were 4.1 ± 1.1 mm (dilation with eye drops only preoperatively), 4.3 ± 1.1 mm (dilation after intracameral epinephrine and ophthalmic viscoelastic device), 6.80 ± 0.00 mm (with PED applied), and 5.7 ± 1.1 mm (end of surgery). A statistically significant difference (P < 0.001) was observed between the mean PD with intracameral medications and with PED application. Postoperative circular pupil was observed in 54 of 57 eyes (94.7%) and the mean eccentricity index (n = 57 eyes) was 0.11 ± 0.22. No significant adverse events were observed.Conclusion:The I-Ring PED safely and effectively provided and maintained adequate pupil expansion and surgical visualization in eyes with small pupils undergoing cataract surgery. Postoperatively 95% of eyes attained circular pupils. This hinged PED is an additional instrumentation option for the safe and effective expansion of inadequately sized pupils during cataract surgery.     

Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) are the mainstay for treatment of chronic myelogenous leukemia (CML). Imatinib was the first TKI approved for use in CML, but resistance to this therapy has emerged as a significant issue, and second-line options are often necessary. Increased-dose imatinib may elicit responses in some patients, but clinical evidence suggests only a minority experience sustained benefit. The second-generation TKIs, dasatinib and nilotinib, have demonstrated efficacy in patients resistant or intolerant to imatinib. Changes in therapy, with the aim of inducing durable response, should occur promptly after imatinib failure is identified as all agents are more effective in chronic phase disease than in later stages. Selection of second-line agents should be driven by efficacy and safety: dasatinib may be more effective in patients with P-loop or F359C mutations; nilotinib may be more effective in those with F317L mutations.     

Intensity-modulated radiation therapy (IMRT) for meningioma

To assess the safety and efficacy of intensity-modulated radiation therapy (IMRT) in the treatment of intracranial meningioma.

Forty patients with intracranial meningioma (excluding optic nerve sheath meningiomas) were treated using IMRT with the NOMOS Peacock system between 1994 and 1999. Twenty-five patients received IMRT after surgery either as adjuvant therapy for incomplete resection or for recurrence, and 15 patients received definitive IMRT after presumptive diagnosis based on imaging. Thirty-two patients had skull base lesions, and 8 had nonskull base lesions. The prescribed dose ranged from 40 to 56 Gy (median 50.4 Gy) at 1.71 to 2 Gy per fraction, and the volume of the primary target ranged from 1.55 to 324.57 cc (median 20.22 cc). The mean dose to the target ranged from 44 to 60 Gy (median 53 Gy). Follow-up ranged from 6 to 71 months (median 30 months). Acute and chronic toxicity were assessed using Radiation Therapy Oncology Group (RTOG) morbidity criteria and tumor response was assessed by patient report, examination, and imaging. Overall survival, progression-free survival, and local control were calculated using the Kaplan-Meier method.

Cumulative 5-year local control, progression-free survival, and overall survival were 93%, 88%, and 89%, respectively. Two patients progressed after IMRT, one locally and one distantly. Each was treated with IMRT after multiple recurrences of benign meningioma over many years. Both were found to have malignant meningioma at the time of relapse after IMRT, and it is likely their tumors had already undergone malignant change by the time IMRT was given. Defined normal structures generally received a significantly lower dose than the target. The most common acute central nervous system (CNS) toxicity was mild headache, usually relieved with steroids. One patient experienced RTOG Grade 3 acute CNS toxicity, and 2 experienced Grade 3 or higher late CNS toxicity, with one possible treatment-related death. No toxicity was observed with mean doses to the optic nerve/chiasm up to 47 Gy and maximum doses up to 55 Gy.

IMRT is a promising new technology that is safe and efficacious in the primary and adjuvant treatment of intracranial meningiomas. A history of local aggression may indicate malignant degeneration and predict a poorer outcome. Toxicity data are encouraging, but the potential for serious side effects exists, as demonstrated by one possible treatment-related death. Larger cohort and longer follow-up are needed to better define efficacy and late toxicity of IMRT.     

Regulation of lysophosphatidic acid-induced COX-2 expression by ERK1/2 activation in cultured feline esophageal epithelial Cells

Lysophosphatidic acid (LPA), a potent bioactive phospholipid, mediates diverse cellular responses by binding to specific G protein-coupled receptors (GPCRs). We investigated the signaling mechanisms underlying LPA-induced COX-2 expression in primary cultures of feline esophageal epithelial cells. The identity of the cultures was confirmed by immunocytochemistry using a cytokeratin antibody. Western blot analysis revealed a concentration-and time-dependent induction of COX-2 in response to LPA. Of the three major MAPKs, only ERK1/2 was activated by LPA in a time-dependent manner. LPA-induced COX-2 expression was significantly attenuated by the MEK inhibitor, PD98059, but not by the JNK inhibitor, SP600125, or the p38 MAPK inhibitor, SB212090. LPA-induced COX-2 expression was repressed by pertussis toxin, GF109204X, and Ki16425, indicating the involvements of PTX-sensitive G_i/o protein, PKC, and the LPA_1/3 receptor, respectively. Our data suggest that in esophageal epithelial cells, LPA-induced COX-2 expression requires activation of PKC and ERK1/2 downstream of the LPA_1/3 receptor, Understanding the regulation of COX-2 expression induced by LPA in esophageal epithelial cells might provide a new therapeutic strategy for esophageal inflammatory diseases.     

Induction of a single dose of streptozotocin (50 mg) in rat model causes insulin resistance with type 2 diabetes mellitus

Streptozotocin (STZ) is a broad-spectrum antibiotic that is toxic to the insulin-producing beta cells of the pancreatic islets. STZ is currently used clinically for the treatment of metastatic islet cell carcinoma of the pancreas and the induction of diabetes mellitus (DM) in rodents. So far, there has been no previous research to show that STZ injection in rodents causes insulin resistance in type 2 diabetes mellitus (T2DM). The purpose of this study was to determine if rats (Sprague–Dawley) developed type 2 diabetes mellitus (insulin resistance) after 72 h of intraperitoneal administration of 50 mg/kg STZ. Rats with fasting blood glucose levels above 11.0 mM, 72 h post-STZ induction, were used. The body weight and plasma glucose levels were measured every week throughout the 60-day treatment period. The plasma, liver, kidney, pancreas, and smooth muscle cells were harvested for antioxidant, biochemical analysis, histology, and gene expression studies. The results revealed that STZ was able to destroy the pancreatic insulin-producing beta cell, as evidenced by an increase in plasma glucose level, insulin resistance, and oxidative stress. Biochemical investigation indicates that STZ can generate diabetes complications through hepatocellular damage, elevated HbA1c, kidney damage, hyperlipidemia, cardiovascular damage, and impairment of the insulin-signaling pathway.     

Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). It is characterized by the t(15;17)(q22;q11.2) chromosomal translocation that creates the promyelocytic leukemia-retinoic acid receptor α (PML-RARA) fusion oncogene. Although this fusion oncogene is known to initiate APL in mice, other cooperating mutations, as yet ill defined, are important for disease pathogenesis. To identify these, we used a mouse model of APL, whereby PML-RARA expressed in myeloid cells leads to a myeloproliferative disease that ultimately evolves into APL. Sequencing of a mouse APL genome revealed 3 somatic, nonsynonymous mutations relevant to APL pathogenesis, of which 1 (Jak1 V657F) was found to be recurrent in other affected mice. This mutation was identical to the JAK1 V658F mutation previously found in human APL and acute lymphoblastic leukemia samples. Further analysis showed that JAK1 V658F cooperated in vivo with PML-RARA, causing a rapidly fatal leukemia in mice. We also discovered a somatic 150-kb deletion involving the lysine (K)-specific demethylase 6A (Kdm6a, also known as Utx) gene, in the mouse APL genome. Similar deletions were observed in 3 out of 14 additional mouse APL samples and 1 out of 150 human AML samples. In conclusion, whole genome sequencing of mouse cancer genomes can provide an unbiased and comprehensive approach for discovering functionally relevant mutations that are also present in human leukemias.     

Acute Toxicity and General Pharmacological Action of QGC EXT

It has been shown that QGC isolated and purified from Rumecis folium found protective effects of gastritis and esophagitis which EXT is an ethanol extract of it. We examined acute toxicity and the general pharmacological action of QGC EXT to search for any side effects of it in rats, mice, guinea pigs, and cats. In a single dose toxicity study, QGC EXT didn't show toxicological effects in rats and mice, and the LD(50) was over 5 g/kg in both animals, and there were also no changes in weight, feed and water intake during these toxicological experimental periods. We examined the general pharmacological action on central controlled behavior responses, and peripheral organs including blood pressure, heart rate, respiration and gastrointestinal system, We found that there were no significant changes in body temperature, locomotors activity, stereotyped behaviors, sleeping time, and convulsion. In other studies, writhing reaction, normal body temperature, there did not appear to be any changes. The large intestine movement and electrical field stimulation-induced contraction was not changes by its EXT. In addition, the influences on blood pressure, heart rates, and respiration by QGC EXT were not found. These results indicate that QGC EXT may be very safe as a new drug, since its LD(50) was very high over 5 g/kg and any side effects were not found.