Clinical and genetic characterization of a large primary open angle glaucoma pedigree

Purpose: To both characterize the clinical features of large primary open angle glaucoma (POAG) pedigree from a village in southern India and to investigate the genetic basis of their disease.

Materials and methods: Eighty-four members of a large pedigree received complete eye examinations including slit lamp examination, tonometry, gonioscopy, and ophthalmoscopy. Some were further studied with perimetry. Those diagnosed with POAG were tested for disease-causing mutations in the myocilin and optineurin genes with Sanger sequencing.

Results: Fourteen of 84 family members were diagnosed with POAG, while eight were clinically judged to be POAG-suspects. The family structure and the pattern of glaucoma in the pedigree are complex. Features of glaucoma in this pedigree include relatively early age at diagnosis (mean 50 ± 14 years) and maximum intraocular pressures ranging from 14 to 36 mm Hg with a mean of 23 mm Hg ± 6.5 mm Hg. Patients had an average central corneal thickness (mean 529 ± 37.8 microns) and moderate cup-to-disc ratios (0.74 ± 0.14). No mutations were detected in myocilin, optineurin, or TANK binding kinase 1 (TBK1).

Conclusions: We report a five-generation pedigree with a complex pattern of POAG inheritance that includes 22 POAG patients and glaucoma suspects. Although the familial clustering of POAG in this pedigree is consistent with dominant inheritance of a glaucoma-causing gene, mutations were not detected in genes previously associated with autosomal dominant glaucoma, suggesting the involvement of a novel disease-causing gene in this pedigree.     

RETRACTED ARTICLE: PEDF inhibits VEGF- and EPO- induced angiogenesis in retinal endothelial cells through interruption of PI3K/Akt phosphorylation

Retinal angiogenesis in diabetes may lead to visual impairment and even irreversible blindness in people of working age group worldwide. The main pathological feature of proliferative diabetic retinopathy (PDR) is hypoxia, and overproduction of growth factors like vascular endothelial growth factor (VEGF) and erythropoietin (Epo). This results in pathological proliferation of retinal endothelial cells (RECs), leading to new vessel formation (angiogenesis). Inhibition of angiogenesis is a promising strategy for treatment of PDR and other retinal neovascular disorders. Pigment epithelium-derived factor (PEDF), a 50-kDa protein secreted by retinal pigment epithelium, inhibits the growth of new blood vessel induced in the eye in a variety of ways with a yet elusive mechanism. Here, we investigated the possible mechanism by which PEDF inhibits VEGF- and Epo-induced angiogenic effects in RECs is mediated through PI3K/Akt pathway. PEDF treatment induced the apoptosis in RECs by activating caspase-3 and DNA fragmentation. We found a dose-dependent increase in cell survival with VEGF or Epo, which was attenuated in the presence of PEDF. In addition, PEDF significantly (P < 0.05) inhibited migration and in vitro tube formation in RECs in the presence of VEGF as like PI3K/Akt inhibitor. Of interest, PEDF effectively abrogated VEGF-mediated phosphorylation of PI3K/Akt. Further studies using RECs transfected with constitutively active and dominant-negative forms of Akt suggest that PEDF could inhibit VEGF- and also Epo-induced angiogenesis by disruption of PI3K/Akt signaling.     

Alterations in host responsiveness in patients with prostatic cancer following cryosurgery or transurethral resection.

Anesthesia, stress, trauma or the operation per se have been reported to result in alterations of host resistance in a wide range of diseases. The effect of such changes on the thymolymphatic system of patients with prostatic cancer is not known. While evaluating in vitro parameters of cellular immunologic responsiveness in patients with prostatic cancer, we have observed a depression two to seven days following cryosurgery or transurethral resection (TUR) of the proliferation of phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBL). Contrary to the reduced proliferation of PBL cultured in autologous and homologous serum from patients receiving TUR, patients receiving cryosurgery, while also showing reduction in autologous serum, showed increased responsiveness when cultured in homologous serum. Although transient, depression of lymphocyte proliferation, particularly if involving tumor-cloned T-cells, may provide reduced surveillance to potential metastatic tumor cells leading to an alteration of tumor-host homeostasis. The potential of reduced surveillance, at least in the case of TUR, appears to be supported by observations that patients dying from prostatic cancer at our institution had an antecedent TUR. Identifying those patients with changes in responsiveness before surgery, as well as those prone to develop or undergo further reductions in responsiveness after surgery, would appear to be relevant in the management of patient with prostatic as well as other malignancies. Pre- and/or postoperative immunotherapy in such patients may be indicated.     

Evaluation of cellular immunologic responsiveness in the clinical management of patients with prostatic cancer. II. Effect of oestrogen, cryosurgery and transurethral resection on thymic-dependent lymphocytic blastogenesis.

The effect of oestrogen, cryosurgery and transurethral resection (TUR) of the prostate on the blastogenic response of thymic-dependent peripheral blood lymphocytes (PBL) to the non-specific mitogen, phytohaemagglutinin (PHA) was evaluated as one in vitro criteria of each of these treatment modalities on the cellular immunologic responsiveness of 24 patients with prostatic cancer. A depression 5 days following receipt of oestrogen and 2-7 days following cryosurgery or TUR of the responsiveness of PHA-stimulated PBL was observed. Oestrogen-induced aberrations of responsiveness may not only be of relevance in prostatic cancer patients, but also suggested association between uterine cancer and prolonged administration of diethylstilboesterol and the development of vaginal tumours in offspring found in association with maternal ingestion during pregnancy. Particularly striking was that contrary to the reduced responsiveness of PBL cultured in autologous and homologous serum from patients receiving TUR, patients receiving cryosurgery, while also showing reduction in autologous serum, showed increased responsiveness when cultured in homologous serum. Although transient, depression of lymphocyte responsiveness, particularly if involving tumour-cloned T cells, may provide reduced surveillance to potential tumour cells leading to an alteration of tumour-host homeostasis. The potential of reduced tumour surveillance at least in the case of TUR, appears to be supported by observations that patients expiring from prostatic cancer at our institution had an antecedent TUR. The possibility of identifying those patients possessing aberrations of responsiveness prior to therapy, as well as those prone to develop or undergo further reduction in their responsiveness following the presently evaluated treatment modalities would appear to be of real and relevant concern in the management of the patient with prostatic, as well as other types of malignant neoplasms. The possibility of pre-operative and/or post-operative immunotherapy in such patients may be indicated pending further study.     

Lipid effects of glyburide/metformin tablets in patients with type 2 diabetes mellitus with poor glycemic control and dyslipidemia in an open-label extension study

BACKGROUND: Because both type 2 diabetes and elevated plasma lipid levels are important independent risk factors for cardiovascular disease and coronary heart disease, the choice of an antihyperglycemic agent for patients with type 2 diabetes--in whom abnormal plasma lipid levels are often seen-should take into account effects on lipids as well as on markers of glycemic control. OBJECTIVE: This study assessed the effects on lipid levels of glyburide/metformin tablets in the treatment of type 2 diabetes, particularly in a group of patients who had poor glycemic control and dyslipidemia at baseline. METHODS: This 52-week, open-label study was an extension of a 32-week, double-blind, placebo-controlled study. The patient population was drawn from 3 groups: those who completed the double-blind study, those who were discontinued from the double-blind study, and those who were ineligible for the double-blind study based on predefined measures of glycemic control (screening fasting plasma glucose > 240 mg/dL and glycosylated hemoglobin [HbA1c] < or = 12%, or HbA1c 11%-12%) and were directly enrolled in the open-label extension study. Patients with an HbA1c of < 9% received glyburide/ metformin tablets 1.25 mg/250 mg BID; those with an HbA1c > or = 9% received glyburide/ metformin tablets 2.5 mg/500 mg BID. Changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels were assessed for 52 weeks. RESULTS: The study population included 828 patients: 515 who completed the double-blind study, 138 who were discontinued from the double-blind study, and 175 who were enrolled directly. Direct enrollees had poor glycemic control and dyslipidemia at baseline. Improvements in plasma lipid levels were seen as early as week 13. At week 52, the mean change in TC from baseline was -8.0 mg/dL for the total population (95% CI, -10.9 to -5.2; P < 0.05) and -23.2 mg/dL for direct enrollees (95% CI, -30.1 to -16.4; P < 0.05). The mean decrease in LDL-C from baseline for the total population was 2.86 mg/dL (95% CI, -5.3 to -0.4; P < 0.05), compared with a reduction of 13.3 mg/dL for direct enrollees (95% CI, -18.5 to -8.1; P < 0.05). Mean HDL-C levels were minimally affected. Mean TG levels decreased by 27.8 mg/dL for the entire population (95% CI, -42.9 to -12.8; P < 0.05) and by 99.7 mg/dL for direct enrollees (95% CI, -152.5 to -46.8; P < 0.05). CONCLUSION: In this open-label extension study, treatment with glyburide/ metformin tablets for type 2 diabetes had a durable, favorable effect on lipid levels, particularly in those with poor glycemic control and dyslipidemia at baseline.     

The role of physicians and medical organizations in the development, analysis, and implementation of health care policy

Health policy is developed in the United States through a complicated interplay of governmental and private agencies and businesses, physician organizations, and societies as well as a host of other private ventures. The end result is rarely precisely what any individual or group may desire as the consequences of any action are never entirely predictable. There are many pathways to influence policy development within this system, and many of these are influenced by physicians as individuals and through organized medical societies. Opportunities abound to constructively engage the system, and it is important that physicians operating within this system understand where and how they may influence policy development. Changes are made or considered on a daily basis that impact patient's access to care, implementation and access to technological and biological innovation, reporting requirements, insurance, physician's reimbursement, and so on. This article reviews the most important channels by which physician input is incorporated in the system. The role of specialty societies, general medical societies, Congress, and Centers for Medicare and Medicaid Services are reviewed. The role of other players will also be addressed to show the many routes by which policy may evolve. Much of the discussion revolves around reimbursement because reimbursement often determines the availability and use of procedures and technology for our patients.     

Wear Mechanism of Multilayer Coated Carbide Cutting Tool in the Milling Process of AISI 4340 under Cryogenic Environment

Cryogenic technique is the use of a cryogenic medium as a coolant in machining operations. Commonly used cryogens are liquid nitrogen (LN2) and carbon dioxide (CO₂) because of their low cost and non-harmful environmental impact. In this study, the effects of machining conditions and parameters on the wear mechanism were analysed in the milling process of AISI 4340 steel (32 HRC) under cryogenic conditions using a multilayer coated carbide cutting tool (TiAlN/AlCrN). A field emission scanning electron microscope with energy-dispersive X-ray analysis was used to examine the wear mechanisms comprehensively. At low machining parameters, abrasion and adhesion were the major wear mechanisms which occurred on the rake face. Machining at high machining parameters caused the removal of the coating material on the rake face due to the high temperature and cutting force generated during the cutting process. In addition, it was found that continuously adhered material on the rake face would lead to crater wear. Furthermore, the phenomenon of oxidation was also observed when machining at high cutting speed, which resulted in diffusion wear and increase in the crater wear. Based on the relationship between the cutting force and cutting temperature, it can be concluded that these machining outputs are significant in affecting the progression of tool wear rate, and tool wear mechanism in the machining of AISI 4340 alloy steel.     

Lowering of intraocular pressure after phacoemulsification in primary open-angle and angle-closure glaucoma: Correlation with lens thickness

Purpose:To assess anterior chamber configuration changes during phacoemulsification in primary angle-closure suspect (PACS/PAC) and primary open-angle glaucoma (POAG).Methods:Prospective observational comparative study of anterior segment optical coherence tomography (AS-OCT) findings before and after phacoemulsification on three groups of patients (PACS/PAC, POAG, and controls). Data were collected over a period of 9 months. Main outcome measures included mean change in anterior chamber depth (ACD), angle opening distance (AOD), and trabecular iris space area (TISA).Results:153 patients (51 PACS/PAC, 51 POAG, and 51 controls) were included in the study. Change in all parameters (ACD, AOD at 500 um, and AOD at 750 um) between the groups demonstrated a greater change in PACS/PAC as compared to POAG and controls. AOD at 750 μm in the temporal quadrant, which has been considered to be having the highest correlation or best representation of the angle, increased in all groups after phacoemulsification (463.59 ± 10.99 vs. 656.27 ± 9.73 mm in PACS; 521.29 ± 16.36 vs. 674.37 ± 8.72 mm in POAG; 549.27 ± 12.40 vs. 702.82 ± 13.04 mm in controls, (P < 0.001). After phacoemulsification, intraocular pressure (IOP) decreased by 2.75 ± 1.17 mm Hg in PACS/PAC (P < 0.001), 2.14 ± 1.33 mm Hg in POAG and 1.90 ± 1.25 mm Hg in controls and it was statistically significant in the PACS group compared to control (P < 0.001).Conclusion: Phacoemulsification with intraocular lens implantation is associated with increase in the ACD and angle parameters and a corresponding decrease in IOP. Findings were more pronounced in PACS/PAC suggesting early phacoemulsification may be a treatment option in this group.