Clinical, anatomic, and electrophysiologic evaluation following intravitreal bevacizumab for macular edema in retinal vein occlusion

PURPOSE: To investigate clinical, anatomic, and electrophysiologic response after single intravitreal injection of bevacizumab for macular edema attributable to retinal vein occlusion. DESIGN: Prospective nonrandomized, interventional case series. METHODS: Twenty-one patients with macular edema attributable to vein occlusion received intravitreal injection of bevacizumab 1.25 mg. Nine patients had central retinal vein occlusion (CRVO), and 12 patients had branch retinal vein occlusion (BRVO). Complete ophthalmic examination including optical coherence tomography (OCT) was done at baseline and follow-up visits. Fifteen patients underwent fluorescein angiography at baseline. Selected patients underwent electroretinography (ERG) and visual evoked potential (VEP) at baseline and follow-up. Follow-up was for 12 weeks. RESULTS: At baseline, mean visual acuity was 20/381 (median, 20/400) and showed improvement to mean 20/135 (median, 20/60) after one month, (P = .001). At 12 weeks, mean visual acuity was 20/178 (median, 20/80) (P = .001). The mean central retinal thickness (CRT) was 647.81 microm (median, 609.00 microm) at baseline and decreased to mean 293.43 microm (median, 222.00 microm) at one month (P = .001). At 12 weeks, mean CRT was 320.90 mum (median, 280.00 microm) (P = .001). ERG and VEP showed no worsening of the waveforms. There was no significant difference in the visual outcome between the BRVO and CRVO groups. CONCLUSION: Intravitreal injection of bevacizumab appears to result in significant short-term improvement of visual acuity and macular edema secondary to vein occlusion. The present report confirms the previous studies. No ocular toxicity or adverse effects were observed. However, prospective, randomized, controlled long-term studies are required with an adequate number of patients.     

Addition of Plasmapheresis Decreases the Incidence of Acute Antibody-Mediated Rejection in Sensitized Patients with Strong Donor-Specific Antibodies

Background and objectives: The objective of this study was to investigate the effects of desensitization protocols using intravenous Ig with or without plasmapheresis in patients with donor-specific anti-HLA antibodies on prevention of antibody-mediated rejection and downregulation of donor-specific antibodies.Design, setting, participants, & measurements: Thirty-five complement-dependent cytotoxicity T cell cross-match–negative but complement-dependent cytotoxicity B cell and/or flow cytometry cross-match–positive kidney transplant recipients were treated with high-dosage intravenous Ig plus Thymoglobulin induction treatment. Donor-specific antibody strength was stratified as strong, medium, or weak by Luminex flow beads. Group 1 patients had weak/moderate and group 2 strong donor-specific antibodiesResults: Whereas no group 1 patients had acute rejection, 66% of group 2 had acute rejection (44% antibody-mediated rejection, 22% cellular rejection). The protocol was then changed to the addition of peritransplantation plasmapheresis to patients with strong donor-specific antibodies (group 3). This change resulted in a dramatic decrease in the acute rejection rate to 7%. During a median 18 mo of follow-up, patient survival was 100, 100, and 93% and graft survival was 100, 78, and 86% in groups 1, 2, and 3, respectively. During follow-up, 17 (52%) patients lost donor-specific antibodies completely, and 10 (30%) lost some of donor-specific antibodies and/or decreased the strength of existing donor-specific antibodies.Conclusions: These results indicated that in patients with strong donor-specific antibodies, the addition of plasmapheresis to high-dosage intravenous Ig decreases the incidence of acute rejection. The majority of the patients, whether they received intravenous Ig alone or with plasmapheresis, lost their donor-specific antibodies during follow-up.Donor-specific anti-HLA antibodies (DSA) in patients who are sensitized through pregnancy, previous blood transfusions, or organ transplantation is an important obstacle in kidney transplantation. Sensitized patients wait longer on the deceased-donor transplantation list, may not receive a transplant, and may have greater morbidity and mortality. Some sensitized patients may have living donor candidates, but transplantation cannot be performed because of cross-match positivity. Recent desensitization protocols using the combination of plasmapheresis (PP) or immunoadsorption to remove DSA and/or intravenous Ig (IVIG) and rituximab to downregulate antibody-mediated immune responses have made kidney transplantation feasible by abrogating complement-dependent cytotoxicity (CDC) T cell cross-match positivity. In previous studies, two protocols were examined: High-dosage IVIG (2.0 g/kg) (1–3) and PP with low-dosage IVIG (100 mg/kg after each PP session) (4–8); however, acute antibody-mediated rejection (AMR) continued to be an important barrier and was still observed in at least 30 to 40% of the recipients included in these desensitization protocols, even when rituximab was added to the protocol.Whereas CDC T cell cross-match positivity is an absolute contraindication to kidney transplantation, the clinical significance of CDC B cell or flow cytometry (FC) T and/or B cell cross-match positivity are less clear. Most studies have demonstrated that CDC T cell cross-match–negative but CDC B or FC T/B cell cross-match–positive patients with DSA are at higher risk for developing acute cellular, antibody-mediated, and chronic rejection and graft loss (9,10). The role of desensitization protocols for these patients has not been studied in a large cohort. We previously reported our initial experience using low-dosage IVIG (300 mg/kg) and Thymoglobulin induction treatment in 15 patients (11,12). Because of early AMR in three patients, the IVIG dosage was increased to a total of 2.0 mg/kg in subsequent patients. Now, we present our experience in CDC T cell–negative but CDC B cell or FC T and/or B cell cross-match–positive kidney transplant recipients with DSA, who were stratified according to mean fluorescence indices of Luminex flow beads. The results showed that patients with strong DSA were at much higher risk for developing acute AMR early after transplantation, and the addition of peritransplantation PP to high-dosage IVIG and Thymoglobulin treatment significantly decreased the incidence of AMR. The majority of the patients, whether they received IVIG alone or with PP, lost DSA during follow-up.     

Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats,Dogs, and Humans

Enterohepatic recirculation (EHC) can greatly enhance plasma drug exposures and therapeutic effects. This study aimed to develop a population pharmacokinetic model that can simultaneously characterize the extent and time-course of EHC in three species using fimasartan, a novel angiotensin II receptor blocker, as a model drug. All fimasartan plasma concentration profiles in 32 rats (intravenous doses, 0.3–3 mg/kg; oral doses, 1–10 mg/kg), 34 dogs (intravenous doses, 0.3–1 mg/kg; oral doses, 1–10 mg/kg), and 42 healthy volunteers (single or multiple oral doses, 20–480 mg) were determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and simultaneously modeled in S-ADAPT. The proposed model quantitatively characterized EHC in three species after oral and intravenous dosing. The median (range) fraction of drug undergoing recirculation was 76.3% (64.9–88.7%) in rats, 33.3% (24.0–45.9%) in dogs, and 65.6% (56.5–72.0%) in humans. In the presence compared with the absence of EHC, the area under the curve in plasma was predicted to be 4.22-fold (2.85–8.85) as high in rats, 1.50-fold (1.32–1.85) in dogs, and 2.91-fold (2.30–3.57) in humans. The modeled oral bioavailability in rats (median (range), 38.7% (20.0–59.8%)) and dogs (median, 7.13% to 15.4%, depending on the formulation) matched the non-compartmental estimates well. In humans, the predicted oral bioavailability was 25.1% (15.1–43.9%) under fasting and 18.2% (12.2–31.0%) under fed conditions. The allometrically scaled area under the curve predicted from rats was 420 ng ⋅ h/mL for 60 mg fimasartan compared with 424 ± 63 ng ⋅ h/mL observed in humans. The developed population pharmacokinetic model can be utilized to characterize the impact of EHC on plasma drug exposure in animals and humans.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9764-2) contains supplementary material, which is available to authorized users.KEY WORDS: animal to human scaling, enterohepatic recirculation, fimasartan, population pharmacokinetics, S-ADAPT     

Aminoacidopathies: A review of 3 years experience of investigations in a Kuwait hospital

Summary We present a summary of the results of quantitative amino acid analysis in 800 subjects over a three-year period in Al-Sabah Hospital, Kuwait. Thirty-five patients with aminoacidopathy were identified, all but two of whom were the offspring of first-degree consanguineous marriages: nine cases of phenylketonuria, one benign hyperphenylalaninaemia, seven non-ketotic hyperglycinaemia, five tyrosinaemia, five homocystinuria, four citrullinaemia, two cystinuria, one hyperprolinaemia, and one maple syrup urine disease. The clinical and biochemical findings in these cases are described.     

Structural basis for substrate discrimination by E. coli repair enzyme,AlkB

E. coli AlkB, a repair enzyme of the dioxygenase family, catalyses the removal of mutagenic methylated nucleotides from the genome. Known for substrate promiscuity, AlkB''s catalytic mechanism and conformational changes accompanying substrate binding have been extensively dissected. However, the structural parameters of various substrates governing their recognition by AlkB still remain elusive. In this work, through solution-state vibrational spectra of methylated substrates bound to AlkB in combination with computational analysis, we show that the recognition specificity is dictated by the protonation states of the substrates. Specificity is conferred predominantly through hydrogen bonding and cation–π interactions. Furthermore, we report on the interaction of AlkB with normal, unmodified nucleotides, wherein the presence of an exocyclic amino group serves as an essential criterion for the initial process of substrate recognition. Taken together, these results provide a rationale for structural determinants of substrate specificity as well as mode of lesion discrimination employed by AlkB.

Positive charge on methylated nucleotides is a prime criterion for substrate recognition by E. coli AlkB.     

Rifaximin,a pregnane X receptor (PXR) activator regulates apoptosis in a murine model of breast cancer

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized and divided among four groups of six animals each. Group I (control 0.9% normal saline, 3 ml kg⁻¹, p.o.); Group II (toxic control, MNU 47 mg kg⁻¹, i.v.); Group III (RFX, 25 mg kg⁻¹, p.o.); Group IV (RFX, 50 mg kg⁻¹, p.o.). Toxicity was induced by single i.v. injection of MNU. MNU treatment was evident with increased alveolar bud count, differentiation score, up-regulated inflammatory enzyme markers (COX, LOX, NO and H₂S) and oxidative stress markers (TBAR''s, protein carbonyl, SOD, catalase and Ach). The mammary gland surface architecture was studied using SEM, carmine staining and H&E staining. The treatment with RFX elicited noticeable restoration of the overall histological architecture in the experimental animals similar to the control. In the MNU treated toxic group, the levels of oxidative stress markers significantly increased in comparison to the control, which was subsequently restored after RFX treatment. Furthermore, RFX up regulated the levels of caspase 3 and caspase 8, when compared to the MNU treated animals. MNU associated toxicity was also ascertained, when determined for UCHL-1, COX, NF-κBp65, BAD, and BCL-xl expression, while RFX demonstrated modulation of the same.

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats.     

Type 2 Diabetes and Anxiety Symptoms Among Women in New Delhi,India

Objectives. We explored the relationship between mental health and type 2 diabetes among women in New Delhi, India, in 2011.Methods. We recruited a convenience sample of 184 diabetic women from 10 public and private clinics. They completed a finger-stick blood test and a questionnaire assessing demographic characteristics, depression and anxiety symptoms, and diabetes-related disabilities restricting their performance of daily tasks. A subsample of 30 women participated in follow-up qualitative interviews at their homes.Results. More than one quarter of our sample of diabetic women reported high levels of anxiety symptoms, whereas 18% reported high levels of depression symptoms. Anxiety symptoms were patterned according to recency of diabetes diagnosis, with 40% of women diagnosed less than 2 years before their interview reporting high anxiety symptom levels, as opposed to 23% of women diagnosed more than 2 years in the past. Depression and anxiety scores differed with respect to their relationship to recency of diagnosis, number of children, blood glucose level, and functional disabilities restricting performance of daily tasks.Conclusions. Screening for anxiety among people with diabetes has been overlooked in the past. Anxiety appears more prevalent than depression, especially during the first 2 years of the disease.Chronic and noncommunicable diseases (CNCDs) are emerging as major research foci in tandem with their increasing global prevalence. In both developed and developing regions of the world, including South Asia, CNCDs are now leading causes of morbidity and mortality.1 With their complicated etiologies, long durations, frequent comorbidities, and lack of “cures,” CNCDs pose unique challenges for global health. In particular, CNCDs can have far-reaching personal and interpersonal effects that are difficult to capture in epidemiological and biomedical studies, yet are crucial to the trajectory of these illnesses. It is therefore necessary to adopt an analytic perspective that embraces the complex natural histories of chronic diseases as well as their potential comorbidities.A particularly well-studied instance of comorbidity is the overlap between type 2 diabetes and depression. This comorbidity has been estimated to affect anywhere from 11% to 71% of individuals with diabetes, depending on the population studied and the diagnostic method used,2–4 and it is strongly associated with physical and mental morbidity and even mortality.2–6 Clinical and epidemiological studies have demonstrated the cyclical nature of diabetes–depression comorbidity,7 and medical social scientists have identified some of the social determinants linking the 2 conditions, including socioeconomic status (SES),8 the social significance of foods and activity patterns,9,10 and gendered social roles.11–13The similarity between depression and anxiety symptoms, etiologies, and methods of diagnosis, as well as their common comorbidity,14 suggests that anxiety should be as great a concern in CNCD comorbidity as depression. Indeed, according to findings from the World Mental Health Survey, diabetes is roughly equally associated with depression and anxiety around the world.15 Yet, with one very recent exception,16 the potential impact of anxiety disorders on diabetes has received much less attention than diabetes–depression comorbidity.Here we detail the findings of an exploratory mixed-method study of type 2 diabetes (hereafter diabetes) and mental health symptoms among women in New Delhi, India, with a special focus on symptoms of anxiety. India is home to the second-largest population of individuals with type 2 diabetes in the world.17 The limited existing evidence suggests that depression and anxiety are also common,18–20 although prevalence studies are few. Little is known about how diabetes and poor mental health co-occur in this setting or about what social determinants might shape their comorbidity.On the basis of the observation that high levels of anxiety symptoms were significantly more prevalent than depression symptoms in our study, we believe that it is important to consider the causes and correlates of anxiety comorbid with diabetes. We propose a socially grounded interpretation of the patterns emerging from our preliminary data and offer suggestions for future research designed to assess the broader applicability of this interpretation for CNCD–anxiety comorbidity in other contexts.