Autoimmune bullous diseases: ocular manifestations and management

The ocular manifestations of autoimmune bullous diseases are common and potentially sight-threatening. Major ophthalmic involvement is most commonly seen in mucous membrane pemphigoid (cicatricial pemphigoid), epidermolysis bullosa acquisita, linear IgA bullous disease, pemphigus vulgaris and paraneoplastic pemphigus. The main pathological process is related to autoimmune-induced conjunctival inflammation with consequent lid and corneal pathology, which may eventually result in permanent visual loss. Ocular involvement can be asymptomatic. Early detection is aided by careful attention to symptoms and signs of early ophthalmic disease. Ocular disease can be difficult to treat and management usually involves systemic therapy with immunomodulators to control inflammation and prevent progression to irreversible blindness, as well as surgical intervention in advanced disease. Recent advances in treatment, including methotrexate, mycophenolate mofetil, monoclonal antibodies and topical tacrolimus therapies, have led to promising results.     

Early detection and prediction of cardiotoxicity in chemotherapy-treated patients

As breast cancer survival increases, cardiotoxicity associated with chemotherapeutic regimens such as anthracyclines and trastuzumab becomes a more significant issue. Assessment of the left ventricular (LV) ejection fraction fails to detect subtle alterations in LV function. The objective of this study was to evaluate whether more sensitive echocardiographic measurements and biomarkers could predict future cardiac dysfunction in chemotherapy-treated patients. Forty-three patients diagnosed with breast cancer who received anthracyclines and trastuzumab therapy underwent echocardiography and blood sampling at 3 time points (baseline and 3 and 6 months during the course of chemotherapy). The LV ejection fraction; peak systolic myocardial longitudinal, radial, and circumferential strain; echocardiographic markers of diastolic function; N-terminal pro-B-type natriuretic peptide; and high-sensitivity cardiac troponin I were measured. Nine patients (21%) developed cardiotoxicity (1 at 3 months and 8 at 6 months) as defined by the Cardiac Review and Evaluation Committee reviewing trastuzumab. A decrease in longitudinal strain from baseline to 3 months and detectable high-sensitivity cardiac troponin I at 3 months were independent predictors of the development of cardiotoxicity at 6 months. The LV ejection fraction, parameters of diastolic function, and N-terminal pro-B-type natriuretic peptide did not predict cardiotoxicity. In conclusion, cardiac troponin plasma concentrations and longitudinal strain predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab. The 2 parameters may be useful to detect chemotherapy-treated patients who may benefit from alternative therapies, potentially decreasing the incidence of cardiotoxicity and its associated morbidity and mortality.     

Targeting vascular endothelial growth factor: a promising strategy for treating age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the industrialised world. While treatment options for advanced AMD have been rather limited until recently, the introduction of intravitreal injections of anti-angiogenic agents appears to be a promising and revolutionary mode of treatment for this blinding disease. Vascular endothelial growth factor (VEGF) appears to play a pivotal role in the pathogenesis of choroidal neovascularisation, one of the cornerstones of advanced AMD. Pegaptanib, the first anti-VEGF treatment approved for AMD patients, is a VEGF-neutralising aptamer that specifically inhibits one isoform of VEGF (VEGF-165). Although evidence suggested that pegaptanib was superior to previous treatment options, results with this agent were still unsatisfactory. Ranibizumab is a humanised anti-VEGF monoclonal antibody fragment that inhibits all isotypes of VEGF. This new drug has demonstrated a high efficacy profile in terms of inhibiting disease progression and even improving visual acuity. Bevacizumab is a full-length anti-VEGF antibody that was originally approved for use in metastatic colon cancer and is under investigation as a low-cost off-label alternative for patients with AMD. There is growing evidence that this drug may be an effective and safe alternative to the more expensive ranibizumab, although prospective multicentre trials are required to fully investigate this issue. Undoubtedly, the concept of directly injecting anti-VEGF drugs into the vitreal cavity brings new hope to many AMD patients.     

Hepatic and peripheral insulin sensitivity and diabetes remission at 1 month after Roux-en-Y gastric bypass surgery in patients randomized to omentectomy

OBJECTIVE

Early after Roux-en-Y gastric bypass (RYGB), there is improvement in type 2 diabetes, which is characterized by insulin resistance. We determined the acute effects of RYGB, with and without omentectomy, on hepatic and peripheral insulin sensitivity. We also investigated whether preoperative diabetes or postoperative diabetes remission influenced tissue-specific insulin sensitivity after RYGB.

RESEARCH DESIGN AND METHODS

We studied 40 obese (BMI 48 ± 8 kg/m²) participants, 17 with diabetes. Participants were randomized to RYGB alone or in conjunction with omentectomy. Hyperinsulinemic-euglycemic clamps with isotopic-tracer infusion were completed at baseline and at 1 month postoperatively to assess insulin sensitivity.

RESULTS

Participants lost 11 ± 4% of body weight at 1 month after RYGB, without an improvement in peripheral insulin sensitivity; these outcomes were not affected by omentectomy, preoperative diabetes, or remission of diabetes. Hepatic glucose production (HGP) and the hepatic insulin sensitivity index improved in all subjects, irrespective of omentectomy (P ≤ 0.001). Participants with diabetes had higher baseline HGP values (P = 0.003) that improved to a greater extent after RYGB (P = 0.006). Of the 17 participants with diabetes, 10 (59%) had remission at 1 month. Diabetes remission had a group × time effect (P = 0.041) on HGP; those with diabetes remission had lower preoperative and postoperative HGP.

CONCLUSIONS

Peripheral insulin sensitivity did not improve 1 month after RYGB, irrespective of omentectomy, diabetes, or diabetes remission. Hepatic insulin sensitivity improved at 1 month after RYGB and was more pronounced in patients with diabetes. Improvement in HGP may influence diabetes remission early after RYGB.Of the estimated 26 million people in the U.S. with type 2 diabetes and the 79 million with prediabetes (1), ∼80% are overweight or obese. Roux-en-Y gastric bypass (RYGB) surgery for treatment of obesity leads to long-term diabetes remission in ∼80% of patients (2), whereas very limited effects are observed with lifestyle intervention (3). Improvements in diabetes are reported to occur immediately after RYGB (4), with ∼30% of patients being discharged from the hospital with discontinuation of all diabetes medications (5).Impaired insulin sensitivity (insulin resistance) at the liver and in the periphery (primarily skeletal muscle) is an underlying mechanism of and precursor to diabetes (6). Several studies have described a long-term improvement in peripheral and hepatic insulin sensitivity 6 months to 1 year after RYGB (7–9), which is considered to occur secondary to weight loss. The mechanisms of the immediate improvement in diabetes after RYGB, before substantial weight loss, are not well delineated. Improvements in insulin sensitivity are reported early after RYGB, by hyperglycemic clamp at 1 and 4 weeks postoperatively (10) or by intravenous glucose tolerance tests (11) and homeostasis model assessment (HOMA) during the first week postoperatively (11,12). These approaches to measure insulin sensitivity, however, cannot distinguish between peripheral and hepatic insulin sensitivity. The hyperinsulinemic-euglycemic clamp method in conjunction with isotopically labeled tracer infusion allows measurement of peripheral (primarily skeletal muscle) insulin sensitivity as well as hepatic glucose production (HGP) and hepatic insulin sensitivity. Two studies have used this technique to assess insulin sensitivity early after RYGB, and interestingly, did not find a significant improvement in peripheral insulin sensitivity 2 to 4 weeks after RYGB; however, hepatic insulin sensitivity was not assessed (13,14). Recently, Camastra et al. (7) reported that peripheral and hepatic insulin sensitivity did not change at 2 weeks after RYGB in patients with and without diabetes.Increased visceral fat is considered an important risk factor for diabetes and insulin resistance (15). We recently reported, however, that surgical removal of the greater omentum (omentectomy) in conjunction with RYGB did not augment the improvement in insulin sensitivity long-term after RYGB (8). Here we report the acute effects of RYGB with or without omentectomy on hepatic and skeletal muscle insulin sensitivity. This was assessed by hyperinsulinemic-euglycemic clamp with tracer infusion at 1 month after RYGB. We also tested the hypothesis that an early remission of diabetes after RYGB is associated with improved hepatic and peripheral insulin sensitivity.     

Ultrasonographic Evidence of Intra-Abdominal Umbilical Vein Dilatation: Is It a True Varix?

Fetal intraabdominal umbilical vein (FIUV) dilatation, or varix, is a rare ultrasonographic (US) finding of focal dilatation of the umbilical vein. This article describes FIUV tortuosity in cases with suspected varix and provides ultrasonographic criteria for its diagnosis. Cases of suspected FIUV varix referred to our unit for final diagnosis and follow-up were studied. Each woman underwent comprehensive US evaluations that included basic grayscale scan and color Doppler scan. In 12 singleton pregnancies, primary grayscale scan confirmed FIUV dilatation. Supplementary color Doppler scans, however, revealed linear bidirectional blood flow and FIUV tortuosity in all cases. Color Doppler scans did not depict true FIUV dilatations or varix but rather a tortuous course of the vein. A normal pregnancy outcome can be expected in these cases.     

The unique features of Th9 cells and their products

Although it was discovered more than two decades ago, new information concerning the biological activities of IL-9 has been provided in recent years, after the isolation of cells that selectively produce this cytokine, designated "Th9." Th9 cells are generated in vitro by polarization, mainly by TGF-β and IL-4, during activation with the specific antigen, or with anti-CD3/CD28 antibodies. This review deals mainly with Th9 generated by the former, "physiological" mode of activation. Of particular interest is the unique production kinetics of IL-9: the cytokine is produced very rapidly, but after reaching its peak (day 3 in our studies), it declines sharply to trace levels. In addition to IL-9, Th9 cells also produce similar amounts of another cytokine, IL-10, but the production kinetics of these two cytokines are strikingly different. Antigen-activated Th9 in our studies also developed pathogenic capacity, but only during the short time period of peak IL-9 production. Interestingly, no IL-9-producing cells were detected in sites of inflammation induced by Th9, in contrast to Thl and Thl7. The unique features of Th9 cells and their products are discussed with regards to the known and assumed functions of the cytokine.