Endothelial cell loss due to repeated traumatic wound dehiscence after penetrating keratoplasty

A patient with keratoconus suffered two traumatic ruptures of her corneal graft wound, both of which were successfully repaired with restoration of graft clarity. There were also two apparently unrelated episodes of rejection. The endothelium was monitored by specular microscopy during this period. Our findings suggest that the insult to a transplanted cornea from an episode of rejection may be greater than that from traumatic wound rupture.     

Regulation of autoimmune response

Recent work on such apparently disparate fields as T-cell receptor peptide-induced regulation, superantigens, antigen-induced tolerance, models of peripheral tolerance, apoptosis, and T-cell receptor antagonists demonstrates a similarity in immune response from a regulatory perspective. In many systems, a ‘tolerance’ pathway is observed, characterized broadly as an initial disturbance in the immune system, with a resulting predominance of effector cells, followed by a homeostatic response (often requiring CD8⁺ cells) which leads the effector population into T-cell receptor downregulation, T-cell inactivation, anergy and, often, eventual apoptotic death. In the regulated immune response, mixed populations of anergized and apoptosing T cells can be found. In some cases, anergy appears to lead to death while, in other instances, cells revert to a functional state. This review focuses on recent papers examining each of these topics in an attempt to obtain a preliminary, integrated picture of immune regulation in autoimmune diseases.     

Enzyme immunoassay compared with cell culture and immunofluorescence for detecting genital chlamydia.

A novel enzyme immunoassay test (Pharmacia EIA) was evaluated against cell culture for the detection of chlamydial genital infection. Specimens were obtained from 525 patients (257 men and 268 women). Sensitivity, specificity, predictive value of positive (PVP) and predictive value of negative (PVN) for the new test were, respectively, 83.6, 98.5, 94.4 and 95.1% for men and 86, 97.2, 87.8 and 96.8% for women. Discrepancies were further evaluated by repeating the EIA, and by direct immunofluorescence on the EIA transport buffer. The sensitivity, specificity, PVP and PVN of the EIA against the combination of cell culture and direct immunofluorescence were, respectively 85.9, 100, 100, and 95.5% for men, and 90.5, 98.1, 92.3 and 97.7% for women. Overall agreement between the EIA and the combination of cell culture and direct immunofluorescence was 97%. The Pharmacia EIA is rapid and simple to perform and does not require elaborate equipment.     

Placental transport of Zidovudine in the rhesus monkey

Objective: This study was undertaken to characterize the pharmacokinetics of zidovudine (ZDV) and ZDV-glucuronide (ZDVG) in the material and :fetal circulations of the rhesus monkey.Methods: Cannulas were placed in the maternal external jugular and the fetal internal jugular and carotid artery in 8 pregnant monkeys at .120-130 days gestation. ZDV (3.5 mg/kg) was administered to 5 monkeys and ZDVG (3.5 mg/kg) to 3 monkeys as single intravenous bolus infusions through the maternal catheter. Maternal and fetal blood , samples were collected every 20 min for the first 2 h and then every hour for the next 4 h. Maternal and fetal concentrations of ZDV and ZDVG were determined using high, performance liquid chromatography (HPLC) with ultraviolet (UV) detection.Results: In monkeys who received ZDV, the terminal half-life (T1/2) for ZDV was 37+/-15 and 33 +/- 13 min in the maternal and fetal compartments, respectively. The apparent T1/2 for maternal ZDVG was 124 +/- 44 and 142 +/- 50 min in the maternal and fetal compartments, respectively. Peak levels of ZDV and ZDVG in the fetal compartment were reached 40 min after injection. The mean fetal/maternal concentration ratios for ZDV and ZDVG ranged from 0.20 +/- 0.20 at 20 min to a maximum of 0.74 +/- 1.0 at 120 min and from 0.28 +/- 0.08 at 20 min to 1.4 +/- 1.3 at 180 min, respectively. In monkeys who received ZDVG, the T1/2 for ZDWG in the maternal and fetal compartments was 47 +/- 26 and 119 +/- 164 min, respectively. ZDVG reached its peak in the fetal compartment at 60 min post-injection. The fetal/maternal rafio ranged from 0.08 +/- 0.11 at 20 min to 4.2 +/- 4.2 at 180 min post-injection.Conclusions: These data demonstrate that 1) ZDV and ZDVG rapidly cross the placenta to the fetal compartment, 2) ZDV crosses more rapidly than ZDVG, and 3) some metabolism of ZDV to ZDVG occurs in the fetal compartment.     

Quantitative comparison of intrabrain diffusion in adults and preterm and term neonates and infants

OBJECTIVE: Quantitative measurements of mean water diffusivity (D(av)) were made in human neonates, infants, and adults to assess changes in brain tissue that occur with maturation. SUBJECTS AND METHODS: Values of D(av) were obtained by calculating the average of the diffusion measurements made with diffusion-sensitizing gradients placed along three orthogonal directions. The mean diffusivity, a rotationally invariant determination of apparent diffusion coefficient, was measured in five healthy prematurely born neonates and infants, in 10 healthy term neonates and infants, and in five adults. RESULTS: Values of D(av) were found to decrease with maturation in most parts of the brain. In prematurely born neonates and infants with a postmenstrual age (postgestastional age + postnatal age) under 36 weeks, the average value of D(av) in frontal white matter was 1.90 x 10(-3) mm2 sec(-1). The corresponding value was measured as 1.62 x 10(-3) mm2 sec(-1) in neonates and infants born at term with a postnatal age of no more than 43 days and 0.79 x 10(-3) mm2 sec(-1) in the adult brain. CONCLUSION: Values of D(av) are known to decrease in neonates and young infants in the period immediately after ischemic insult. This decrease and the associated increase in signal intensity seen on diffusion-weighted imaging have been used to monitor ischemic brain injury in neonates and infants. Therefore, the decrease in D(av) that occurs with maturation, which we report in this study, must be considered if quantitative diffusion measurements are used to assess ischemic neonatal brain injury.     

Inhibitor design by wrapping packing defects in HIV-1 proteins

Two viral proteins, HIV-1 protease and HIV-1 integrase, have been targeted for inhibitor design to prevent assembly and maturation of HIV-1 virions. The enzymatic mechanism of these proteins involves side-chain groups that serve as general acids or bases. Furthermore, catalytic activity requires that water be removed from the microenvironment surrounding the chemical reaction site or be constrained to serve as an activated nucleophile. Here, we identify previously unrecognized structural features that promote water removal from polar catalytic regions. Packing defects in the form of hydrogen bonds that are insufficiently dehydrated intramolecularly, named "dehydrons," are strategically placed in the structure to induce an anhydrous enzymatic pathway. Dehydrons become electrostatically enhanced and stabilized upon further desolvation. Thus, packing defects act synergistically with the polar active groups to enhance the enzymatic electrostatics. However, because dehydrons are sticky, they constitute targets for inhibitor design. We noticed that inhibitors attach to polar surfaces by further desolvating dehydrons, thus blocking the active sites or the sites involved in harnessing the substrate. The dehydrons are thus required for functional reasons, making them suitable targets. The differences in success when targeting HIV-1 protease, feline immunodeficiency virus protease, and HIV-1 integrase are rationalized in terms of the dehydron distribution, revealing possible improvements in the targeting strategy. Principles of design optimization are proposed to create an inhibitor that can be neutralized only at the expense of the loss of catalytic function. The possibility of using drugs that wrap dehydrons to block protein-protein associations is also discussed.     

Indeterminate biliary strictures: a simplified approach

Introduction: Pre-operative evaluation of biliary strictures remains challenging. The dilemma that exists is how to balance the risk of failing to detect malignancy and the potential morbidity caused by unnecessary surgery in patients with benign etiologies. With emerging novel diagnostic modalities, this study aims to assess the efficacy of diagnostic techniques and facilitate a clinical approach to indeterminate biliary strictures.

Areas covered: Conventional imaging modalities are crucial in identifying the location of a stricture and are helpful for choosing further diagnostic modalities. Utilization of endoscopic techniques, including endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS), is key in establishing a diagnosis. The emergence of novel diagnostic modalities, such as fluorescence in-situ hybridization (FISH), peroral cholangioscopy (POC), intraductal endoscopic ultrasound (IDUS) and confocal laser endomicroscopy (CLE), enhance the diagnostic yield in the evaluation of indeterminate biliary strictures.

Expert commentary: More reliable and validated visual criteria for differentiating malignancy from benign biliary conditions, utilizing advanced imaging modalities such as POC and CLE, need to be established. It is of significance to further evaluate these novel diagnostic modalities through ongoing trials and to develop a diagnostic algorithm that reconciles cost-effectiveness with diagnostic accuracy.