Synthetic Evolution of a Supramolecular Harpooning Mechanism to Immobilize Vesicles at Antifouling Interfaces

The immobilization of vesicles has been conceptualized as a method to functionalize biointerfaces. However, the preservation of their integrity post immobilization remains a considerable challenge. Interfacial interactions can cause vesicle rupture upon close surface contact and non-specific protein adsorption impairing surface functions. To date, immobilization of vesicles has relied solely on either entrapment or prior modification of vesicles, both of which require laborious preparation and limit their applications. This work develops a bioinspired strategy to pin vesicles without prior modification while preserving their intact shape. This work introduces antifouling diblock copolymers and ultrathin surface-attached hydrogels containing a brush-like interface consisting of a bottle brush copolymer of N-(2-hydroxypropyl) methacrylamide (HPMA) and N-(3-methacrylamidopropyl)-N,N-dimethyldodecan-1-aminiumiodide (C12+). The presence of positive charges generates an attractive force that pulls vesicles toward the surface. At the surface, the amphiphilic properties of the combs facilitate their insertion into the membrane, mimicking the harpooning mechanism observed in antimicrobial peptides. Importantly, the antifouling poly(HPMA) backdrop serves to safeguard the vesicles by preventing deformation and breakage. Using a combination of thermodynamic analysis, surface plasmon resonance, and confocal laser scanning microscopy, this work demonstrates the efficiency of this biomimetic system to capture vesicles while maintaining an antifouling interface necessary for bioapplications.     

High affinity of sigma1-binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C8–C7 isomerase

1. The sigma-drug binding site of guinea-pig liver is carried by a protein which shares significant amino acid sequence similarities with the yeast sterol C₈–C₇ isomerase (ERG2 protein). Pharmacologically - but not structurally - the sigma₁-site is also related to the emopamil binding protein, the mammalian sterol C₈–C₇ isomerase. We therefore investigated if sterol C₈–C₇ isomerase inhibitors are high affinity ligands for the (+)-[³H]-pentazocine labelled sigma₁-binding site.
2. Among the compounds which bound with high affinity to native hepatic and cerebral as well as to yeast expressed sigma₁-binding sites were the agricultural fungicide fenpropimorph (K_i 0.005 nM), the antihypocholesterinaemic drugs triparanol (K_i 7.0 nM), AY-9944 (K_i 0.46 nM) and MDL28,815 (K_i 0.16 nM), the enantiomers of the ovulation inducer clomiphene (K_i 5.5 and 12 nM, respectively) and the antioestrogene tamoxifen (K_i 26 nM).
3. Except for tamoxifen these affinities are essentially identical with those for the [³H]-ifenprodil labelled sterol C₈–C₇ isomerase of S. cerevisiae. This demonstrates that sigma₁-binding protein and yeast isomerase are not only structurally but also pharmacologically related. Because of its affiliations with yeast and mammalian sterol isomerases we propose that the sigma₁-binding site is localized on a sterol isomerase related protein, involved in postsqualene sterol biosynthesis.

     

Abdominal pain in an HIV-infected man

A case is presented of a 34-year-old man with a 10-year history of HIV infection (CD4 counts 750-1100/mm3) who initially presented with upper right quadrant pain that was crampy, achy and periumbilical, not affected by food, and was indicative of early-stage acalculous cholecystitis. Over a three month period, tests failed to identify the cause of his pain. It was first labeled gastroenteritis and then irritable bowel syndrome. By the third month, his pain was mostly in the right upper quadrant. This area was sore when touched and worse after ingestion of fatty foods. A test detected elevated transaminases. It appeared that he had acalculous cholecystitis, which is one of several hepatobiliary complications of HIV. In HIV-infected individuals, acalculous cholecystitis is often an infectious disease of the biliary tract. Patients present with right upper quadrant and/or epigastric pain that is worse after fatty meals. Eventually, sonographs can detect a thickening of the gall bladder wall and dilation of the hepatic ducts, but early in the disease it is unlikely that the test result will be abnormal. The condition is often caused by CMV and cryptosporidium, but other pathogens may also cause acalculous cholecystitis. Perforation of the gall bladder and development of potentially irreversible abnormalities which complicate infection may result if the condition is left untreated. Although frequently connected with infectious diseases, cholecystitis may also occur in patients with high CD4 counts and no other HIV-related conditions.     

Intraperitoneal Versus Interpleural Morphine or Bupivacaine for Pain after Laparoscopic Cholecystectomy

Background: Opioids can produce peripheral analgesic effects by activation of opioid receptors on sensory nerves. This study was designed (1) to examine a novel route of opioid administration, the intraperitoneal injection; (2) to compare this to interpleural application, and (3) to compare opioid with local anesthetic effects under both conditions.

Methods: At the end of laparoscopic cholecystectomy, 110 patients received the following injections in a double-blind, randomized manner: Group 1 (n = 18) was given intraperitoneal morphine (1 mg in 20 ml saline) and 20 ml intravenous saline. Group 2 (n = 17) received intraperitoneal saline and 1 mg intravenous morphine. Group 3 (n = 15) received 20 ml 0.25% intraperitoneal bupivacaine and intravenous saline. Group 4 (n = 20) received interpleural morphine (1.5 mg in 30 ml saline) and 30 ml intravenous saline. Group 5 (n = 20) received interpleural saline and 1.5 mg intravenous morphine. Group 6 (n = 20) received 30 ml 0.25% interpleural bupivacaine and intravenous saline. Postoperative pain was assessed using a visual analog scale, a numeric rating scale, and the McGill pain questionnaire. Pain localization, supplemental analgesic consumption, vital signs, and side effects were recorded for 24 h.

Results: Neither intraperitoneal nor interpleural morphine produced significant analgesia after laparoscopic cholecystectomy (P > 0.05, Kruskal-Wallis test), whereas interpleural bupivacaine was effective (P < 0.05, Kruskal-Wallis test, up to 6 h postoperatively) but not intraperitoneal bupivacaine (P > 0.05, Kruskal-Wallis test). Shoulder pain was not prevalent in the majority of patients during the first 6 h. By 24 h, about half of the patients complained of shoulder pain, which was rated "low" by about one-third of all patients. No significant side effects occurred.     

Failure rates among perfect users and during perfect use: a distinction that matters

To make an informed decision when choosing a contraceptive, women and couples need to know how effective different methods are when used perfectly, where perfect use is defined as following the directions for use. In this article, we show that unbiased estimates of pregnancy rates during perfect use can be guaranteed only if information on consistency and correctness of use is available for each menstrual cycle. The estimated probability of pregnancy during a year of perfect use among the subset of women who always used a method perfectly will be biased upward.     

Targeting for thalamic deep brain stimulator implantation without computer guidance: assessment of targeting accuracy

The authors assess the accuracy of targeting nucleus ventralis intermedius (Vim) with fast spin echo inversion recovery (FSE/IR) magnetic resonance imaging (MRI) in 18 successful deep brain stimulator (DBS) implants for medically refractory tremor. FSE/IR-MRI-derived coordinates are compared to the final coordinates employed for DBS lead placement, selected with intraoperative neurophysiology. The authors conclude that FSE/IR MRI is sufficiently reliable to serve as the sole means of anatomically targeting Vim for DBS lead placement. An independent computer workstation is not required for accurate targeting; however, intraoperative neurophysiology remains essential.     

Frequency of urolithiasis in individuals seropositive for human immunodeficiency virus treated with indinavir is higher than previously assumed

PURPOSE: Indinavir was approved by the Food and Drug Administration in 1996 as a human immunodeficiency type 1 protease inhibitor to treat human immunodeficiency virus infection. Prompted by the high number of patients receiving indinavir who present with renal colic at our institution, we performed a detailed investigation of the true frequency of urolithiasis during indinavir treatment. MATERIALS AND METHODS: We evaluated 105 patients with a mean age of 38.1 years who were treated with indinavir from 1996 to 1997. Before indinavir treatment was initiated all patients underwent renal ultrasonography, urinalysis, and determination of serum sodium, potassium, calcium, uric acid and creatinine. It was recommended that all patients drink 2 l of fluids daily, and all remained under continuous surveillance. RESULTS: Metabolic evaluation and ultrasonography showed no abnormality in any case. A stone episode occurred in 13 men (12.4%) as renal colic during observation. Colic recurred in 1 patient after 2 and 5 months, and in 1 after 2 months. Median duration of indinavir treatment until an acute stone episode was 21.5 weeks (range 6 to 50). A total of 12 stones passed spontaneously. Three patients underwent ureteroscopic calculous removal and 1 was treated with extracorporeal shock wave lithotripsy. CONCLUSIONS: Despite adequate patient information and compliance the rate of nephrolithiasis during indinavir therapy was 12.4%.     

Inhibitory effect of melatonin on products of lipid peroxidation resulting from chronic ethanol administration

Despite decades of research, the role of free radicals in alcohol-induced organ injury is still a matter of debate. The present work was designed to investigate the potential protective effect of melatonin, a reported radical scavenger and antioxidant, on free radical toxicity induced by chronic ethanol administration. The major end-point of oxidative damage measured in this report was lipid peroxidation. Four groups of male Sprague-Dawley rats were used. The first group served as untreated controls and received a daily injection of alcoholic (<1% ethanol) saline. The second group of rats received daily at 18:00 a single subcutaneous injection of melatonin (10 mg/kg). Group 3 rats received only ethanol (3 g/kg) for 30 consecutive days; the ethanol was given at 18:30. The final group of rats was given both melatonin and ethanol with melatonin preceding ethanol by 30 min. Products of lipid peroxidation [malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)] were measured in the brain, heart, liver, lung and testes. At the conclusion of the study, MDA + 4-HDA levels were significantly increased in brains, hearts, lungs and testes, but not livers, of alcohol-treated compared with control rats. The percentage increases in lipid peroxidation products were 21.8%, 28.8%, 35.9% and 45.3% for brain, heart, lung and testes, respectively. In animals given melatonin 30 min before ethanol, the increases in MDA + 4-HDA levels were significantly reduced in all organs investigated, with levels not different from those in control rats. Based on these findings, it is speculated that melatonin's direct and indirect antioxidative actions inhibited alcohol-induced lipid peroxidation. These results suggest a new strategy for the treatment of alcohol-related diseases using melatonin as an antioxidant to reduce the damage inflicted by aggressive radical species.     

The HIV wasting syndrome

Wasting syndrome, one of the most common complications of HIV disease, is more often found in people of low socioeconomic status and women. The pathophysiology of wasting and its treatment are discussed. Perturbations of metabolism, malnutrition, androgen deficiency, treating underlying illnesses, nutritional considerations, and pharmacologic approaches are explored. The first step to treating HIV wasting syndrome is to provide appropriate antiretroviral therapy, including meticulous prophylaxis and treatment of opportunistic infections (OIs). Other treatments include using oral supplements or total parenteral feeding to maintain nutritional levels, approved appetite stimulants, such as Megestrol acetate and dronabinol, or the controversial use of anabolic steroids. Concerns about steroid use include potential for abuse, and the possibility of developing malignancies and severe gonadal dysfunction.