Function of circle of Willis

Nearly 400 years ago, Thomas Willis described the arterial ring at the base of the brain (the circle of Willis, CW) and recognized it as a compensatory system in the case of arterial occlusion. This theory is still accepted. We present several arguments that via negativa should discard the compensatory theory. (1) Current theory is anthropocentric; it ignores other species and their analog structures. (2) Arterial pathologies are diseases of old age, appearing after gene propagation. (3) According to the current theory, evolution has foresight. (4) Its commonness among animals indicates that it is probably a convergent evolutionary structure. (5) It was observed that communicating arteries are too small for effective blood flow, and (6) missing or hypoplastic in the majority of the population. We infer that CW, under physiologic conditions, serves as a passive pressure dissipating system; without considerable blood flow, pressure is transferred from the high to low pressure end, the latter being another arterial component of CW. Pressure gradient exists because pulse wave and blood flow arrive into the skull through different cerebral arteries asynchronously, due to arterial tree asymmetry. Therefore, CW and its communicating arteries protect cerebral artery and blood–brain barrier from hemodynamic stress.     

Molecular insights into the mechanism of nonrecurrent F8 structural variants: Full breakpoint characterization and bioinformatics of DNA elements implicated in the upmost severe phenotype in hemophilia A

Hemophilia A (HA) provides excellent models to analyze genotype–phenotype relationships and mutational mechanisms. NhF8ld's breakpoints were characterized using case‐specific DNA‐tags, direct‐ or inverse‐polymerase chain reaction amplification, and Sanger sequencing. DNA‐break's stimulators (n = 46), interspersed repeats, non‐B‐DNA, and secondary structures were analyzed around breakpoints versus null hypotheses (E‐values) based on computer simulations and base‐frequency probabilities. Nine of 18 (50%) severe‐HA patients with nhF8lds developed inhibitors, 1/8 affecting one exon and 8/10 (80%) affecting multi‐exons. NhF8lds range: 2–165 kb. Five (45%) nhF8lds involve F8‐extragenic regions including three affecting vicinal genes (SMIM9 and BRCC3) but none shows an extra‐phenotype not related to severe‐HA. The contingency analysis of recombinogenic motifs at nhF8ld breakpoints indicated a significant involvement of several DNA‐break stimulator elements. Most nhF8ld's breakpoint junctions showed microhomologies (1–7 bp). Three (27%) nhF8lds show complexities at the breakpoints: an 8‐bp inverted‐insertion, and the remnant two, inverted‐ and direct‐insertions (46–68 bp) supporting replicative models microhomology‐mediated break‐induced replication/Fork Stalling and Template Switching. The remnant eight (73%) nhF8lds may support nonhomologous end joining/microhomology‐mediated end joining models. Our study suggests the involvement of the retroposition machinery (e.g., Jurka‐targets, Alu‐elements, long interspersed nuclear elements, long terminal repeats), microhomologies, and secondary structures at breakpoints playing significant roles in the origin of the upmost severe phenotype in HA.     

Chronic ACE inhibition reduces intimal hyperplasia in experimental vein grafts.

Intimal hyperplasia is an important factor in the pathophysiology of vein graft failure. Local renin-angiotensin systems recently have been shown to modulate the development of intimal hyperplasia in arteries after intimal injury. The effect of chronic angiotensin-converting enzyme (ACE) inhibition on the development of intimal hyperplasia in experimental vein grafts was examined in this study. Ten New Zealand White rabbits received 10 mg/kg of captopril daily in their drinking water. One week later the right carotid artery was divided and bypassed with the reversed right external jugular vein in these rabbits and in 10 matched controls. Captopril was continued for 28 days after operation, when all the grafts were harvested. Five grafts from each group were perfusion fixed, and the intimal thickness in the proximal, middle, and distal segments was determined. Rings from the remaining grafts (n = 20 in each group) were studied in vitro under isometric tension, and their responses to norepinephrine (NE), histamine (HIST), serotonin (5-HT), angiotensin I (AI), and angiotensin II (AII) was measured. The intimal thickness of the proximal, middle, and distal segments of the captopril-treated grafts were significantly less than controls, being reduced in all segments by approximately 40% (p less than 0.0001). With regard to vasoreactivity, the captopril-treated grafts were hypersensitive to 5-HT (control ED50 5.5 +/- 0.5 X 10(-7) mol/L vs. captopril-treated 1.1 +/- 0.2 X 10(-6) mol/L; p less than 0.005) although the maximal response was significantly reduced (control 1.6 +/- 0.3 g vs. captopril-treated 0.8 +/- 0.1 g; p less than 0.05). There were no differences in sensitivity between control and captopril-treated rings with respect to NE, HIST, AI, or AII. Four of the ten captopril-treated segments, however, failed to respond to AI, and the maximal active tension of the responders was significantly reduced (control 0.47 +/- 0.06 g vs. 0.20 +/- 0.05 g; p less than 0.02). These results suggest that ACE is involved in the modulation of vein graft intimal hyperplasia, and that ACE inhibitors may have therapeutic applications in patients undergoing vein bypass procedures.     

Alterations in serotonergic receptor expression in experimental vein grafts

Rabbit external jugular veins, normally unresponsive to serotonin (5-HT), develop a constrictive response when grafted into the arterial circulation. The mechanisms responsible for this alteration were examined in this study. The right external jugular vein was grafted into the right carotid artery in 37 New Zealand white rabbits. The vein grafts were harvested at 3, 7, 9, 14, and 28 days after operation; contralateral external jugular veins were harvested at 9 days in six animals. Rings of these vessels were mounted under isometric tension, and dose-response curves to 5-HT were obtained. None of the grafts harvested at day 3 responded to 5-HT. All the grafts harvested from day 7 through day 28 constricted to 5-HT. The maximal response increased from 258 +/- 30 mg at 7 days to 734 +/- 108 mg at 28 days. No change occurred in the sensitivity to 5-HT with time. The increase in maximal response was paralleled by a linear increase in percent intimal area (intimal area/intimal + media areas) from 11.6% +/- 2.1% at 3 days to 48.7% +/- 1.9% at 28 days. Preincubation with ketanserin, a 5-HT2 and alpha 1-adrenergic antagonist, produced a concentration-dependent rightward shift in the 5-HT dose-response curve. The median effective dose for 5-HT increased progressively from 1.9 +/- 0.3 x 10(-6) mol/L (in the absence of ketanserin) to 6.1 +/- 1.7 x 10(-5) mol/L (ketanserin 8 x 10(-7) mol/L; p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Complexation of poly(monobenzyl itaconate) and poly(N-vinyl-2-pyrrolidone) in dilute solution

Upon mixing dilute solutions (10^?4 – 10^?2 mol/l) of poly(monobenzyl itaconate) (PMBI) and poly(N-vinyl-2-pyrrolidone) (PVP) in methanol, soluble polycomplex particles are formed. Here we report on the spectrophotometric determination of the turbidity of different solutions of PVP and PMBI as a function of polymer concentration and PVP molecular weight. Viscosity measurements were also performed. The polycomplex is weak. Polycomplex particles are more compact and much larger than separated chains of polyacid and polybase. No definite stoichiometry is observed and a microgel-like structure is proposed.     

Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation

The proximate cause of autoantibodies characteristic of systemic autoimmune diseases has been controversial. One hypothesis is that autoantibodies are the result of polyclonal nonspecific B cell activation. Alternatively, autoantibodies could be the result of antigen-driven B cell activation, as observed in secondary immune responses. We have approached this question by studying monoclonal anti-DNA autoantibodies derived from unmanipulated spleen cells of the autoimmune MRL/lpr mouse strain. This analysis shows that anti-DNAs, like rheumatoid factors (19), are the result of specific antigen-driven stimulation. In addition, correlation of sequences with fine specificity shows that: (a) somatic mutations can cause specificity for dsDNA and that such mutations are selected for; (b) arginine residues play an important role in determining specificity; and (c) anti-idiotypes that recognize the majority of anti-DNA are probably not specific for any one family of V regions.     

Vanishing Bile Duct Syndrome Associated with Azithromycin in a 62‐Year‐Old Man

Abstract: Vanishing bile duct syndrome is a severe cholestatic disease associated with toxic effects of medications. Stevens‐Johnson syndrome is a hypersensitivity disorder that may also be caused by medications. We present a case of a 62‐year‐old male patient who developed vanishing bile duct syndrome a month after Stevens‐Johnson syndrome. These adverse drug reactions were associated with the use of azithromycin (500 mg daily for 3 days). The patient was initially treated for Stevens‐Johnson syndrome with steroids, antihistamines and proton pump inhibitors and fully recovered. However, a month after the beginning of Stevens‐Johnson syndrome, he developed vanishing bile duct syndrome and was treated with steroids, ursodeoxycholic acid, antihistamines and tacrolimus. Unfortunately, the treatment was unsuccessful and he was listed for liver transplantation which was performed 7 months after the beginning of jaundice. This is the first case of vanishing bile duct syndrome associated with the use of azithromycin and one of few that reports vanishing bile duct syndrome and Stevens‐Johnson syndrome co‐occurrence.     

Pentadecapeptide BPC 157 (PL 14736) improves ligament healing in the rat

We improved medial collateral ligament (MCL) healing throughout 90 days after surgical transection. We introduced intraperitoneal, per‐oral (in drinking water) and topical (thin cream layer) peptide therapy always given alone, without a carrier. Previously, as an effective peptide therapy, stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, an anti‐ulcer peptide effective in inflammatory bowel disease therapy (PL 14736)) particularly improved healing of transected tendon and muscle and wound healing effect including the expression of the early growth response 1 (egr‐1) gene. After MCL transection BPC 157 was effective in rats when given once daily intraperitoneally (10 µg or 10 ng/kg) or locally as a thin layer (1.0 µg dissolved in distilled water/g commercial neutral cream) at the site of injury, first application 30 min after surgery and the final application 24 h before sacrifice. Likewise, BPC 157 was effective given per‐orally (0.16 µg/ml in the drinking water (12 ml/day/rat)) until sacrifice. Commonly, BPC 157 µg‐ng‐rats exhibited consistent functional, biomechanical, macroscopic and histological healing improvements. Thus, we suggest BPC 157 improved healing of acute ligament injuries in further ligament therapy. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1155–1161, 2010