Pharmacokinetic/Pharmacodynamic Modeling of a Cell-Penetrating Peptide Phosphorodiamidate Morpholino Oligomer in mdx Mice

Pharmaceutical Research - Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) have shown promise in treating Duchenne muscular dystrophy (DMD). We evaluated a semi-mechanistic...     

Near infrared spectroscopy-measured changes in cerebral blood volume and cytochrome aa3 in newborn lambs exposed to hypoxia and hypercapnia, and ischemia: a comparison with changes in brain perfusion and O2 metabolism.

OBJECTIVES: Validation of near infrared spectroscopy (NIRS)-measured changes in cerebral blood volume (deltaCBV) and cytochrome aa3 (deltaCytaa3) as estimators of changes in brain perfusion and oxygenation in the newborn lamb during hypoxia and hypercarbia, and additional hypotension. METHODS AND MATERIALS: In 33 newborn lambs brain perfusion assessed by carotid artery blood flow (deltaQcar: ml/min)and cerebral metabolic rate of oxygen (deltaCMRO2: ml O2/min) were related to NIRS-derived deltaCBV (ml/100 g) and deltaCytaa3 (microM) during combined hypoxia and hypercarbia and additional hypotension. Combined hypoxia and hypercapnia was induced by ventilation with 6-8% of O2 and 10% of CO2 during 30 min, and additional hypotension ( < 35 mmHg for 5 min) was induced by careful withdrawal of blood. RESULTS: CBV increased during hypoxia and hypercarbia, decreased during additional hypotension and was related to deltaQcar: (0.009 ml/100 g change per ml/min Qcar: P < 0.0001). Cytaa3 increased during hypoxia and hypercarbia, decreased during subsequent additional hypotension andshowed a reverse relationship with deltaCMRO2 (-1.65 microM change per ml O2/min CMRO2: P <0.0001). Cytaa3 remained above baseline during reperfusion. CONCLUSIONS: deltaCBV estimates changes in brain perfusion, but overestimates brain perfusion during hypotension. The pattern of deltaCytaa3 suggests less oxygen utilisation by brain tissue during hypoxia and subsequent reperfusion.     

Frequency and spectrum of abnormalities in the bone marrow of the wrist: MR imaging findings

Objective. To describe the frequency of marrow abnormalities on wrist MR imaging and the MR findings of these various abnormalities. Design and patients. Five hundred and nineteen patients were studied at 1.5 T. Two observers recorded the presence and location of avascular necrosis, occult fractures and arthritic edema [focal osteoarthritis, ulnolunate abutment, rheumatoid arthritis, septic arthritis, gouty arthritis and scapholunate advanced collapse (SLAC)]. Results and conclusion. One hundred and eighty-seven (36%) patients demonstrated marrow abnormalities in the wrist, of which 101 were diagnosed as arthritis [64 (34%) as focal osteoarthritis, 17 (9%) as ulnolunate abutment, 15 (8%) as rheumatoid arthritis, 2 as septic arthritis, 2 as SLAC, and 1 as gouty arthritis]. Seventy-two patients had occult fractures and in 27 patients avascular necrosis was seen. MR imaging can reveal various abnormalities in bone marrow of the wrist when findings on radiography are normal or equivocal. Received: 29 May 1998 Revision requested: 8 July 1998 Revision received: 8 December 1998 Accepted: 22 January 1999     

Chlorhexidine 0.5%/70% Alcohol and Iodine 1%/70% Alcohol Both Reduce Bacterial Load in Clean Foot Surgery: A Randomized,Controlled Trial

No consensus exists regarding which cleansing technique, solution, and concentration should be used in orthopedic surgery. The aim of this randomized, controlled trial was to compare the effect of chlorhexidine 0.5%/70% alcohol with iodine 1%/70% alcohol on lowering positive cultures before elective foot surgery and to study any wound complications, infections and allergic reactions. Consecutive patients ≥18 years of age scheduled for a hallux valgus correction or arthrodesis of the first metatarsophalangeal joint were included. Swabs were taken from 2 sites before and twice after preparing the skin and were quantitatively and qualitatively analyzed. The study group consisted of 49 patients with a mean age of 52.3 ± 14.4 (range 22 to 75) years of whom 42 (86%) were female. No significant differences were observed for positive cultures between the chlorhexidine (73%, 2%, and 12%) and iodine (68%, 7%, and 9%) group at any time point. Coagulase-negative staphylococci were the most commonly isolated micro-organisms found after skin preparation. Occasionally, Bacillus spp and Corynebacterium spp were cultured. The complication rate 2 weeks postoperatively was 0% in the chlorhexidine group versus 8.7% (n?=?2) in the iodine group (delayed wound healing; p?=?.215). The complication rate at 6 weeks postoperatively was, respectively, 3.8% (n?=?1) versus 4.3% (n?=?1; both showed swelling and redness; p > .999). There was no significant difference in postoperative wound problems or infection rates between the 2 skin preparation solutions. Chlorhexidine 0.5%/70% alcohol and iodine 1%/70% alcohol both decreased the amount of positive cultures in elective foot surgery.     

Metastatic Ewing sarcoma masquerading as olfactory neuroblastoma

Ewing sarcoma is a malignant tumor of bone that rarely spreads to the head and neck. We describe an unusual case of metastatic Ewing sarcoma involving the calvarium mimicking olfactory neuroblastoma, an uncommon neuroectodermal tumor of the anterior skull base. Pertinent clinical, radiological, and pathologic features of these tumors are described, with particular attention to their imaging characteristics.     

Antithrombotic agents in the treatment of severe sepsis

Sepsis, a systemic inflammatory syndrome, is a response to infection and when associated with multiple organ dysfunction is termed severe sepsis. It remains a leading cause of mortality in the critically ill. The response to the invading microorganisms may be considered as a balance between a pro-inflammatory and an anti-inflammatory reaction. While an inadequate pro-inflammatory reaction and a strong anti-inflammatory response could lead to overwhelming infection and the death of the patient, a strong and uncontrolled pro-inflammatory response, manifested by the release of pro-inflammatory mediators may lead to microvascular thrombosis and multiple organ failure. Endotoxin triggers sepsis via the release of various mediators such as tumour necrosis factor-alpha and interleukin-1 (IL-1). These cytokines activate the complement and coagulation systems, release adhesion molecules, prostaglandins, leukotrienes, reactive oxygen species and nitric oxide. Other mediators involved in the sepsis syndrome include IL-1, -6 and -8; arachidonic acid metabolites; platelet activating factor; histamine; bradykinin; angiotensin; complement components and vasoactive intestinal peptide. These pro-inflammatory responses are counteracted by IL-10. Most of the trials targeting the different mediators of the pro-inflammatory response have failed due to a lack of correct definition of sepsis. Understanding the exact pathophysiology of the disease will enable more advanced treatment options. Targeting the coagulation system with various anticoagulant agents including, activated protein C, and tissue factor pathway inhibitor (TFPI) is a rational approach. Many clinical trials have been conducted to evaluate these agents in severe sepsis. While trials on antithrombin and TFPI were not so successful, the double-blind, placebo-controlled, Phase III trial of recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) was successful, creating a significant decrease in mortality when compared to the placebo group. A better understanding of the pathophysiologic mechanism of severe sepsis will provide better treatment options, and combination antithrombotic treatment may provide a multipronged approach for the treatment of severe sepsis.     

Direct free fatty acid uptake into human adipocytes in vivo: relation to body fat distribution

We sought to assess whether direct uptake of circulating free fatty acids (FFAs) by adipocytes occurs in vivo in overnight postabsorptive humans and, if so, whether there are regional differences in uptake between lean and obese women and men. We used bolus injections of radiolabeled FFA tracers followed by carefully timed adipose tissue biopsies. First, we validated a method to measure direct adipocyte FFA uptake and then quantitated this process using the modified methods in normal-weight postabsorptive men and women. We then used a continuous infusion of radiolabeled FFA to measure direct and indirect (VLDL) regional adipose tissue uptake in obese men and women. Direct FFA uptake was greater in women than men: 8.2 +/- 0.6 vs. 4.0 +/- 0.5% (P < 0.0001) of FFAs were taken up by subcutaneous adipose tissue, respectively. Abdominal subcutaneous fat took up FFAs more avidly than femoral fat in men, but this did not occur in women. Similar sex and regional difference were found to occur in obese women and men. Gene expression of fatty acid transporters was greater in abdominal than femoral fat in men (P < 0.05) but not in women (P = 0.80). We observed sex- and site-specific recycling of circulating FFAs into subcutaneous fat. This is a novel FFA disposal pathway that may also play a role in the development or maintenance of body fat distribution. Regional variations in facilitated fatty acid transport may contribute to this process.     

Structure-Preserving Finite-Element Schemes for the Euler-Poisson Equations

We discuss structure-preserving numerical discretizations for repulsive and attractive Euler-Poisson equations that find applications in fluid-plasma and self-gravitation modeling. The scheme is fully discrete and structure preserving in the sense that it maintains a discrete energy law, as well as hyperbolic invariant domain properties, such as positivity of the density and a minimum principle of the specific entropy. A detailed discussion of algorithmic details is given, as well as proofs of the claimed properties. We present computational experiments corroborating our analytical findings and demonstrating the computational capabilities of the scheme.