Recombinant Kunitz protease inhibitory domain of the amyloid beta-protein precursor as an anticoagulant in venovenous extracorporeal circulation in rabbits

Investigations were performed to characterize a recombinant Kunitz protease inhibitory domain of the amyloid beta-protein precursor (rKPI) as anticoagulants. After a single intravenous infusion of wild type rKPI into dogs, its elimination fit a two compartment model with a t1/2alpha and t1/2beta of 5 and 77 min, respectively. Further investigations determined if a variant form of rKPI with 178-fold more potent anti-factor Xa activity (rKPI-DD135, Ki = 0.9 nM) could serve as an anticoagulant in a rabbit model of extracorporeal circulation using a venovenous shunt. A prospective investigation was initiated to compare standard heparin (n = 8) at 400 U/kg with different infusion concentrations of rKPI-DD135. After a single intravenous infusion of 1.89 mg/kg of rKPI-DD135 followed by a constant infusion at 0.003 (n = 3), 0.03 (n = 7), or 0.3 (n = 5) mg/kg/min, the anti-factor Xa activity of the animals' plasma rapidly reaches a steady state for the two lower infusion concentrations of the agent. All infusions of rKPI-DD135 prolong the activated clotting time with less variation than that seen with heparin administration. rKPI-DD135 anticoagulation does not prevent a drop in the platelet counts. Fibrinogen levels decrease only slightly when the circuit is anticoagulated with rKPI-DD135. rKPI-DD135 markedly prolongs the APTT, has little effect on the PT, and reduces plasma prekallikrein and plasminogen activation. The 0.3 mg/kg/min infusion concentration of rKPI-DD135 results in reduced deposition of 111Indium-labeled platelets on the circuit when compared to heparin. Last, after a steady state level is achieved, 60% of the plasma anti-factor Xa activity of rKPI-DD135 is eliminated within 60 min after stopping the infusion. These data show the rKPI-DD135 can provide single agent anticoagulation in a rabbit extracorporeal circuit. Development of short acting factor Xa inhibitors may be useful anticoagulants for cardiopulmonary bypass.     

Strategies of antiretroviral therapy in adults

Recent progress in antiretroviral treatment has led to dramatic improvements in HIV-related morbidity and mortality. These improvements have been fostered by advances in our understanding of HIV-related pathogenesis, the use of plasma HIV RNA levels to monitor patients, and the availability of 13 licensed antiretroviral drugs. Numerous drug combinations, especially those containing three or more agents, can suppress plasma HIV RNA levels below the lower limit of detection in the majority of treated patients. Urologists should be familiar with the limitations of this therapeutic response: patient adherence, drug resistance, a residual burden of chronically infected cells which are refractory to treatment, an unknown impact on HIV in genital secretions, and potential transmissibility through sexual contact.     

Pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) to patients with peritoneal carcinomatosis

The pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) was characterized in patients with peritoneal carcinomatosis. Cisplatin was added into the perfusate with escalating doses from 100 mg/m2 to 400 mg/m2. The hyperthermic perfusion was maintained for 90 minutes with a flow rate of 1.5 L/min and a target peritoneal temperature of 42.5 degrees C after a tumor debulking procedure. Samples of both the perfusate and blood were obtained during the perfusion and 30 minutes after the perfusion. Cisplatin plasma and perfusate concentrations were determined by flameless atomic absorption spectrometry with a lower limit of detection of 2 ng/ml and a coefficient of variation (CV) < 10%. Fifty-six patients were enrolled in the study. The mean (+/- SD) percentage of cisplatin present in the perfusate at the completion of perfusion was 27.8% +/- 20% of the total dose. The maximum cisplatin concentrations in the perfusate were 10 times higher than those in plasma. The area under the concentration-time curve (AUC) of the perfusate was 13 times higher than the AUC of plasma. A two-compartment model with an additional peritoneal cavity compartment fits to the data best based on the Akaike information criterion. However, the interpatient variability was considerably high (CV < 100%). In conclusion, cisplatin administered by hyperthermic peritoneal perfusion resulted in a pharmacological advantage by obtaining higher and direct drug exposure to the tumor in the peritoneal cavity while limiting systemic absorption and toxicity. Using a complex two-compartment model, the authors were able to characterize the pharmacokinetics of cisplatin given intraperitoneally via this technique.     

Open-label titration study of the safety of RMP-7 in patients with the acquired immune deficiency syndrome

RMP-7, a nine-amino acid bradykinin analogue, has been shown in animals to temporarily increase the permeability of the blood brain barrier to small molecules including amphotericin B, when administered intravenously. We sought to evaluate the safety of escalating doses of RMP-7 administered to human volunteers with the acquired immune deficiency syndrome (AIDS). Six HIV antibody-positive adults with CD4+ cell counts <50/mm³ received three increasing doses of RMP-7 on successive days: 30 ng/kg, 100 ng/kg and 300 ng/kg infused over 2, 2 and 10 min, respectively. Adverse experiences were dose-related, mild-moderate in intensity, primarily related to vasodilation and resolved rapidly without sequelae. Mean maximum increases in pulse rate at 30 ng/kg, 100 ng/kg and 300 ng/kg were 4.0, 7.8 and 28.2 beats per min, respectively. The maximum changes in average mean arterial pressure were +7.7, +5.6 and −0.2 mmHg from baseline, respectively. Minor increases in liver enzymes were noted in three patients, all with pre-existing enzyme elevations. Despite the high frequency of both occult and overt cardiovascular abnormalities in advanced HIV infection, RMP-7 is shown to be safe in this group of AIDS patients at all dosage levels tested, with adverse effects similar to previous experience in healthy humans.     

Specific language impairment in families: evidence for co-occurrence with reading impairments.

Two family aggregation studies report the occurrence and co-occurrence of oral language impairments (LIs) and reading impairments (RIs). Study 1 examined the occurrence (rate) of LI and RI in children with specific language impairment (SLI probands), a matched control group, and all nuclear family members. Study 2 included a larger sample of SLI probands, as well as their nuclear and extended family members. Probands and their family members who met specific criteria were classified as language and/or reading impaired based on current testing. In Study 1, the rates of LI and RI for nuclear family members (excluding probands) were significantly higher than those for control family members. In the SLI families, affected family members were more likely to have both LI and RI than either impairment alone. In Study 2, 68% of the SLI probands also met the diagnostic classification for RI. The language and RI rates for the other family members, excluding probands, were 25% and 23% respectively, with a high degree of co-occurrence of LI and RI (46%) in affected individuals. Significant sex ratio differences were found across generations in the families of SLI probands. There were more male than female offspring in these families, and more males than females were found to have both LIs and RIs. Results demonstrate that when LIs occur within families of SLI probands, these impairments generally co-occur with RIs. Our data are also consistent with prior findings that males show impairments more often than females.     

Respiratory failure. Conventional and high-tech support

Although significant progress has been made in the treatment of patients with acute lung failure in the critical care setting, the mortality rate from acute lung injury and ARDS is unacceptably high, given the numbers of patients treated for these syndromes each year. The improved understanding of the pathophysiology of respiratory failure from basic science and clinical research is reflected in improved survival rates over the years. Advances in the mechanical ventilator (through microprocessor technology); biosurface technology; liquid ventilation; and, in some cases, returning to so-called "antiquated" practices of patient care (e.g., prone positioning) seem to have had an impact nonetheless. As refinement continues to occur in these areas, morbidity and mortality from lung failure will have a lesser impact on patients as physicians treat the consequences of organ failure in the ICU.     

A Novel Herbal Extract Blend Product Prevents Particulate Matters-Induced Inflammation by Improving Gut Microbiota and Maintaining the Integrity of the Intestinal Barrier

Air pollutants of PM2.5 can alter the composition of gut microbiota and lead to inflammation in the lung and gastrointestinal tract. The aim of this study was to evaluate the protective effect of a novel herbal extract blend, FC, composed of Lonicera japonica extract, Momordica grosvenori extract, and broccoli seed extract, on PM2.5-induced inflammation in the respiratory and intestinal tract. A549 cells and THP-1 cells, as well as C57BL/6 mice, were stimulated with PM2.5 to establish in vitro and in vivo exposure models. The models were treated with or without FC. The expression of inflammatory cytokines and tight junction proteins were studied. Proteomic analysis was performed to elucidate mechanisms. Mouse feces were collected for gut microbiota analysis. FC was shown to modulate the upregulation of pro-inflammatory cytokines mRNA expression in A549 and THP-1 cells and downregulated tight junction proteins mRNA expression in A549 cells due to PM2.5 stimulation. In animal models, the decreased expression of the anti-inflammatory factor il-10, tight junction protein ZO-1, and the elevated expression of COX-2 induced by PM2.5 were improved by FC intervention, which may be associated with zo-1 and cox-2 signaling pathways. In addition, FC was shown to improve the gut microbiota by increasing the abundance of beneficial bacteria.