Randomized Evaluation of an Inflatable Femoral Artery Compression Device After Cardiac Catheterization

Mechanical femoral artery compression devices have several limitations. We compared a novel disposable beltheld pneumatic compression device to manual compression alone in 213 patients randomized into two equal groups. Both were comparable for age, gender, current therapy with aspirin (ASA) and warfarin, diameter of the arterial sheath, previous procedures via the same artery, procedure duration, and blood pressure. Manual compression time was 12 ± 3 minutes. Pneumatic compression was reduced during 60 minutes. Patient discomfort was assessed as none (82% vs 88%), mild (13% vs 8%), moderate (3% vs 4%), or severe (2% vs 0%) for the manual versus pneumatic group, respectively. Bleeding and hematoma occurred in 7.5% of patients with no difference between the treatment groups. However, manual compression was significantly more effective in the higher range of systolic blood pressure, and pneumatic in the lower range, with a cut point of approximately 170 mmHg. Predictors for bleeding were systolic blood pressure and dose of ASA. Among 113 patients with systolic blood pressure < 160 mmHg and low dose (75 mg) or no ASA, only / patient (0.9%) experienced bleeding while 31% of 16 patients with both elevated systolic blood pressure and high dose ASA (150–330 mg) bled. We conclude that pneumatic femoral artery compression does not reduce bleeding and hematoma compared with manual compression. The use of low dose (75 mg) or no ASA, as well as giving special attention to patients with elevated systolic blood pressure, may reduce the risk of bleeding after cardiac catheterization .     

The Persistence of Extramedullary Leukemic Infiltrates during Bone Marrow Remission of Acute Leukemia

Leukemic cell infiltrates were found at autopsy in the tissues of 10 of 15patients with acute leukemia dying during "complete bone marrow remission." The kidney was the most common site of leukemic cell infiltratesfollowed by the liver, testes, bowel, lung, central nervous system, and lymphnodes.

These findings indicate that leukemic cells are not completely eradicatedby current chemotherapy even in patients in whom no leukemic cells can beidentified in the bone marrow.

The distribution of residual leukemic cells demonstrates that the centralnervous system is not the only reservoir of leukemic cells in patients duringbone marrow remission.

Submitted on July 10, 1964 Accepted on December 20, 1964     

Inhibition of the Local Inflammatory Response in Man by Antimetabolites

The effects of chemotherapy on the local inflammatory response in man werestudied in 33 patients.

Inhibition of the mononuclear cell phase of the response at 4, 8 and 24hours was noted. The median on-therapy values at these hours were 0, 8.5and 23 per cent compared to control values of 4, 24.5 and 86 per cent, respectively.

The 24-hour values for the individual types of therapy were 13.5 per centfor intensive combination therapy with 4 antitumor agents, 21 per cent for6-mercaptopurine given i.v. daily for 5 days, 2 per cent for methotrexate giveni.v. daily for 5 days, 37 per cent for intermittent methotrexate and 56 percent for other therapy. Recovery was substantial within 5 days of the end oftherapy.

The inhibition was not correlated with alterations in the levels of circulatinggranulocytes or lymphocytes, nor with the numbers of granulocytes enteringthe inflammatory site.

Complicating infections were noted in eight patients, seven of whom werein the most strongly inhibited group. Observations of the response in ten untreated patients with acute leukemia showed both impaired granulocyte andmononuclear phases of the response.

Submitted on March 15, 1965 Accepted on May 18, 1965     

Studies on Lymphocytes. II. The Production of Lymphocytosis by Intravenous Heparin in Calves

1. Intravenous commercial heparin produces a lymphocytosis in the calf.The effect is not due to the preservative commonly present in heparin.

2. The lymphocytosis is mediated to a great extent by an increased inputof lymphocytes into the blood via the thoracic duct.

3. The necessity of considering, plus controlling the heparin effect onblood lymphocyte levels and on the output of thoracic duct lymphocytes inall studies on lymphocyte production, migration and behavior, is discussedand emphasized.

Submitted on March 29, 1962 Accepted on June 25, 1962     

Murine malaria: dissociation of natural killer (NK) cell activity and resistance to Plasmodium chabaudi

Striking differences in the resistance to P. chabaudi infection among different inbred mouse strains have previously been correlated with the level of both the spontaneous and the infection-induced enhanced level of NK cell activity. We have examined this putative correlation in individual animals of backcross progeny derived from A/J (malaria-susceptible, low NK cell activity) and B10.A (malaria-resistant, high NK cell activity) progenitors. We have found that NK cell activity and resistance to malaria segregated independently. Furthermore, C57BL/6-bg/bg mice which are deficient in NK cell activity were found to be as resistant to malaria as their heterozygous C57BL/6-bg/+siblings. We conclude that low NK cell activity, characteristic of A/J strain mice, is not a sufficient determinant of the exquisite susceptibility of these animals to infection with Plasmodium chabaudi.     

Clinical Studies with Vincristine

Forty patients with malignant neoplastic disease received vincristine in aneffort to define the toxicity, the tolerated dose, the effect of varying doseschedules, and the antitumor properties. The toxicity of vincristine is doserelated, and the tolerated dose for the weekly schedule is 0.05 mg. per Kg.for the majority of patients. The tolerated dose per unit time is independentof the schedule of administration. The toxic manifestations relate primarilyto the neuromuscular system and the gastrointestinal tract. At the tolerateddose or below, these manifestations are reversible and not accumulative.Hematologic toxicity is rare, and thrombocytosis occurs in some patients.Vincristine produces tumor regression in the majority of the patients withlymphoma where its activity compares favorably with that of the alkylatingagents and vinblastine. There is suggestive evidence that cross-resistance between vincristine and the alkylating agents and between vincristine and vinblastine does not occur.

Accepted on December 28, 1962     

Arg64 variant of the beta3-adrenergic receptor is associated with gallstone formation

OBJECTIVES: The beta3-adrenergic receptor (ADRB3) is a transmembrane receptor highly expressed in adipose tissue and thought to be involved in the regulation of lipolysis. ADRB3 is also highly expressed in gallbladder tissue where it may be involved in gallbladder contraction. Because polymorphisms of ADRB3 are present in populations with a high prevalence of gallstones (e.g., Pima-Indians, obese subjects), we hypothesized that known polymorphisms for ADRB3 (Trp64Arg) may represent an independent risk factor for gallstone disease. METHODS: The EMIL cross-sectional study investigated the health behavior and prevalence of chronic diseases in a small Southwestern German town of 12,475 inhabitants. From 3,893 randomly selected citizens 2,147 subjects were enrolled and screened for gallstones employing ultrasonography. Blood samples were drawn for biochemical analysis and isolation of genomic DNA. ADBR3 genotypes were determined by TaqMan SNP Assay. RESULTS: We identified 171 (8%) gallstone carriers of whom 143 participated (46 male, 97 female), with a mean age of 51.4, and mean BMI of 29.3 kg/m2. For these subjects an age, gender and BMI matched partner without gallstones was recruited from the study population. Genotyping for ADRB3 revealed an Arg64 allele frequency of 5.9 versus 0.7% (HR = 11.9, P < 0.05) compared with controls. CONCLUSIONS: Our results indicate that the ADRB3 Trp64Arg polymorphism is associated with gallstone disease thereby representing a genetic marker that identifies subjects at higher risk for gallstone formation.     

Nucleotide and actin binding properties of the isolated motor domain from Dictyostelium discoideum myosin

Nucleotide and actin binding properties of the truncated myosin head (S1dC) from Dictyostelium myosin II were studied in solution using rabbit skeletal myosin subfragment 1 as a reference material. S1dC and subfragment 1 had similar affinities for ADP analogues, ɛADP and TNP-ADP. The complexes of ɛADP and BeF_x or AlF₄ ^- were less stable with S1dC than with subfragment 1. Stern-Volmer constants for acrylamide quenching of S1dC complexes with ɛADP, ɛADP·AlF ₄ ^- and ɛADP.BeF_x were 2.6, 2.9 and 2.2 M^-1, respectively. The corresponding values for subfragment 1 were 2.6, 1.5 and 1.1 M^-1. The environment of the nucleotide binding site was probed by using a hydrophobic fluorescent probe, PPBA. PPBA was a competitive inhibitor of S1dC Ca²⁺-ATPase (K_i = 1.6 μm). The binding of nucleotides to subfragment 1 enhanced PPBA fluorescence and caused blue shifts in the wavelength of its maximum emission in the order: ATP ≈ ADP·AlF^4- ≈ ADP·BeF_x > ATPSγS > ADP > PP_i. In the case of S1dC, the effects of different nucleotides were smaller and indistinguishable from each other. S1dC bound actin tighter than S1 (K_d = 7 nm and 60 nm, respectively). The actin activated MgATPase activity of S1dC varied between preparations, and the V_max and K_m values ranged between 3 and 7 s^-1 and 60 and 190 μm, respectively. S1dC showed lower structural stability than S1 as revealed by their thermal inactivations at 35° C. These results show that the nucleotide and actin binding of S1dC and subfragment 1 are similar but there are some differences in nucleotide and phosphate analogue-induced changes and the communication between the nucleotide and actin binding sites in these proteins This revised version was published online in July 2006 with corrections to the Cover Date.     

Pharmacokinetics and Kinetic-Dynamic Modelling of Aminophenones as Methaemoglobin Formers

Methaemoglobin, the oxidized form of haemoglobin, can be formed by a variety of agents, most of which act to oxidize haemoglobin directly or indirectly. Cyanide has a higher affinity for methaemoglobin than for mitochondrial cytochromes, making methaemoglobin formation a basis for the treatment of cyanide poisoning. We used the beagle dog model to investigate the relationship between drug concentration and methaemoglobin levels for two candidate anti-cyanide compounds. The compounds studied were the aminophenones p-aminopropiophenone (PAPP) and p-aminoheptylphenone (PAHP). Both PAPP and PAHP were given as intravenous boluses and as two different oral formulations. The kinetics of both compounds appeared to follow a three-compartment open model for intravenous bolus administration and a two-compartment open model for oral administration. The first distribution phase seen with the intravenous administration was obscured by the absorption phase during oral administration. Bioavailability for all formulations varied between 20 and 47%. For both compounds there was a delay between the appearance of drug in the plasma and the appearance of methaemoglobin (counter-clockwise hysteresis) which is suggestive of an active metabolite causing methaemoglobin formation. The pharmacodynamics were fit with an effect-compartment kinetic-dynamic model linked to a sigmoid E_max pharmacodynamic model. Maximum amounts of methaemoglobin occurred between 2 and 4 h for PAHP and between 1 and 3 h for PAPP. When administered intravenously estimates of EC50 were lower than the estimates of EC50 from oral administration for both compounds. This might be because of oral first-pass inactivation or a ‘first-pass’ activation through the lungs contributing to the formation of an active metabolite. The phenones as a class appear to have the drug cleared and methaemoglobin return to near baseline within 12 h. Both compounds seem to produce sufficient methaemoglobin to treat acute cyanide poisoning and to serve as prophylactic agents against acute cyanide poisoning in a military setting.