Potential applications of cell cycle manipulation to clinical response.
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Biomedical subjects
Publications and source records attributed to E E Harris.
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Phylogenetic relationships of mangabeys within the Old World monkey tribe Papionini are inferred from analyses of nuclear DNA sequences from five unlinked loci. The following conclusions are strongly supported, based on congruence among trees derived for the five separate gene regions: (1) mangabeys are polyphyletic within the Papionini; (2) Cercocebus is the sister taxon to the genus Mandrillus; and (3) Lophocebus belongs to a clade with Papio and Theropithecus, with Papio as its most likely sister taxon. Morphologically based phylogenies positing mangabey monophyly were evaluated by mapping the sequences for each locus on these trees. The data seem to fit these trees poorly in both maximum-parsimony and likelihood analyses. Incongruence among nuclear gene trees occurred in the interrelationships among Lophocebus, Papio, and Theropithecus. Several factors that may account for this incongruence are discussed, including sampling error, random lineage sorting, and introgression.
PURPOSE: Chemotherapy plays an increasingly important role in the treatment of both node-negative and node-positive breast cancer patients, but the optimal sequencing of chemotherapy and radiation therapy is not well established. The purpose of this study is to evaluate the interaction of sequence and type of chemotherapy and hormonal therapy given with radiation therapy on the cosmetic outcome and the incidence of complications of Stage I and II breast cancer patients treated with breast-conserving therapy. METHODS AND MATERIALS: The records of 1053 Stage I and II breast cancer patients treated with curative intent with breast-conserving surgery, axillary dissection, and radiation therapy between 1977-1991 were reviewed. Median follow-up after treatment was 6.7 years. Two hundred fourteen patients received chemotherapy alone, 141 patients received hormonal therapy alone, 86 patients received both, and 612 patients received no adjuvant therapy. Patients who received chemotherapy +/- hormonal therapy were grouped according to sequence of chemotherapy: (a) concurrent = concurrent chemotherapy with radiation therapy followed by chemotherapy; (b) sequential = radiation followed by chemotherapy or chemotherapy followed by radiation; and (c) sandwich = chemotherapy followed by concurrent chemotherapy and radiation followed by chemotherapy. Compared to node negative patients, node-positive patients more commonly received chemotherapy (77 vs. 9%, p < 0.0001) and/or hormonal therapy (40 vs. 14%, p < 0.0001). Among patients who received chemotherapy, the majority (243 patients) received concurrent chemotherapy and radiation therapy with two cycles of cytoxan and 5-fluorouracil (5-FU) administered during radiation followed by six cycles of chemotherapy with cytoxan, 5-fluorouracil and either methotrexate (CMF) or doxorubicin(CAF). For analysis of cosmesis, patients included were relapse free with 3 years minimum follow-up. RESULTS: The use of chemotherapy had an adverse effect on cosmetic outcome compared to no chemotherapy, which was of borderline significance at 3 years (92% excellent or good cosmetic outcome vs. 96% respectively, p = 0.057); however, cosmesis was not different at 5 years (91 vs. 93% respectively, p = 0.67). Cosmesis was not significantly different between patients treated sequentially and those treated concurrently (3 year: 87 vs. 93% respectively, p = 0.33), nor was it different between patients who received CMF vs. CAF (3 year: 92 vs. 93% respectively, p = 0.89). Hormonal therapy did not influence cosmetic outcome (p = 0.78). The incidence of Grade 4 or 5 arm edema (> or = 2 cm difference in arm circumference) was 2% without chemotherapy vs. 8% with chemotherapy (p = 0.00002). However, the incidence of arm edema was not affected by sequencing or type of chemotherapy (all p > or = 0.52). Patients treated sequentially had a 10% incidence of Grade 4 or 5 arm edema vs. 7% in the patients treated concurrently (p = 0.52). The incidence was 7 vs. 9% in patients treated with CMF vs. CAF (p = 0.73). The incidence of clinical pneumonitis and rib fracture was not influenced by use of chemotherapy, sequence of chemotherapy or use of hormonal therapy (all p > or = 0.06). CONCLUSIONS: Chemotherapy can be given concurrently with radiation therapy in the treatment of Stage I and II breast cancer with breast-conserving therapy without seriously compromising cosmetic outcome or incidence of complications compared to patients receiving other sequences of chemotherapy. Hormonal therapy did not affect cosmesis or complications. The chemotherapeutic regimen of cytoxan and 5-FU concurrent with radiation therapy followed by more chemotherapy is one reasonable option for breast conservation therapy in patients requiring chemotherapy.
We suggest four ways in which human gross anatomy instructors can reinforce respect and compassion in students. First, encourage respectful language in the laboratory. The term "donor" should be used instead of "cadaver" or "corpse" in referring to the donated body because this promotes appreciation for the students' first "patient." Second, provide the students with the actual name, age, history, and likely cause of death of the donor so that they more fully appreciate the donor as having once been a living human being. Third, prompt students to explore feelings and discuss topics stimulated by the intense experience of human dissection. Suggested topics include the students' feelings about dissecting a human being, the difficulty in deciding to donate one's body, the central importance of anatomy to a medical practitioner's role, and the historical development of the study of anatomy. Fourth, hold a memorial ceremony, in which both students and faculty participate, as a positive closure to an emotionally and intellectually intense course. Additionally, a ceremony reinforces salutary values in students, enhances social bonding among students, and encourages their appreciation of various cultural and religious beliefs. These methods introduce a new dimension of experience for anatomy students. We have developed these methods in response to what we view as a negative trend in the medical profession in which health care becomes technical and patients become objects. It is our role as faculty to reinforce respectful and compassionate attitudes in medical students from the very beginning.
Acute lobar nephronia, or focal pyelonephritis, is an uncommon form of renal infection with a distinct computerized tomographic appearance. A patient is presented with lobar nephronia characterized by fever, flank pain, urosepsis, and painful abdominal mass. Differentiating this condition from abscess or other renal mass is important, because the treatment of lobar nephronia is nonsurgical. The infection responds to antibiotic therapy.
Automated microdilution MIC results, obtained with the Autoreader (Sensititre, Inc., Salem, N.H.) following 5 h of incubation, were compared with manually read, concurrent control MICs following 18 h of incubation in a three-laboratory comparative study. A total of 704 members of the family Enterobacteriaceae or similar gram-negative organisms were tested against 17 antimicrobial agents. Autoreader MICs were within 1 doubling dilution of control values in 92.9% of instances. Discrepancies of +/- 2 doubling dilutions and +/- 3 or greater doubling dilutions were noted in 4.5 and 2.6%, respectively, of the 7,687 drug-organism combinations analyzed. The majority of errors occurred when beta-lactam antimicrobial agents were tested with a variety of different species. MICs at 5 h, when Pseudomonas aeruginosa was used, were possible in only half the isolates tested and yielded data on only a limited number of drugs in the remaining instances. Excluding results obtained with penicillin and ampicillin, which were uniformly poor, Staphylococcus aureus Autoreader values were within +/- 1 doubling dilution of control values in 93.6% of instances, 5.4% varied by +/- 2 dilutions, and only 1% of test values by +/- 3 or more dilutions from control values for 82 isolates tested against nine antimicrobial agents. Of eight additional S. aureus isolates tested that were resistant to methicillin, only one was read correctly by the Autoreader, with results on the remaining seven appearing as either insufficient growth or as total resistance to all drugs tested. Interlaboratory reproducibility was excellent for selected isolates of S. aureus and gram-negative bacilli. The accuracy of the Sensititre Autoreader MIC results was comparable to that of other same-day quantitative systems for members of the family Enterobacteriaceae and S. aureus, while the economic and procedural advantages of the broth microdilution method was maintained.
A series of inhibitors of angiotensin converting enzyme (ACE, dipeptidyl carboxypeptidase, EC 3.4.15.1) is described which addresses certain conformational aspects of the enzyme-inhibitor interaction. In this study the alanylproline portion of the potent ACE inhibitor enalaprilat (2) is replaced by a series of monocyclic lactams containing the required recognition and binding elements. In order to more fully assess the lactam ring conformations and the key backbone angle psi as defined in 3 with respect to possible enzyme-bound conformations, a series of model lactams was investigated with use of molecular mechanics. The results point to a correlation between inhibitor potency (IC50) and the computed psi angle for the lowest energy conformation of the model compounds. Thus the psi angle as defined in 3 is an important determinant in the binding of inhibitors to ACE. The inhibition data in conjunction with the computational data have served to define a window of psi angles from 130 degrees to 170 degrees which seems to be acceptable to the ACE active site.
The Sensititre Autoreader is a microcomputer-driven instrument capable of automatically reading antimicrobial susceptibility microdilution trays. The instrument measures the fluorescence liberated by bacterial enzymatic activity on fluorogenic substrates as an indicator of growth in each well. A mathematical algorithm converts the fluorescent signals from an antimicrobial dilution series to an MIC endpoint. A three-center study evaluated the performance of the Autoreader in comparison with MIC determined visually in a duplicate set of control plates lacking fluorogenic substrate. Among 828 isolates of gram-negative bacilli tested against 17 antimicrobial agents, Autoreader 18-h MIC were within +/- 1 twofold dilution of control MIC values (agreement) in 95.3% of instances. In 3.5% of the instances, Autoreader values occurred +/- 2 half-step dilutions from control values (minor discrepancy), and in only 1.2% of instances did Autoreader values deviate from control values by greater than +/- 2 dilution steps (major discrepancy). Agreement, minor discrepancies, and major discrepancies were noted among 148 gram-positive cocci tested against 11 antimicrobial agents in 93.5, 4.8, and 1.7% of the instances, respectively. Over half of the major discrepancies noted with gram-negative bacilli occurred with Proteus mirabilis-beta-lactam combinations, a problem that was resolved when a lower initial inoculum was used. Inter-and intralaboratory reproducibility was excellent. Standard Sensititre susceptibility trays may be instrument read at 18 h reproducibly and accurately with only slight modification of conventional procedures to include fluorogenic enzyme substrates in the incubation broth.
A cationic amino acid copolymer (CP530) with a molar ratio of lysine, leucine, tryptophan and phenylalanine of 11:2:1:1 and a Mr of about 2300 was prepared and its inhibitory effects on the complement cascade was compared with those of polylysine with a Mr of about 3000. The effects by these two cationic peptides appeared to be at the early stage of complement activation. CP530 and polylysine inhibited the binding of C1q to insoluble IgG aggregates with a concentration required for 50% inhibition of 0.7 and 0.9 mM, respectively. Both compounds were also potent inhibitors of immune hemolysis (a concentration causing 50% inhibition, 0.5 and 3.5 microM respectively) as well as assembly of EAC cell intermediates required for formation of C3 and C5 convertases (a concentration of 50% inhibition of 1.0 microM for CP530 and 3.8 microM for polylysine). However, CP530 was shown to be distinctly more effective against the activation of C1r . Cls complex induced by insoluble IgG aggregate-bound C1q, requiring 0.15 mM for 50% inhibition compared to greater than 10 mM for polylysine. The 50% inhibition value for soluble IgG aggregate-induced activation of C1 in whole serum was 0.7 mM for CP530 and 5.0 mM for polylysine. The greater inhibition of C1 activation by CP530 than that exerted by polylysine could be attributable to the presence of non-lysyl residues which provide the structural basis for specificity and potency.
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Several phosphonamides, phosphoramides, and phosphates having the general structure R-Y-P(O)(OH)-X-CH(CH3)-CO-Pro have been synthesized and tested for inhibition of angiotensin-converting enzyme (dipeptidyl carboxypeptidase; peptidyl-dipeptide hydrolase, EC 3.4.15.1). Inhibition was found to depend on the nature of R, Y, and X such that the maximal effect was observed when X = NH, Y = CH2, and R = phi CH2 (50% inhibition at 7 nM). Substitution of CH2 or O at X and O at Y produced significantly less potent inhibitors. Groups shorter or longer than R = phi CH2 led to less active inhibitors, presumably due to nonoptimal interaction of the side chain with the S1 subsite.
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4-Chlorobenzaldehyde 1-(4-chlorophenyl)-4(1H)-pyridinylidene hydrazone fluorusulfonate (4) was found to have excellent anticoccidial activity in chickens. The synthesis and biological evaluation of related analogues are presented. Presumably 4 shares a common mechanism of action with robenidine (25) since it was not active on a robenidine tolerant strain of E. tenella. Structural comparisons of the two molecules are presented.
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