17ß-Estradiol Concentration and Direct ß2-Adrenoceptor Inhibition Determine Estrogen-Mediated Reversal of Adrenergic Immunosuppression.

Background: Sympathetic innervation of lymphoid organs, and the presence of 17ß-estradiol (estrogen or E2) and adrenergic receptors (ARs) on lymphocytes, suggests that sympathetic stimulation and hormonal activation may influence immune functions. Purpose: Modeling and simulating these pathways may help to understand the dynamics of neuroendocrine-immune modulation at the cellular and molecular levels. Methods: Dose- and receptor-dependent effects of E2 and AR subtype-specific agonists were established in vitro on lymphocytes from young male Sprague-Dawley rats and were modeled in silico using the MATLAB Simbiology toolbox. Kinetic principles were assigned to define receptor-ligand dynamics, and concentration/time plots were obtained using Ode15s solvers at different time intervals for key regulatory molecules. Comparisons were drawn between in silico and in vitro data for validating the constructed model with sensitivity analysis of key regulatory molecules to assess their individual impacts on the dynamics of the system. Finally, docking studies were conducted with key ligands E2 and norepinephrine (NE) to understand the mechanistic principles underlying their interactions. Results: Adrenergic activation triggered proapoptotic signals, while E2 enhanced survival signals, showing opposing effects as observed in vitro. Treatment of lymphocytes with E2 shows a 10-fold increase in survival signals in a dose-dependent manner. Cyclic adenosine monophosphate (cAMP) activation is crucial for the activation of survival signals through extracellular signal-regulated kinase (p-ERK) and cAMP responsive element binding (p-CREB) protein. Docking studies showed the direct inhibition of ERK by NE and ß2-AR by E2 explaining how estrogen signaling overrides NE-mediated immunosuppression in vitro. Conclusion: The cross-talk between E2 and adrenergic signaling pathways determines lymphocyte functions in a receptor subtype and coactivation-dependent manner in health and disease.

Colonoscopy by a family physician: a 9-year experience of 1048 procedures.

BACKGROUND: In the last 15 years, family physicians and general internists have adopted flexible fiberoptic endoscopy as a procedure to screen patients at risk of premature death from colorectal cancer. There has been controversy regarding the ability of non-fellowship-trained primary care physicians to extend this experience to full colonoscopy. METHODS: The results of 1048 consecutive colonoscopy examinations performed by a family physician over a 9-year period were tabulated. Outcomes measured included the reach-the-cecum rate (RCR), use of medication, complication rate, and diagnostic yield. In a convenience sample of 110 cases, the effectiveness of the non-narcotic analgesic ketorolac was assessed by the RCR. Outcomes of cases in which ketorolac was used were compared with cases in which traditional sedation and analgesia were used. RESULT: A high diagnostic yield without significant complications was noted. The RCR for nonmedicated patients was 36%. Among all medicated cases, the RCR was 93%. In patients who were given the non-narcotic analgesic ketorolac, the RCR was 96%, compared with 95% in patients not given ketorolac. CONCLUSIONS: A family physician in rural practice was able to attain and sustain a state-of-the-art, reach-the-cecum rate over a 9-year period. This service resulted in a high diagnostic yield, high degree of safety, and satisfactory results for the community. Ketorolac is an effective alternative for patients who may be hypersensitive to narcotic analgesia/sedation.

Insertion techniques.

The author provides a systematic and rational approach to the endoscopic examination of the colon. Anatomy, instrumentation, and technique are reviewed. Attention to completeness of the examination and patient safety is stressed.

Surgical glove failure rate.

Surgical gloves were collected after day-time operations for a 4-week period. Glove punctures were located by inflating each glove with compressed air and immersing the inflated glove in water. During the period of the study 681 surgical operations were performed. A total of 3790 gloves was collected, 334 gloves (8.8%) had perforations at the end of the surgical procedure. Defects occurred in one or more gloves in 32.0% of all operations.

Experimental pharmacology of auromomycin in L1210 tumor cells in vitro and in vivo.

The antibiotic protein auromomycin (AUR) is composed of a chromophore and an apoprotein. The in vitro cytotoxic activity of AUR is associated with the chromophore, whereas the apoprotein is not cytotoxic. Exposure to AUR blocks cell cycle traverse in G2-M phase. Both AUR and the chromophore exhibit antitumor activity against murine L1210 leukemia, both in vitro and in vivo. Similarly, neocarzinostatin and its chromophore also show antitumor activity against L1210 tumor cells in vitro and in vivo. AUR and neocarzinostatin apoproteins have no antitumor activity. The pharmacokinetics of 125I-labeled AUR in L1210 tumor-bearing mice shows a triexponential drug decay and initial rapid clearance of drug from the blood. The distribution of AUR-associated radioactivity into various tissues is rapid, and at the end of 24 hr, there is little drug accumulation in the tissues. During the first hr, greater than 50% of the administered drug is eliminated in the urine. As the chromophores alone possess antitumor activity, the effect of these antitumor proteins in cancer chemotherapy might be significantly increased by the administration of protein preparations containing biologically active and stable chromophores.

Light spectroscopic studies of the binary complex of Lactobacillus casei thymidylate synthetase and 5-fluoro-2'-deoxyuridylate.

In contrast to previous reports, fluorescence and ultraviolet difference spectroscopy are shown to reflect the interaction of the inhibitor, 5-fluoro-2'-deoxyuridylate, with thymidylate synthetase isolated from amethopterin-resistant Lactobacillus casei. Analysis of the quenching of protein fluorescence upon nucleotide binding yields a value of 2.1 X 10(5) M-1 for the association constant for binary complex formation. The ultraviolet difference spectrum for the nucleotide-enzyme complex exhibited a broad trough with the greatest loss of absorbance centered at 275 nm. Results of previous circular dichroic studies of nucleotide-enzyme binary complexes showed apparently parallel changes in ellipticity in the 267-269-nm and 290-nm regions, which were interpreted to reflect coordinated alteration in nucleotide and enzyme structure, respectively. When examined by difference circular dichroic spectroscopy, the nucleotide-enzyme interaction is accompanied by a substantial loss in ellipticity from 250 to 300 nm which is greatest at 280 nm. We interpret the results obtained from the three light spectroscopic techniques as indications of subtle alterations in the environments of certain tyrosine and tryptophan residues in the enzyme which are caused by the association of 5-fluoro-2'-deoxyuridylate with the enzyme.

Case report: metal fumes fever.

A young male foundry worker had headache, nonproductive cough, orthopnea, formication, rigor, fever, and substernal pain after exposure to concentrated metal fumes. Examination revealed bilateral basal rales. Serial spirometry suggested a transitory restrictive impairment with persistent mild to moderate obstructive impairment. Leukocytosis, hypoxemia, and the other symptoms resolved with no therapy other than the patient's removal from the polluted area.

Progressive infantile idiopathic scoliosis.

Infantile idiopathic scoliosis is unique in that it differs considerably from idiopathic scoliosis seen in the older child. Early recognition of the progressive type is essential if serious deformity is to be prevented. Treatment must be aimed at controlling the curvature by serial casts and the Milwaukee brace to support the spinal column without interference with the local mechanics of growth. Most children eventually require spinal fusion, but this should be delayed until early adolescence. If a curvature cannot be controlled satisfactorily, however, surgical fusion may be indicated earlier than desired. Never should a curve be allowed to progress beyond 60 degrees. Two cases are presented to illustrate these principles.