Experimental study of acute-phase reactions

Summary The ability of acute-phase rabbit serums to react with somatic pneumococcal polysaccharide has been confirmed. The complement-fixation test is applicable to the detection of this reaction.Immune serums were obtained from rats, which reacted specifically with rabbit acute-phase serums, but only weakly with normal rabbit serum. The Cx-reactive protein appearing in the blood of rabbits in the acute phase of inflammatory reactions to inoculation with various agents (pneumococcus andH.pertussis cultures, diphtheria toxin,E.coli culture filtrates, pyrogens) was immunologically identical, irrespective of the nature of the agent used.Presented by Academician N. N. Anichkov     

Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes

Insulin-like growth factor (IGF), hepatocyte growth factor (HGF), and heparin-binding epidermal growth factor-like growth factor (HB-EGF) are cardiogenic and cardiohypertrophic growth factors. Although the therapeutic effects of IGF and HGF have been well demonstrated in injured hearts, it is uncertain whether natural upregulation of HB-EGF after myocardial infarction (MI) plays a beneficial or pathological role in the process of remodeling. To answer this question, we conducted adenoviral HB-EGF gene transduction in in vitro and in vivo injured heart models, allowing us to highlight and explore the HB-EGF-induced phenotypes. Overexpressed HB-EGF had no cytoprotective or additive death-inducible effect on Fas-induced apoptosis or oxidative stress injury in primary cultured mouse cardiomyocytes, although it significantly induced hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. Locally overexpressed HB-EGF in the MI border area in rabbit hearts did not improve cardiac function or exhibit an angiogenic effect, and instead exacerbated remodeling at the subacute and chronic stages post-MI. Namely, it elevated the levels of apoptosis, fibrosis, and the accumulation of myofibroblasts and macrophages in the MI area, in addition to inducing left ventricular hypertrophy. Thus, upregulated HB-EGF plays a pathophysiological role in injured hearts in contrast to the therapeutic roles of IGF and HGF. These results imply that regulation of HB-EGF may be a therapeutic target for treating cardiac hypertrophy and fibrosis.     

Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease

BACKGROUND: 6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease. METHODS: We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy. RESULTS: In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction. CONCLUSIONS: 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.     

Comparison of conventional bacteriology with nucleic acid amplification (amplified mycobacterium direct test) for diagnosis of tuberculous meningitis before and after inception of antituberculosis chemotherapy

The role of nucleic acid amplification techniques in the rapid diagnosis of tuberculous meningitis remains uncertain. We compared the performance of Ziehl-Neelsen (ZN) staining, the Gen-Probe amplified Mycobacterium tuberculosis direct test (MTD), and culture with 341 cerebrospinal fluid specimens from 152 adults (73 with and 79 without tuberculous meningitis) before and after inception of antituberculosis chemotherapy. The sensitivity, specificity, and positive and negative predictive values of ZN staining before treatment were 34/66 (52%), 79/79 (100%), 34/34 (100%), and 79/111 (71%), compared with 25/66 (38%), 78/79 (99%), 25/26 (96%), and 79/120 (66%) for MTD. The sensitivity of combined ZN staining and MTD (either positive) was 45/66 (68%). The sensitivity of staining and culture fell more rapidly than that of MTD after the start of treatment: after 5 to 15 days of treatment, MTD was more sensitive than ZN staining (12/43 [28%] versus 2/43 [2%]; P = 0.013). Slower bacterial clearance was observed if M. tuberculosis was resistant to isoniazid and/or streptomycin: resistant organisms were more likely to be cultured from cerebrospinal fluid after 2 to 5 days of treatment than fully sensitive organisms (P < 0.001). The sensitivities of ZN staining, MTD, and the two tests combined were improved by repeated sampling to 38/59 (64%), 35/59 (59%), and 49/59 (83%), respectively. In conclusion, ZN staining of the cerebrospinal fluid is at least as good as MTD for the rapid diagnosis of tuberculosis and is much faster and less expensive. However, the combination of these methods on serial samples detects more cases. Alternative tests are still urgently required.     

Strategies for postoperative nausea and vomiting

Significant improvement towards a better control of postoperative nausea and vomiting have been achieved in recent years. Today, we understand better who is likely to vomit or to be nauseous after surgery. Significant amounts of the huge literature on anti-emetic interventions have been systematically reviewed, critically appraised and quantitatively synthesized. Thus, we know what anti-emetic interventions work, and how well they work, and we know their adverse effect profile. We also know which interventions have no worthwhile efficacy. A rational approach to postoperative nausea and vomiting includes three steps: identification of patients at risk, keeping the baseline risk low, and prophylactic administration of anti-emetics in those patients who are most likely to need them. For patients who are identified as high-risk patients, all measurements should be simultaneously initiated (multimodal anti-emesis).     

Measurement of pre- and post-synaptic proteins in cerebral cortex: effects of post-mortem delay

Assessments of synaptic density in human brain are often based on measurements of synaptic proteins. Little information is available on their post-mortem stability. We have investigated this by ELISAs of the pre-synaptic proteins syntaxin and synaptophysin, and the post-synaptic protein PSD-95, in rat and human cortex. The rat brains were cooled in situ from 37 to 20 or 4 degrees C over 3 h, and then kept at 20 or 4 degrees C for a further 24-72 h, to simulate post-mortem storage at room temperature or in a mortuary refrigerator. Synaptophysin and PSD-95 levels in rat cerebral cortex were not significantly decreased after 72 h of incubation at 20 degrees C. Syntaxin was stable for 24 h but decreased by 39-44% at 48-72 h. Storage at 4 degrees C resulted in a similar reduction of syntaxin levels over 72 h. In human brain tissue from 160 people aged 24-102 years, post-mortem delay had little effect on synaptic protein levels in superior temporal cortex, but was associated with a decline in PSD-95 and syntaxin in mid-frontal cortex after 24 h. The more robust stability of synaptophysin may be related to its multi-transmembrane structure.     

A dynamic simulation of bisphenol A dosimetry in neuroendocrine organs

Bisphenol A (BPA) is a known xenoestrogen with similar properties to 17beta-estradiol. BPA and estrogen are hydrophobic compounds, and this affects the pharmacokinetics of both compounds in mammals. In a previous study we measured the distribution of BPA in female F344 rats exposed to oral doses of 0.1, 10 and 100 mg/kg. The results showed distribution to target neuroendocrine organs at all doses tested. Using these results, we developed a pharmacokinetic model to predict the dynamic uptake and excretion of BPA by various routes of exposure (po, iv, sc, ip). The model was able to simulate the entire time course (48 h) following various routes of exposure in rats over the dose ranges tested. The model indicated that the ultimate tissue uptake of BPA was established by the rapid initial transfer of free BPA into tissues. After free BPA enters the systemic circulation, metabolism and excretion reactions cause a relatively short duration and rapid decline. This period is followed by a slower long-term decline characteristic of BPA's biphasic pharmacokinetics. Plasma protein and tissue binding reactions established the long-term half-life of BPA in the body. Route differences in tissue uptake were directly related to the competition between transfer and binding reactions during the absorption phase.     

The antiemetic efficacy of droperidol added to morphine patient-controlled analgesia: a randomized,controlled, multicenter dose-finding study

The antiemetic dose response of droperidol when it is added to patient-controlled analgesia with morphine is not well known. We randomly allocated adults who received postoperative morphine patient-controlled analgesia (1-mg bolus, 5-min lockout) to one of four regimens: no droperidol (control) or 5, 15, or 50 micro g of droperidol per milligram of morphine. Efficacy and adverse effects were recorded during 24 h and were analyzed with number needed to treat (NNT) and number needed to harm with 95% confidence intervals. Data from 82 controls, 82 patients receiving droperidol 5 micro g, 82 receiving droperidol 15 micro g, and 83 receiving droperidol 50 micro g were analyzed. Average consumption of droperidol per 24 h was 0.2 mg with the 5- micro g regimen, 0.61 mg with the 15- micro g regimen, and 2.04 mg with the 50- micro g regimen. In controls, the incidence of nausea was 48.8%; with droperidol 5 micro g, it was 42.7% (NNT compared with control, 16 [95% confidence interval, 4.7 to -11]); with 15 micro g, it was 32.9% (NNT, 6.3 [3.3-100]); and with 50 micro g, it was 21.7% (NNT, 3.7 [2.4 to 7.6]). In controls, the incidence of vomiting was 24.4%; with droperidol 5 micro g, it was 23.2% (NNT compared with control, 82 [7 to -8.5]); with 15 micro g, it was 22.0% (NNT, 41 [6.5 to -9.6]); and with 50 micro g, it was 12% (NNT, 8.1 [4.2-142]). In controls, the incidence of pruritus was 12.2%; with droperidol 5 micro g, it was 6.1% (NNT compared with control, 16 [6.7 to -37]); and with 15 and 50 micro g, it was 2.4% (NNT, 10 [5.7-52]). In controls, the incidence of sedation was 2.4%; with droperidol 5 micro g, it was 8.5% (number needed to harm (NNH) compared with control, 16 [7.7 to -123]); with 15 micro g, it was 6.1% (NNH, 27 [10 to -40]); and with 50 micro g, it was 18.1% (NNH, 6.4 [4.1-15]). There were no extrapyramidal symptoms and no cardiac adverse events. There was no difference in patient satisfaction. The optimal antiemetic dose of droperidol is 15-50 micro g/mg of morphine. Larger doses may have more antivomiting efficacy but are likely to be unacceptably sedating.     

Preoperative urodynamic evaluation may predict voiding dysfunction in women undergoing pubovaginal sling

PURPOSE: We determine which urodynamic parameters can best predict postoperative voiding dysfunction following pubovaginal sling surgery. MATERIALS AND METHODS: The records of 98 consecutive women who had undergone pubovaginal sling surgery with allograft fascia lata between July 1998 and July 2000 were reviewed. Urodynamic and followup data were sufficient for evaluation for 73 patients. Urodynamic and clinical parameters were correlated with urinary retention, time to return of efficient voiding and development of postoperative urgency symptoms. RESULTS: Average time to return of efficient voiding was 3.92 days (median 3). Of 21 women who voided without a detrusor contraction urinary retention developed in 4 (23%) versus 0 of 48 who voided with detrusor contraction (p = 0.007). Urinary retention was defined as the need to perform even occasional self-catheterization. All 4 women with urinary retention had a detrusor pressure of less than 12 cm. H(2)O (0 in 3, 4 in 1). None of the women with a detrusor pressure of greater than 12 cm. H(2)O had urinary retention (p = 0.047). The presence of Valsalva voiding in women without a detrusor contraction did not affect the incidence of urinary retention (11.1%) compared to those who did not demonstrate Valsalva voiding (5.1%) (p = 0.603). Peak flow rate, detrusor instability on preoperative urodynamics and post-void residual urine volume were not associated with postoperative urinary retention. Finally, post-void residual urine volume predicted delayed return to normal voiding (p = 0.001). There were no other urodynamic parameters that were significantly associated with urinary retention, delayed return to normal voiding or postoperative urgency symptoms including peak flow rate, capacity or compliance. CONCLUSIONS: Women who void without or with a weak detrusor contraction are most likely to have urinary retention postoperatively. Therefore, we conclude that preoperative urodynamic evaluation may be used to counsel women regarding the risk of urinary retention following the pubovaginal sling procedure.