Biomedical subjects
Publications and source records attributed to S Metz.
The potency and selectivity of a series of 5-hetero-2-iminohexahydroazepines were examined as inhibitors of the three human NOS isoforms. The effect of ring substitution of the 5-carbon for a heteroatom is presented. Potencies (IC(50)'s) for these inhibitors are in the low micromolar range for hi-NOS with some examples exhibiting a 500x selectivity versus hec-NOS.
BACKGROUND: The intriguing monotony in the occurrence of intercaval conduction block during typical atrial flutter suggests an anatomic or electrophysiological predisposition for conduction abnormalities. METHODS AND RESULTS: To determine the location of and potential electrophysiological basis for conduction block in the terminal crest region, a high-density patch electrode (10x10 bipoles) was placed on the terminal crest and on the adjacent pectinate muscle region in 10 healthy foxhounds. With a multiplexer mapping system, local activation patterns were reconstructed during constant pacing (S(1)S(1)=200 ms) and introduction of up to 2 extrastimuli (S(2), S(3)). Furthermore, effective refractory periods were determined across the patch. If evident through online analysis, the epicardial location of conduction block was marked for postmortem verification of its endocardial projection. Marked directional differences in activation were found in the terminal crest region, with fast conduction parallel to and slow conduction perpendicular to the intercaval axis (1.1+/-0.4 versus 0.5+/-0.2 m/s, P<0.01). In the pectinate muscle region, however, conduction velocities were similar in both directions (0.5+/-0.3 versus 0.6+/-0.2 m/s, P=NS). Refractory patterns were relatively homogeneous in both regions, with local refractory gradients not >30 ms. During S(3) stimulation, conduction block parallel to the terminal crest was inducible in 40% of the dogs compared with 0% in the pectinate muscle region. CONCLUSIONS: Even in normal hearts, inducible intercaval block is a relatively common finding. Anisotropic conduction properties would not explain conduction block parallel to the intercaval axis in the terminal crest region, and obviously, refractory gradients do not seem to play a role either. Thus, the change in fiber direction associated with the terminal crest/pectinate muscle junction might form the anatomic/electrophysiological basis for intercaval conduction block.
The relation of inosine-5'-monophosphate dehydrogenase (IMPDH; the rate-limiting enzyme in GTP synthesis) to mitogenesis was studied by enzymatic assay, immunoblots, and RT-PCR in several dissimilar transformed pancreatic ss-cell lines, using intact cells. Both of the two isoforms of IMPDH (constitutive type 1 and inducible type 2) were identified using RT-PCR in transformed beta cells or in intact islets. IMPDH 2 messenger RNA (mRNA) and IMPDH protein were both regulated reciprocally by changes in levels of their end-products. Flux through IMPDH was greatest in rapidly growing cells, due mostly to increased uptake of precursor. Glucose (but not 3-0-methylglucose, L-glucose, or fructose) further augmented substrate uptake and also increased IMPDH enzymatic activity after either 4 or 21 h of stimulation. Serum or ketoisocaproate also increased IMPDH activity (but not uptake). Two selective IMPDH inhibitors (mycophenolic acid and mizoribine) reduced IMPDH activity in all cell lines, and, with virtually identical concentration-response curves, inhibited DNA synthesis (assessed as bromodeoxyuridine incorporation) in response to glucose, serum, or ketoisocaproate. Inhibition of DNA synthesis was reversible, completely prevented by repletion of cellular guanine (but not adenine) nucleotides, and could not be attributed to toxic effects. Despite the fact that modulation of IMPDH expression by guanine nucleotides was readily detectable, glucose and/or serum failed to alter IMPDH mRNA or protein, indicating that their effects on IMPDH activity were largely at the enzyme level. Precursors of guanine nucleotides failed, by themselves, to induce mitogenesis. Thus, adequate IMPDH activity (and thereby, availability of GTP) is a critical requirement for beta-cell proliferation. Although it is unlikely that further increases in GTP can, by themselves, initiate DNA synthesis, such increments may be needed to sustain mitogenesis.
BACKGROUND: In minimally invasive cardiac surgery use of a lateral minithoracotomy is associated with early postoperative rehabilitation but also relatively high pain levels during the first 3 postoperative days. Cryoablation therapy was evaluated prospectively. METHODS: From April 1999 until September 1999, 57 patients underwent lateral minithoracotomy for mitral valve operation (n = 18) or minimally invasive direct coronary artery bypass grafting (n = 39). Intraoperatively, patients were randomly assigned to cryoablation or intercostal application of local anesthetic agents. A standardized questionnaire was used for prospective pain assessment on postoperative days 1 to 7. RESULTS: From postoperative day 1 to 7 pain levels declined in all groups. Overall pain levels were significantly lower in the cryo group than in the control group (p < 0.0001, GLM). According to diagnoses, pain levels were significantly lower after MIDCABG and cryo versus control; after mitral valve operation they were lower in the cryo group and almost reached significance. CONCLUSIONS: Cryoablation is easy to perform and leads to a significant reduction in pain and lower request for additional pain medication after lateral minithoracotomy in minimally invasive cardiac operation.
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BACKGROUND: The aim of this study was to evaluate pain and quality of life after minimally invasive cardiac operations in comparison with conventional cardiac operations. METHODS: From October 1996 to May 1997 a total of 338 patients were interviewed daily using standard scoring systems (myocardial revascularization, n = 160; mitral valve reconstruction or replacement, n = 58; aortic valve replacement, n = 120). RESULTS: Regarding ventricular function and intensive care and hospital stay, there were no significant differences between groups. Pain decreased until the seventh postoperative day in all patients. Patients with a lateral minithoracotomy (minimally invasive revascularization and mitral valve operations) had lower pain levels from the third postoperative day onward. There were no differences in quality of life, postoperative wound healing, or stability of the bony thorax. CONCLUSIONS: In cardiac operations overall pain levels are relatively low. After minimally invasive procedures with lateral minithoracotomy, earlier mobilization is possible because of a better stability of the bony thorax, resulting in lower pain levels.
A type of hair loss closely resembling human alopecia areata has been described in C3H/HeJ mice. In order to test the assumed analogy with human alopecia areata, we investigated the efficacy of treatment with the contact allergen squaric acid dibutylester. In 12 C3H/HeJ mice with alopecia areata an allergic contact dermatitis was induced and elicited weekly on one side of the back by topical applications of squaric acid dibutylester. Overt hair regrowth was observed only on the treated side of the back in nine of 12 mice. Histopathologic examination revealed a change in the distribution of the inflammatory infiltrate from a dense perifollicular lymphocytic infiltrate around the mid and lower regions of hair follicles in untreated skin to a uniform presence in the upper dermis in treated skin. Immunohistomorphometric studies revealed that treatment with squaric acid dibutylester increased the CD4+/CD8+ ratio from approximately 1:2 in untreated alopecia areata to 1:1 in treated alopecia areata. Additional immunohistochemical investigations showed an aberrant expression of major histocompatibility complex class I, major histocompatibility complex class II and intercellular adhesion molecule 1 on keratinocytes of the mid and lower parts of hair follicles in untreated alopecia areata. In successfully treated skin ectopic major histocompatibility complex class I and II expression was clearly reduced, whereas intercellular adhesion molecule 1 expression showed only minor changes. In conclusion, alopecia areata-like hair loss in C3H/HeJ mice responded to treatment with the contact sensitizer squaric acid dibutylester analogous to human alopecia areata. Moreover, successful treatment changes the aberrant expression of major histocompatibility complex class I and II in a way similar to that observed in human alopecia areata. These observations support the concept that alopecia areata-like hair loss in C3H/HeJ mice can be utilized as an appropriate model for the study of human alopecia areata.
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BACKGROUND: This prospective clinical trial focuses on pain and quality of life (QOL) after minimally invasive direct coronary artery bypass (MIDCAB) grafting versus conventional coronary artery bypass grafting (CABG). METHODS: Group A consisted of 65 consecutive MIDCAB patients using an anterolateral mini-thoracotomy and the "off-pump" technique. Group B consisted of 95 computer-matched patients who underwent conventional CABG with cardiopulmonary bypass (CPB). Pain was graduated using the visual analog scale (VAS), and the verbal rating scale (VRS) [Troidl 1990]. QOL was evaluated at the time of discharge and three months after surgery using modified Nottingham Health Questionnaires that separate physical, social, activity, emotional, pain, and sleeping conditions. RESULTS: Postoperative pain was higher after MIDCAB on postoperative day (POD) 1 (p< 0.002). From POD 4 onwards MIDCAB patients had less pain compared with the conventional group (p<0.04). MIDCAB patients required less pain medication from POD 4 onwards (p<0.05). QOL was significantly better in the MIDCAB group on POD 7 for physical (p< 0.038), activity (p< 0.016), pain (p< 0.041), and sleep (p<0.038) conditions. The three-month questionnaire showed significantly better levels for MIDCAB patients regarding physical (p< 0.03) and pain (p< 0.001) conditions, and a trend for activity (p< 0.08) and emotional (p<0.08) conditions. CONCLUSION: Compared to patients undergoing conventional surgery, MIDCAB patients suffer more pain in the first three postoperative days, probably as a result of the lateral thoracotomy. From POD 4 onwards, MIDCAB patients are significantly better, experiencing less pain and showing better physical, activity, and sleeping conditions even three months after surgery. This can be attributed to the absence of median sternotomy and/or the avoidance of cardiopulmonary bypass.
A series of analogues of 2-iminopiperidine have been prepared and shown to be potent inhibitors of the human nitric oxide synthase (NOS) isoforms. Methyl substitutions on the 4-position (3) or 4- and 6-positions (8) afforded the most potent analogues. These compounds exhibited IC50 values of 0.1 and 0.08 microM, respectively, for hiNOS inhibition. Substitution with cyclohexylmethyl at the 6-position (13) afforded an inhibitor that showed the best selectivity for hiNOS versus heNOS (heNOS IC50/hiNOS IC50 = 64). Following oral administration, inhibitors were found to decrease serum nitrite/nitrate levels in an in vivo rat endotoxin assay. This series of 2-iminopiperidines were prepared via the described synthetic methodologies. The effect of ring substitutions on potency and selectivity for this class of cyclic amidines as NOS inhibitors is described.
OBJECTIVE: Evaluation of less invasive aortic valve replacement to minimize surgical trauma and achieve a better postoperative quality of life. METHODS: Thirty-three patients had aortic valve replacement using a 4-6 cm small incision and partial sternotomy only. Partial sternotomy was performed proximal (16), S-shaped (14) or horizontal (3). Access for cardiopulmonary bypass was via sternotomy (24) or the right femoral vessels (9). Patient age was 58+/-13 years, 21 had aortic stenosis and 12 aortic incompetence. RESULTS: Surgical exposure was sufficient and allowed for uncomplicated AVR in all patients. Mechanical valves (20), conventional bioprostheses (3), stentless bioprostheses (9) or a homograft (1) were implanted. Crossclamp time was not prolonged in comparison to the conventional technique. Intensive care stay and hospital stay were 1 and 10 days, respectively. One patient had to be reoperated for paravalvular leakage, two patients (horizontal sternotomy) had sternal dehiscence. Postoperative pain was low in most patients. CONCLUSION: Less invasive aortic valve replacement is feasible with good functional results. The S-shaped sternotomy approach is advantageous whereas the horizontal sternotomy is no longer performed due to a high rate of instability. This new technique will be further evaluated in comparison to the conventional approach.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
The enzyme-linked immunosorbent assay (ELISA) using HLA class I molecules purified from pooled platelets has the potential to detect HLA antibodies with increased efficiency without sacrificing sensitivity or specificity. This test, which was originally developed in our institution, has been independently validated by recent studies and is now commercially available. We now present evidence of its usefulness as a routine HLA antibody screening test for renal transplant patients. A total of 515 patients were tested monthly by ELISA (13.9 tests/patient) and by antiglobulin-enhanced panel reactivity (6.3 tests/patient). In patients found to be unsensitized, the incidence of false-positive results was less for ELISA than for the panel studies. In patients who were highly sensitized, both tests performed equally well, whereas discordant results were registered mainly in cases of mild sensitization. Because 66% of our patients were not sensitized, the ELISA was effective in reducing the number of more involved tests aimed at characterizing the antibodies. These results provide a foundation to use the pooled platelet HLA ELISA on a routine basis for HLA antibody screening.
Tumor relapse occurs frequently in patients with ductal pancreatic head cancer despite the absence of residual tumor detectable at primary surgery. Therefore it has to be assumed that current tumor staging procedures fail to detect minimal amounts of disseminated tumor cells present in secondary organs, which might be the seed for subsequent metastatic relapse. We evaluated lymph nodes from 18 patients without overt metastases who had undergone radical tumor resection (R0 resection). Lymph nodes judged as "tumor-free" by routine histopathology were further examined for the presence of single tumor cells using immunohistochemistry with the antiepithelial monoclonal antibody Ber-EP4. Sixteen of 37 "tumor-free" lymph nodes (43.2%), obtained from 13 of 18 patients (72.2%), displayed Ber-EP4+ tumor cells. Twelve of these 18 patients presented at pT2 stage. Nine of 12 patients (75%) staged as pN0 had these cells. Two of six pN1 patients had no Ber-EP4+ in histopathologically tumor-free lymph nodes. Using multivariate Cox's regression analysis, the presence of Ber-EP4+ cells in "tumor-free" lymph nodes was an independent factor for a significantly reduced relapse-free survival (p = 0.006) and overall survival (p = 0.01). Remarkably, all patients who were restaged as lymph node negative by both histopathology and immunohistochemistry survived the observation period without recurrence. The frequent occurrence of disseminated tumor cells in patients with pancreatic cancer and their prognostic impact support the need for a refined staging system of excised lymph nodes, which should include immunohistochemical examination. Thus patients with a minimal residual tumor load who might benefit from an adjuvant therapy could be selected.
The possibility that an agent in addition to the human immunodeficiency virus (HIV) may contribute to the etiology of non-Hodgkin's lymphoma in persons with acquired immunodeficiency syndrome (AIDS) was studied using participants from the Multicenter AIDS Cohort Study (MACS) of homosexual and bisexual men enrolled in 1984-1985 and also in 1987-1991. A nested case-control analysis was conducted. The primary source of information on potential exposures and characteristics of the participants was the baseline study entry interview that was conducted prior to the development of AIDS. A total of 84 cases of non-Hodgkin's lymphoma were identified and compared with 527 participants who developed AIDS but had no evidence of cancer. The groups were similar for most sociodemographic characteristics as well as sexual activity and past history of antecedent illnesses. Although the non-Hodgkin's lymphoma cases reported less frequent use of recreational drugs and cigarettes compared with other persons with AIDS, these differences were not significant. Non-Hodgkin's lymphoma cases reported more frequent intake of aspirin during the week before the interview. However, there were no differences between the comparison groups for long-term aspirin intake or intake of other analgesics. The absence of any specific and strong association between non-Hodgkin's lymphoma and the various behavior-related activities and exposures considered in this analysis suggests that these factors are not related to a second agent in the etiology of HIV-induced non-Hodgkin's lymphoma. The possibility that a very common agent in this study population or that differences in the nature of the immune dysfunction resulting from HIV infection could act as a cofactor for HIV-induced non-Hodgkin's lymphoma cannot be excluded.
We encountered two patients who could be neither ventilated nor intubated after induction of anesthesia. In both cases, transtracheal ventilation failed after emergent cricothyroid membrane puncture with a 14-gauge intravenous (i.v.) catheter. In the first case, two catheters placed in rapid succession kinked, preventing gas exchange. In the second case, absence of a plunger on the needle-over-catheter assembly prevented confirmation of intratracheal placement. Both patients required emergent tracheal access by the surgeon. We suggest that transtracheal ventilation via standard i.v. catheters as a primary emergent rescue technique be reassessed.