Tricyclic alkylamides as melatonin receptor ligands with antagonist or inverse agonist activity

This work reports the design and synthesis of novel alkylamides, characterized by a dibenzo[a,d]cycloheptene nucleus, as melatonin (MLT) receptor ligands. The tricyclic scaffold was chosen on the basis of previous quantitative structure-activity studies on MT1 and MT2 antagonists, relating selective MT2 antagonism to the presence of an aromatic substituent out of the plane of the MLT indole ring. Some dibenzo seven-membered structures were thus selected because of the noncoplanar arrangement of their benzene rings, and an alkylamide chain was introduced to fit the requirements for MLT receptor binding, namely, dibenzocycloheptenes with an acylaminoalkyl side chain at position 10 and dibenzoazepines with this side chain originating from the nitrogen atom bridging the two phenyl rings. Binding affinity at human cloned MT1 and MT2 receptors was measured by 2-[125I]iodomelatonin displacement assay and intrinsic activity by the GTPgammaS test. The majority of the compounds were characterized by higher affinity at the MT2 than at the MT1 receptor and by very low intrinsic activity values, thus confirming the importance of the noncoplanar arrangement of the two aromatic rings for selective MT2 antagonism. Dibenzocycloheptenes generally displayed higher MT1 and MT 2affinity than dibenzoazepines. N-(8-Methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylmethyl)propionamide (4c) and -butyramide (4d) were the most selective MT2 receptor antagonists of the series, with MT2 receptor affinity comparable to that of melatonin and as such among the highest reported in the literature for MLT receptor antagonists. The acetamide derivative 4b produced a noticeable reduction of GTPgammaS binding at MT2 receptor, thus being among the few inverse agonists described.     

Mechanical performance of dental amalgam--composite interfaces

Composite veneering of amalgam is the most aesthetical solution to extensive direct tooth restoration and is applied with success in specific clinical situations. An in-vitro technique has been used to evaluate the mechanical performance of one amalgam bonded to four different composites. The amalgam-composite interfaces were subjected to tensile stress and shear stress at break tests, using dumb-bell and sandwich specimens in a PC-controlled electronic dynamometer equipped with innovative grips. Mean values were higher for tensile stress than for shear stress. Further studies and clinical experimentation will be necessary to explore the question of long-term reliability.     

IgA nephropathy

Summary Seventy-five biopsy samples from patients with chronic renal disorders were examined by the usual techniques of light microscopy and immunofluorescence; in fifteen patients IgA nephropathy was found. These patients were young adults; the onset of the disease was characterized by macrohematuria, and recurrent episodes of hematuria were observed. Histological examination revealed proliferative endothelio-mesangial glomerulonephritis at various stages of development with focal or diffuse patterns; immunofluorescence revealed constant and intense positive reactions for IgA mainly in association with C3. It is assumed that there is a relationship connecting the more advanced histological changes, a more severe clinical course and the presence of IgM deposits.     

Effects of depth and chest volume on cardiac function during breath-hold diving

Cardiac response to breath-hold diving in human beings is primarily characterized by the reduction of both heart rate and stroke volume. By underwater Doppler-echocardiography we observed a “restrictive/constrictive” left ventricular filling pattern compatible with the idea of chest squeeze and heart compression during diving. We hypothesized that underwater re-expansion of the chest would release heart constriction and normalize cardiac function. To this aim, 10 healthy male subjects (age 34.2 ± 10.4) were evaluated by Doppler-echocardiography during breath-hold immersion at a depth of 10 m, before and after a single maximal inspiration from a SCUBA device. During the same session, all subjects were also studied at surface (full-body immersion) and at 5-m depth in order to better characterize the relationship of echo-Doppler pattern with depth. In comparison to surface immersion, 5-m deep diving was sufficient to reduce cardiac output (P = 0.042) and increase transmitral E-peak velocity (P < 0.001). These changes remained unaltered at a 10-m depth. Chest expansion at 10 m decreased left ventricular end-systolic volume (P = 0.024) and increased left ventricular stroke volume (P = 0.024). In addition, it decreased transmitral E-peak velocity (P = 0.012) and increased deceleration time of E-peak (P = 0.021). In conclusion the diving response, already evident during shallow diving (5 m) did not progress during deeper dives (10 m). The rapid improvement in systolic and diastolic function observed after lung volume expansion is congruous with the idea of a constrictive effect on the heart exerted by chest squeeze.     

Clinical usefulness of prostate-specific antigen and prostatic acid phosphatase in patients with prostatic cancer.

Serum prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) levels were measured in 70 patients with benign prostatic hypertrophy (BPH) and in 70 patients with prostatic cancer. PSA was increased above the cutoff level of 10 ng/ml in 13% of patients with BPH and in 87% of patients with prostatic cancer. In contrast, abnormal PAP levels were found in 14 and 76% of patients, respectively. We concluded that, due to its high specificity, PSA is a useful marker in the management of patients with prostatic carcinoma and that it surpasses PAP in this regard.     

Uric acid concentration in subjects at risk of type 2 diabetes mellitus: relationship to components of the metabolic syndrome

High uric acid concentration is a common finding in subjects with risk factors for cardiovascular disease (CVD), including some characteristics of the metabolic syndrome. However, its exact role in this setting and in the progression to type 2 diabetes mellitus (DM) is not well understood and could be affected by confounding factors such as hypertriglyceridemia. Our study aimed to establish the relationship between uric acid (avoiding the interference of high triglyceride levels), insulin sensitivity, and components of the metabolic syndrome in a group of subjects at high risk of developing DM. Among 201 subjects included in the study, 111 (55.2%) showed an abnormal oral glucose tolerance and uric acid levels higher than those measured in subjects with normal glucose tolerance. Body mass index (BMI), triglycerides, diastolic blood pressure (DBP), and 2-hour glycemia in the oral glucose tolerance test (OGTT) contributed independently to uric acid concentration (R2 =.59). However, uric acid did not affect either insulin sensitivity or glucose tolerance. The recovery tests revealed that a triglyceride concentration > or = 3 mmol/L interfered with the measurement of uric acid level when a colorimetric method was used, but not when a dry-chemistry method was used. In conclusion, uric acid concentration is higher in subjects at high risk of DM with abnormal glucose tolerance and is independently determined by various components of the metabolic syndrome.     

Modified Schoemacher resection for distal gastric cancer

Between October 1979 and February 1987, 30 consecutive patients with cancer of the lower stomach underwent B1-Schoemacher resection with a tubular gastric pouch. Operative mortality was 0% and operative morbidity 10% (leak 3%, anastomotic stricture 3% and abscess 3%). After a mean follow-up of 30 months, the expected 5-year survival was 32%. The causes of death were: 7 distant relapses, 2 noncancer diseases and 1 new primary cancer. The overall incidence of postgastrectomy symptoms was 23% for the whole series and 35% for the patients harboring small tumors. Mild dyspepsia occurred in 71%. The declining concept of total gastrectomy as an essential requirement for curative resection and the recent evidence that B2 for gastric lesions is a carcinogenic operation necessitate alternative procedures. The data show that modified Schoemacher resection can be consider a valid challenge to B2.     

Resectable breast cancer: axillary dissection sparing pectoralis muscles and nerves

In breast cancer surgery, axillary dissection is currently considered an essential step. Nevertheless, procedures commonly used include the resection of the pectoralis minor muscle and/or pectoralis nerves. Since 1984 we have performed axillary dissection by sparing both the pectoralis muscles and their nerves. In this paper we present the surgical technique. The comparison of the two groups with clinical N0 N1a assessment, the former of 103 patients submitted to this kind of surgical procedure, the latter (108 women) treated by resection of the pectoralis minor muscle, showed that the mean number of dissected lymph nodes in both procedures was superimposable.