Sodium periodate/TEMPO as a selective and efficient system for amine oxidation.

A new metal-free protocol for promoting oxidation of amines in aqueous-organic medium was developed. NaIO4 and TEMPO as the catalyst emerged as the most efficient and selective system for oxidation of differently substituted benzyl amines to the corresponding benzaldehydes without overoxidation. Unsymmetrical secondary amines underwent selective oxidation only at the benzylic position thus realising an oxidative deprotection of a benzylic group with an easy amine recovery.

Persistence and degradation of new ß-lactam antibiotics in the soil and water environment.

The development of new antibiotics with low environmental persistence is of utmost importance in contrasting phenomena of antibiotic resistance. In this study, the persistence of two newly synthesized monocyclic ß-lactam antibiotics: (2R)-1-(methylthio)-4-oxoazetidin-2-yl acetate, P1, and (2R,3R)-3-((1R)-1-(tert-butyldimethylsilanyloxy)ethyl)-1-(methylthio)-4-oxoazetidin-2-yl acetate, P2, has been investigated in water in the pH range 3-9 and in two (calcareous and forest) soils, then compared to amoxicillin, a ß-lactam antibiotic used in human and veterinary medicine. P1 and P2 persistence in water was lower than that of amoxicillin with only a few exceptions. P1 hydrolysis was catalyzed at an acidic pH whereas P2 hydrolysis takes place at both acidic and alkaline pH values. P1 persistence in soils depended mainly on their water potential (t1/2: 35.0-70.7d at wilting point; <1d at field capacity) whereas for P2 it was shorter and unaffected by soil water content (t1/2 0.13-2.5d). Several degradation products were detected in soils at both water potentials, deriving partly from hydrolytic pathways and partly from microbial transformation. The higher LogKow value for P2 compared with P1 seemingly confers P2 with high permeability to microbial membranes regardless of soil water content. P1 and P2 persistence in soils at wilting point was shorter than that of amoxicillin, whereas it had the same extent at field capacity.

Monocyclic ß-lactams: new structures for new biological activities.

The azetidinone core-structure offers a unique approach to the design and synthesis of new derivatives with unique biological properties. During the last two decades researches convincingly demonstrated that the prospect of structural modifications of monocyclic ß-lactams with specific substituents is an effective procedure for the detection and improvement of important pharmacological effects different from antibacterial activity. As a matter of fact, new ß-lactam compounds demonstrated biological activity as inhibitors of a wide range of enzymes. This review reports the latest developments on monocyclic ß-lactam compounds activity as anticancer, antitubercular, HFAAH inhibitors, HDAC inhibitors, anti-inflammatory drugs (tryptase inhibitors), Cathepsin K inhibitors, and vasopressin inhibitors. We attempted to highlight the intertwined relationships between structural features and biological activities, by analysing groups anchored on the three positions of the azetidinone ring as sources of molecular diversity.

Morphometric analysis of the canal system of cortical bone: An experimental study in the rabbit femur carried out with standard histology and micro-CT.

The osteonal pattern of cortical bone is gradually built around the intracortical vessels by the progression of the cutting cones (secondary remodelling); therefore, the central canal size can be used as index of the remodelling activity. An experimental model in the rabbit femur was used to investigate, through central canal morphometry and frequency distribution analysis, the remodelling activity, comparing the middle of the diaphysis (mid-shaft) with the extremity (distal-shaft) and at the same level sectors and layers of the cortex in transversal sections. The study documented a higher density of canals in the mid-shaft than in the distal-shaft and a higher remodelling in the distal-shaft. There were no significant differences between dorsal, ventral, medial and lateral sectors at both mid-shaft and distal-shaft levels, while the number of canals was higher in the sub-periosteal layers than in the sub-endosteal. A lower threshold of 40 microm(2) was observed in the central canal area. Sealed osteons in the midshaft were 22.43% of the total number of osteons of the central canal area between 40 and 200 microm(2) and 0.44% of those of the distal-shaft. Micro-CT allowed a 3D reconstruction of the vascular canal system, which confirmed the branched network pattern rather than the trim architecture of the traditional representation. Some aspects like the lower threshold of the central canal size and the sealed osteons documented the plasticity of the system and its capacity for adaptation to changes in the haemodynamic conditions.

Solvation of the Carbonyl Compound as a Predominant Factor in the Diastereofacial Selectivity of Nucleophilic Addition.

Temperature-dependent selectivity in nucleophilic additions is affected by the solvent. The inversion temperature (marked with arrows in the graph) that appears in the nonlinear Eyring plots of ln (anti/syn) versus temperature for the addition of butyllithium to an O-protected alpha-hydroxy aldehyde 1 does not depend on nucleophiles (nBuLi (black triangle), tBuLi (*)), but on the solvent. Its value can be obtained from a plot of the (13)C NMR chemical shift of C=O versus temperature. TBDMS=tBuMe(2)Si.

Prospective study of bone loss in pre- and post-menopausal women on L-thyroxine therapy for non-toxic goitre.

OBJECTIVE: Hyperthyroidism is associated with increased bone turnover and bone resorption, but the effects of suppressive doses of thyroxine in treating non-toxic goitre remain unclear. We carried out a longitudinal study to evaluate the effect on bone of L-thyroxine (L-T4) therapy in women with non-toxic goitre. SUBJECTS: Forty Caucasian women, 19 of whom were pre-menopausal and 21 post-menopausal, were studied before and after 12 months' L-T4 therapy for non-toxic goitre; 40 women matched for age, body mass index and menopausal status were used as controls. DESIGN: The minimal dosage of L-T4 (mean +/- standard error = 1.5 +/- 0.1 micrograms/kg-1 day-1) was given to each patient to obtain subnormal but detectable serum TSH (< or = 0.2 mU/l). Patients and controls were assessed for minor determinants of bone loss rate, such as genetic and behavioural factors. MEASUREMENTS: Bone mineral density (BMD) of the lumbar spine, femoral neck, trochanter and Ward's triangle was measured by dual-energy X-ray absorptiometry at baseline and 12 months; serum and urine markers of bone turnover was measured at baseline, 3, 6 and 12 months. RESULTS: No significant difference was detected in BMD values between patients and controls either at presentation or at the 12-month follow-up. Pre-menopausal patients showed a significant decrease in femoral neck BMD (-1.7 +/- 0.6%, P < 0.05) while controls showed no change +0.2 +/- 0.9%, P = NS). Post-menopausal patients showed a significant decrease in BMD of the lumbar spine (-1.3 +/- 0.6%, P < 0.05; controls +0.0 +/- 0.4%, P = NS), femoral neck (-1.5 +/- 0.6%, P < 0.05; controls -1.2 +/- 0.8%, P = NS) and trochanter (-2.1 +/- 0.8%, P < 0.05; controls -1.4 +/- 0.9%, P = NS). In both pre- and post-menopausal patients the serum markers of bone turnover, alkaline phosphatase and osteocalcin, showed an early and progressive increase. A linear relationship was found only between the 3-month values of serum osteocalcin and the urine hydroxyproline/creatinine ratio in both pre-menopausal (r = 0.87, P < 0.01) and post-menopausal (r = 0.72, P < 0.05) patients. No correlation was found between bone loss or changes in bone turnover markers and L-T4 dose or thyroid hormone levels. CONCLUSIONS: This longitudinal study suggests that TSH-suppressive therapy with L-thyroxine for non-toxic goitre significantly increases the bone mineral turnover and might contribute to a BMD reduction, more marked on cortical bone, in both pre- and post-menopausal women.

Comparison between TRH-stimulated TSH and basal TSH measurement by a commercial immunoradiometric assay in the management of thyroid disease.

In order to assess the current diagnostic role of the TRH test following the introduction of more sensitive "second generation" TSH assays, we studied a series of 259 outpatients, 237 women and 22 men, mean age 44.7 years (range 12-82), 91 of whom (35%) with untreated simple goiter, 133 (51%) with simple nodular goiter on steady state I-thyroxine treatment, 18 (7%) with overt or subclinical hyperthyroidism and 17 (7%) with overt or subclinical hypothyroidism, compared to a control group of 26 euthyroid healthy subjects. Serum TSH was measured by a commercial immunoradiometric assay (clinical sensitivity 0.1 microU/ml). TSH response to TRH was evaluated 30 minutes after giving 200 micrograms TRH i.v. bolus, the results being analyzed both as absolute increase (delta-TSH=stimulated TSH minus basal TSH) and as relative increase (R-TSH stimulated TSH/basal TSH). Using cut-off values of 0.3-3.2 microU/ml, basal TSH measurement was able to detect hypothyroidism (specificity = 100%) and to exclude hyperthyroidism (sensivity = 96.9%), but failed to accurately prove hyperthyroidism (specificity = 93.4%) and, above all, to exclude hypothyroidism (sensitivity = 35.3%) in our ambulatory patients. The delta-TSH values showed a basal TSH dependent linear increase (r = + 0.87, p < 0.001) both including only patients (n = 139) with basal TSH level in the euthyroidism range and including all patients (n = 223) having TSH responsive to TRH. All the patients with detectable basal TSH level displayed detectable TSH response to TRH, as did 19 (= 23.5%) of 81 patients with undetectable (< 0.1 microU/ml) basal value. In particular: a) for subnormal but detectable basal TSH ranging between 0.1 and 0.2 microU/ml, TSH was always hyporesponsive (delta-TSH < or = 2.5 microU/ml), while between 0.2 and 0.3 microU/ml TSH was hyporesponsive in 72.2% and normoresponsive (delta-TSH > 2.5 and < or = 11.9 microU/ml) in the remaining 27.8%; b) for basal TSH values within the normal range (0.3-3.2 microU/ml). TSH was hyporesponsive in 13.7%, normoresponsive in 74.8% and hyperresponsive in 11.5%; c) for high basal TSH values TSH was always hyperresponsive. The analysis of R TSH showed relatively constant values in the range of euthyroidism and hypothyroidism (m +/- SD: 7.4 +/- 2.3 and 7.7 +/- 3.1, respectively), and a marked differentiation of hyperthyroid patients whose R-TSH values were significantly lower (4.2 +/- 3.4) but had a wide individual variability. Linear regression analysis of basal or stimulated TSH and circulating thyroid hormones showed a close negative relationship, being highly significant between delta-TSH and T4 (r = 0.57, p < 0.001) and delta-TSH and FT4 (r = 0.46, p < 0.001). In conclusion, after the introduction of current second generation TSH immunoradiometric assay, the diagnostic role of the TRH test is greatly limited but not to be excluded: it can provide additional information to that obtained with simple basal TSH measurement in the diagnosis of subclinical hypothyroidism and in the precise evaluation of the degree of TSH suppression in patients with a subnormal basal TSH, either for endogenous thyrotoxicosis or I.-thyroxine treatment.

Alternation of hypo- and hypercalcemia in a parathyroidectomized patient with breast cancer.

We report the case of a 54-year-old female patient with postoperative hypoparathyroidism. Despite the fact that she was receiving calcitriol replacement therapy, following the appearance of bone metastases due to breast cancer she developed severe crises of hypo- and hypercalcemia.

HLA haplotypes and susceptibility to Graves' disease.

Graves' disease is a polygenic disease in which the HLA cluster could play a role. The purpose of our study is to identify HLA haplotypes in a family with closely related susceptibility to Graves' disease and foresee the risk of disease in the youngest daughter. The family studied had included the father (47 years), mother (46 years) and 3 daughters (18, 17 and 13 years). The mother and 2 eldest daughters were affected by Graves' disease. HLA-A, -B, -C, -DR and -DQ were performed with standard microlymphotoxicity techniques. A mother's role in passing susceptibility to Graves' disease to daughters is undisputed; it seems to be due to the B35 HLA allele. Also, the third daughter (at 15 years) has an HLA B35 allele, and actually has an incipient humoral hyperthyroidism.