Selective inhibition of osteoclast vacuolar H(+)-ATPase

The proton pump expressed on the plasma membrane of bone resorbing osteoclasts, and which mediates the acidification of the extracellular environment in resorption lacuna, belongs to the family of vacuolar H(+)-ATPases, which are enzymes ubiquitously distributed among all cells and are evolutionary conserved. These pumps have two functional domains: a peripherally associated cytoplasmatic section, and a proton channel composed of several subunits one of which, the 116 kDa subunit, is expressed exclusively in osteoclasts and confers unique functional and pharmacological properties to the osteoclast V-ATPase. It was demonstrated that inhibition of this pump can abolish bone resorption; therefore, osteoclast-selective inhibitors could provide novel and useful agents for the treatment of osteoporosis. This paper reviews the medicinal chemistry approaches that have allowed to obtain such new agents, most of which have been designed starting from the natural macrolide antibiotic bafilomycin A(1), a potent and selective inhibitor of all V-ATPases. Identification of SAR and of minimal structural requirements for bafilomycin activity have allowed to obtain (2Z,4E)-5-(5,6-dichloroindolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide (SB-242784) which inhibits the osteoclastic proton pump and bone resorption in vitro. Although it inhibits the activity of non-osteoclastic proton pumps as well, it appears to have reasonable selectivity and its administration for 6 months prevented the loss of femoral and vertebral BMD in ovariectomized rats, without any significant renal effects in control and acid-loaded animals. Other independent approaches that did not start from bafilomycin have led to the discovery of a different class of V-ATPase inhibitors, among which 4-(2,6-dichlorobenzoyl)amino-2-trifluoromethyl(benzoimidazol-1-yl)acetyl morpholine (FR177995) was the most effective in preventing bone resorption in an ovariectomized rat model of osteoporosis. These compounds are of great pharmaceutical and medical interest because they allow to target a specific function of the osteoclast; however, only clinical trials might demonstrate whether they have significant advantages over other inhibitors of bone resorption for the treatment of osteoporosis.     

Cohort study of mortality among leather tanners in the Lower Valdarno area

BACKGROUND: Epidemiological studies of tanners have shown increased risk for a number of cancer sites, namely: lung, bladder, kidney and urinary organs as well as stomach, intestine, pancreas, nose and nasal cavities, together with leukemias and soft tissue sarcomas. OBJECTIVE: To study cause specific mortality of leather tanners in Tuscany (Valdarno Inferiore area). METHODS: The cohort included 4874 workers (4150 males and 724 females) employed in 92 tanneries operating in 1996 (Valdarno Inferiore Tanneries Census) which were also operating on 31-12-1970. Ascertainment of vital status was completed for all individuals on 31-12-1998 (end of follow-up), and the cause of death was known for all deceased subjects. Demographic and work history data were obtained from factory payrolls. Regional mortality rates were used for comparison to calculate SMR (Standardised Mortality Ratio) and 90% Confidence Intervals (CI). In addition to the overall cohort analysis, for men only separate analyses were completed for finishers, chrome tanners and vegetable tanners. RESULTS: The study showed an increased mortality from lung cancer among finishers, Standardised Mortality Ratio (SMR) 145, 19 observed (obs) (90% Confidence Intervals, 90% CI 95-212), from bladder cancer in the overall cohort (SMR 134, 9 obs, 90% CI 70-233) and among finishers (SMR 125, 2 obs, 90% CI 22-393) and from pancreatic cancer among finishers (SMR 120, 2 obs, 90% CI 21-379). Mortality from lymphoemopoietic cancer is above expected, and the increase is mainly due to myeloid leukaemia, both in males (SMR 208, 5 obs, 90% CI 82-437) and females (SMR 599, 2 obs, 90% CI 106-1887). No deaths from soft tissue sarcoma were observed. A new finding of the study was the increased mortality from cancer of the endocrine glands (SMR 566, 4 obs, 90% CI 194-1297), psychiatric disorders (SMR 195, 6 obs, 90% CI 85-385) and blood diseases (SMR 329, 4 obs, IC 90% 112-752). CONCLUSIONS: The observations of increased lung cancer mortality among finishers, of bladder cancer in the overall cohort and among finishers, as well as an increase in pancreatic cancer among the latter, confirm previous epidemiological findings among tanners. The increase in myeloid leukemia mortality for both males and females, and the absence of deaths from cancer of the connective tissue, which includes soft tissue sarcomas, are worthy of note. The results should be valued with caution, given the small number of cases and the novelty of some observations.     

Surface EMG crosstalk between knee extensor muscles: experimental and model results

Surface electromyographic (EMG) crosstalk between vastus lateralis, vastus medialis, and rectus femoris muscles was evaluated by selective electrical stimulation of one muscle and recording from the stimulated and another muscle with linear surface arrays of eight electrodes. The ratio between the amplitude of the signals recorded over nonstimulated and stimulated muscles and their correlation coefficient were used as indices to quantify crosstalk. Single-differential and double-differential detection systems were used with interelectrode distances in the range 10-40 mm. The multichannel EMG signals clearly showed that crosstalk is largely due to nonpropagating potentials that correspond in time to the end of the propagation of the action potentials generated by the stimulated muscle. The crosstalk signal increased with increasing interelectrode distance and was statistically higher for single- than for double-differential recordings. The correlation-based indices of crosstalk were poorly correlated with the amplitude-based indices. Moreover, the characteristic spectral frequencies of the signals detected over the nonstimulated muscles were statistically higher than those from the stimulated muscles. A mathematical model of signal generation was used to explain the experimental findings. This study clarifies many controversial findings of past investigations and creates the basis for crosstalk interpretation, simulation, and reduction.     

In vivo animal functional MRI: improved image quality with a body-adapted mold

PURPOSE: To reduce functional magnetic resonance imaging (fMRI) susceptibility distortion at the air/tissue interphase in animal experiments. MATERIALS AND METHODS: We investigated the applicability of a body-adaptable flexible mold consisting of a fast-setting alginate. This technique was implemented for subcutaneous growing tumors in rats and for the brains of monkeys. RESULTS: The T(2)*-weighted gradient-echo, echo-planar imaging (GE-EPI) data obtained with the body-adapted mold showed a reduction of susceptibility artifacts and improved image quality. With both rat tumor and monkey brain, an optimized match with the anatomical T(1) images was possible. CONCLUSION: The present mold methodology is a rapid, easy, and inexpensive way to reduce magnetic susceptibility during animal GE-EPI.     

Pulmonary hydatidosis--a surgical experience

Twenty-five cases of pulmonary hydatid cysts were studied with emphasis on age, sex and site distribution. In the present study, the youngest patient was of 4 years. Male predominance (2.125:1) with peak incidnce at 21-40 years was observed. Right lung was involved more frequently. Pain chest and haemoptysis were the commonest symptoms. No recurrence and no mortality were reported.     

MR imaging and proton MR spectroscopy in adult Krabbe disease

We present the MR imaging findings in four patients (two pairs of siblings from two unrelated families) with adult Krabbe disease. In the first family, clinical presentation mimicked familial spastic paraplegia. Their MR images showed selective, increased signal intensity on T2-weighted sequences along the corticospinal tracts, most prominently in the proband and barely detectable in her brother. Proton MR spectroscopy showed increased choline and myo-inositol in the affected white matter. In the second family, the clinical presentation differed in that the signs of pyramidal tract involvement were asymmetrical, with concomitant asymmetry on MR images in one. In adults, Krabbe disease may present on MR imaging with selective pyramidal fiber involvement.     

Positive response to immunomodulatory therapy in an adult patient with Rasmussen's encephalitis

Rasmussen's encephalitis (RE) is a rare and progressive neurologic condition of uncertain etiology that typically has a childhood onset. The authors describe a 45-year-old woman with adult-onset progressive aphasia, right hemiparesis, severe drug refractory epilepsy, and left cerebral hemisphere atrophy. High-dose corticosteroids and plasmapheresis were not effective. She improved with high-dose therapy with human IV immunoglobulin.     

Correlation among amniotic fluid index (AFI), cesarean section rate, and labor length in inducted pregnancies beyond 41 weeks' gestation with unfavorable cervix

This paper evaluated how the pregnancy after 41 completed weeks' gestation with amniotic fluid index (AFI) > 6 has a slower response to the prostaglandin E2 (PGE2) induction. Eighty-one post-term pregnancies (41 completed gestations' weeks) with unfavorable cervix were considered in this follow-up. Induction was performed by means of intracervical PGE2 gel (Dinoprostone 0.5 mg). After 12 hours, if the cervix was still unfavorable, then another gel administration followed. Cases that had oxytocin administration were excluded from the study. The median time of spontaneous delivery in the overall series was 25 hours, 14 minutes. We had 18 cases of cesarean section (22.2%). In the group of pregnancies with AFI > 6 (60 cases) and in the group with AFI < or =6 (21 cases), the median time of spontaneous delivery was 29 hours, 25 minutes and 23 hours, 39 minutes, respectively (p-value = 0.02). The rate of cesarean sections was 26.67 and 9.52, respectively in the two groups (p-value >0.05). Two out of four cases of cesarean sections for fetal distress belonged to the group of AFI > 6. All the 14 cases of cesarean section for dystocia belonged to the group with AFI > 6. Considering just patients who did not deliver within 12 hours (57 cases), median time of spontaneous delivery was 33 hours and 24 hours 40 minutes for group AFI > 6 (42 cases) and AFI < or =6 (15 cases), respectively (p-value = 0.0009). Thirty-one cases out of 57 had another PGE2 gel administration. Adjusted odds ratio was 0.33 (0.16-0.65, 95% C.I.) for AFI < or =6 versus AFI > 6.