Cyclipostins: novel hormone-sensitive lipase inhibitors from Streptomyces sp. DSM 13381. I. Taxonomic studies of the producer microorganism and fermentation results

The cyclipostins are a group of hormone-sensitive lipase inhibitors produced by a Streptomyces species. Having verticillate spore chains this strain exhibits significant differences to the known species of the former genus Streptoverticillium. Taxonomic studies and fermentation results are presented.     

Synthesis,characterization, and solvolysis of mono- and bis-S-(glutathionyl) adducts of methylene-bis-(phenylisocyanate) (MDI)

Bifunctional isocyanates are highly reactive compounds that undergo nucleophilic attack by a variety of functional groups available in the biological system. While the etiology of the respiratory disease caused by diisocyanates is not fully understood, a great deal of research has been performed to elucidate the chemical mechanisms involved in the direct and indirect effects of these compounds. Since adducts of isocyanates are found not only to proteins along the entire respiratory tree but also to proteins in the circulatory system, it is likely that a transport mechanism for the isocyanate from the respiratory to the circulatory system exists. The initial reaction of isocyanates with cellular thiols to form thiocarbamates, which are known to release the isocyanate under physiological conditions, is believed to provide a possible carrier mechanism for the isocyanate functional group. Previous work with aliphatic mono-isocyanates and the aromatic diisocyanate toluene diisocyanate has demonstrated the feasibility of this mechanism. Adding to this database, the products of the reaction of the highly water-insoluble, low vapor pressure, methylene-bis-(phenylisocyanate) (MDI) with glutathione were synthesized, and their chemical stability under various pH and buffer conditions was tested. Novel synthetic routes were developed for both the mono- and bis-S-(glutathionyl) adducts with MDI that yielded each compound in analytically pure form. Both compounds were found to be unstable under mild basic conditions (phosphate-buffered saline, pH 7.4, and NaHCO(3), pH 8.2), however to a different degree. Furthermore, a significant influence of the pH value (the rate of degradation increases with pH) and the concentration of free glutathione (increasing thiol stabilizes the adduct) on the stability was observed, indicating a base-catalyzed mechanism of the degradation/formation of the thiocarbamate bond. Unlike the monoadduct, which forms almost exclusively the polyurea upon degradation, a variety of products were formed upon degradation of the bis adduct. Though the disappearance of the bis adduct was complete as measured by HPLC, (1)H NMR spectra showed the existence of residual thiocarbamate bonds in the final mixture. In both cases, no evidence of the free methylene-bis-phenylamine (MDA) could be detected under the applicable conditions.     

Antineoplastic agents. 489. Isolation and structures of meliastatins 1-5 and related euphane triterpenes from the tree Melia dubia

The bark of the giant neem tree Melia dubia was found to contain 11 euphane-type triterpenes. Five new compounds, meliastatins 1-5 (1-5), proved to inhibit growth of the P388 lymphocytic leukemia cell line (ED(50) 1.7-5.6 microg/mL). Four of the others, the previously known methyl kulonate (8), kulinone (9), 16-hydroxybutyrospermol (10), and kulactone (11), were also found to inhibit (ED(50) 2.5-6.2 microg/mL) the P388 cancer cell line. In addition, two new euphane triterpenes were isolated and named dubione A (6) and dubione B (7). Structures for each of the 11 euphane triterpenes were established by spectral techniques that included HRMS and 2D NMR.     

New bone formation with teriparatide [human parathyroid hormone-(1-34)] is not retarded by long-term pretreatment with alendronate,estrogen, or raloxifene in ovariectomized rats

With the ready availability of several osteoporosis therapies, teriparatide [human PTH-(1-34)] is likely to be prescribed to postmenopausal women with prior exposure to agents that prevent bone loss, such as bisphosphonates, estrogen, or selective estrogen receptor modulators. Therefore, we evaluated the ability of once daily teriparatide to induce bone formation in ovariectomized (Ovx) rats with extended prior exposure to various antiresorptive agents, such as alendronate (ABP), 17 alpha-ethinyl estradiol (EE), or raloxifene (Ral). Sprague Dawley rats were Ovx and treated with ABP (28 microg/kg, twice weekly), EE (0.1 mg/kg per d), or Ral (1 mg/kg per d) for 10 months before switching to teriparatide 30 microg/kg per d for another 2 months. Analysis of the proximal tibial metaphysis showed that all three antiresorptive agents prevented ovariectomy-induced bone loss after 10 months, but were mechanistically distinct, as shown by histomorphometry. Before teriparatide treatment, ABP strongly suppressed activation frequency and bone formation rate to below levels in other treatment groups, whereas these parameters were not different from sham values for EE or Ral. Trabecular area for ABP, EE, and Ral were greater than that in Ovx controls. However, the trabecular bone effects of ABP were attributed not only to effects on the secondary spongiosa, but also to the preservation of primary spongiosa, which was prevented from remodeling. After 2 months of teriparatide treatment, lumbar vertebra showed relative bone mineral density increases of 18%, 7%, 11%, and 10% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Histomorphometry showed that trabecular area was increased by 105%, 113%, 36%, and 48% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Teriparatide enhanced mineralizing surface, mineral apposition rate, and bone formation rate in all groups. Compression testing of vertebra showed that teriparatide improved strength (peak load) and toughness in all groups to a proportionately similar extent compared with 10 month levels. These data showed a surprising ability of the rat skeleton to respond to teriparatide despite extensive pretreatment with ABP, EE, or Ral. Therefore, the mature skeleton of Ovx rats remains highly responsive to the appositional effects of teriparatide regardless of pretreatment status in terms of cancellous bone area or rate of bone turnover.     

Are top journals biased against eating disorders topics?

OBJECTIVE: This study investigated whether there is a bias against eating disorders research among the leading psychiatric, psychological, and medical journals. METHOD: The authors performed a comparison between the number of empirical articles published about anorexia nervosa and/or bulimia nervosa and the number of articles published about panic disorder and/or agoraphobia (i.e., disorders of comparable disease burden) in 29 high-impact journals over a 5-year period (1996-2001). RESULTS: There were almost twice as many published empirical articles about panic disorder and/or agoraphobia (N=365) as there were about anorexia nervosa and/or bulimia nervosa (N=169). CONCLUSIONS: The findings indicate a possible bias against eating disorders research among some leading psychiatric journals. Alternative explanations and implications are discussed.     

Prevalence of reduced bone mass in children and adults with spastic quadriplegia

This study was designed to test the hypothesis that non-ambulatory patients with spastic quadriplegia will have reduced bone mass which worsens with increasing age. Forty-eight patients (age 5 to 48 years, median age 15 years; 19 females and 29 males) were studied. Anticonvulsants were used in 29 patients (60.4%). Lumbar spine bone mineral density (LS-BMD) was markedly reduced compared with age-and sex-matched control individuals with a z score of -2.37 +/- 0.21. Twenty-eight (58%) had z scores of less than -2. A history of documented previous fracture was present in 19 patients (39%). Patients with a history of fracture had significantly lower (p = 0.05) LS-BMD z scores (-2.81 +/- 0.29) compared with those without a history of fracture (-2.11 +/- 0.26). Mean serum 25-OH vitamin D was 29.6 +/- 1.9ng/mL (normal 9 to 37.6ng/mL) with three patients having serum 25-OH vitamin D levels less than 15ng/mL. These findings indicate that BMD is markedly reduced in non-ambulatory children and adults with neuromuscular disease. Reductions in bone mass put them at greater risk for non-traumatic fractures.