Classical/nonclassical hybrid cannabinoids: southern aliphatic chain-functionalized C-6beta methyl, ethyl, and propyl analogues

The stereoelectronic requirements for interaction of the southern aliphatic hydroxyl of cannabimimetic pharmacophores with the CB1 and CB2 receptors are explored. The stereoselective syntheses of three series of classical/nonclassical hybrid cannabinoids are described. These compounds were designed to investigate the importance of the southern aliphatic hydroxyl (SAH) pharmacophore for cannabimimetic activity. Variation in the chain length of the SAH moiety in these 6beta-(hydroxyalkyl)dihydrobenzopyran analogues, from 6beta-hydroxymethyl to 6beta-(omega-hydroxyethyl) and 6beta-(omega-hydroxypropyl), and the effects of replacing the hydroxyl functionality by hydride and iodide are reported. Our results indicate that the SAH pharmacophore has less pronounced effects than the C-3 aliphatic chain on cannabinoid activity. Furthermore, it appears that this southern molecular component is capable of interacting with two different subsites on the receptor and that the nature of this interaction is determined by the terminal substituent on the C-6beta alkyl group. One of the subsites can accommodate the relatively polar SAH pharmacophore, while the second subsite interacts with more hydrophobic C-6beta substituents and can accommodate large spherical pharmacophores separated by three methylene carbons from the tricyclic cannabinoid template.     

Diabetic ketoacidosis and rhabdomyolysis following excessive intake of a weight reducing diet

We describe two unusual cases in sheep of subclinical mastitis caused by Streptococcus parasanguinis. This bacterium has been associated with the development of experimental endocarditis; its presence at relatively high concentrations in apparently healthy sheep milk may pose a health risk in persons with predisposing heart lesions.     

A preventive registry for hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is a genetic disorder characterized by a strong family history of colorectal and extracolonic cancers, usually at a young age. This article presents a new provincial service for families with HNPCC. The Steve Atanas Stavro Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital is accruing patients that meet a set of criteria establishing a putative diagnosis of HNPCC. The objectives of the Registry are to develop and assess patient pedigrees, to coordinate screening procedures for at-risk persons, to maintain a prospective database of patient information, to provide education and support for families and to contribute to research. To date, surgeons and patients are the most common referral sources, while oncologists and geneticists are the least common. The ultimate goal of the HNPCC service is the secondary prevention of cancer and a corresponding decrease in mortality for HNPCC family members.     

Biologic effects of 17 alpha-dihydroequilin sulfate

OBJECTIVE: To determine the independent biologic effects of 17 alpha-dihydroequilin sulfate. DESIGN: Prospective randomized study. SETTING: University of Southern California Medical Center. PATIENTS(S): Twenty-one postmenopausal women, mean age 50 +/- 2 (+/-SEM) years, and mean body mass index 27 +/- 2. INTERVENTION(S): Women were randomized to receive daily oral doses of either 1.25 mg of estrone sulfate (E1S), 0.2 mg of 17 alpha-dihydroequilin sulfate, or a combination. Three blood and urine samples were obtained before and after 30 and 90 days of treatment. RESULT(S): After 30 and 90 days of treatment, E1S alone increased sex hormone-binding globulin (SHBG) levels significantly, 19.7% +/- 6.0% and 61.3% +/- 13.0%, whereas 17 alpha-dihydroequilin sulfate reduced SHBG levels, 20.8% +/- 68% and 12.4% +/- 7.5%, respectively. Nevertheless, the combination of E1S and 17 alpha-dihydroequilin sulfate significantly increased SHBG levels, 103% +/- 27.9% and 98.2% +/- 19.1%, compared with baseline at 30 and 90 days. Fewer changes were evident with corticosteroid-binding globulin (CBG). After 90 days of treatment, CBG levels significantly increased 30.9% +/- 5.5% with E1S, decreased by 7.2% +/- 5.0% with 17 alpha-dihydroequilin sulfate, and, with the combination, significantly increased by 10.5% +/- 2.4% compared with baseline. Changes in lipids and lipoproteins were more variable. However, high-density-lipoprotein cholesterol increased significantly with E1S at 30 and 90 days compared with baseline, 96.5% +/- 39% and 91.5% +/- 22.6%, and with the combination increased 66.4% +/- 13.3% and 79.2% +/- 24.4%, respectively. Fewer changes were evident with 17 alpha-dihydroequilin sulfate alone, decreasing 4.4% +/- 22% and 2.6% +/- 21.3%. Urinary ratios of bone collagen equivalents-creatinine and calcium-creatinine decreased in all three groups. However, the combination group resulted in a significantly greater percentage decrease in bone collagen equivalents-creatinine than with E1S alone. CONCLUSIONS(S): 17 alpha-Dihydroequilin sulfate could modify some of the first-pass effects of conjugated equine estrogens and act synergistically with other conjugated equine estrogens to reduce bone resorption.     

Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22-q23

Transient neonatal diabetes mellitus (TNDM) is a rare form of childhood diabetes which usually resolves in the first 6 months of life but which predisposes to type 2 diabetes of adult onset. We recently reported paternal uniparental isodisomy of chromosome 6 (UPD6) in two children with TNDM and proposed that there may be an imprinted gene important in the aetiology of diabetes on chromosome 6. We now describe two unrelated families which independently suggest that the gene is imprinted, is paternally expressed and maps to 6q22-q23. One family has a duplication while the other, with familial TNDM, shows linkage to a marker in this region.     

BIODEGRADATION PROCESS ANALYSIS BY ULTRAFILTRATION

Detailed analysis of biological processes for hazardous waste-water treatment presents extreme difficulty. Complexity of organic and inorganic solute mixtures in solution prohibits GC-MS analysis. Gross parameters must be used to monitor treatment process performance. Ultrafiltration, coupled with gross parameter estimation, provides enhanced definition of treatment. Results, employed to monitor in-situ biodegradation of a hazardous landfill leachate, are discussed.     

Coronal and sagittal clefts in skeletal dysplasias

Objective. To assess the role of coronal and sagittal vertebral clefts in diagnosing skeletal dysplasias. Material and Methods. A search in the database at the International Skeletal Dysplasia Registry revealed 40 different diagnoses in which coronal or sagittal clefts were present, the major groups being: atelosteogenesis, chondrodysplasia punctata, dyssegmental dysplasia, Kniest dysplasia and short rib polydactyly syndrome. We reviewed all firm cases with both AP and lateral films of the spine in these major groups (n = 143), with patients' ages ranging from 20 weeks of gestation up to 26 years of age. Results. Ninety-four percent of all clefts were found in children less than 1 year of age, mainly located in the thoracolumbar region. Fifty-six percent of the clefts were observed in boys. Coronal clefts were more common than sagittal clefts. Clefts were most frequently observed in atelosteogenesis (88%), followed by chondrodysplasia punctata (79%), dyssegmental dysplasia (73%), Kniest dysplasia (63%) and short rib polydactyly syndrome (53%). Conclusion. Vertebral clefts are of major diagnostic value in the groups mentioned above, especially before 1 year of age. The search did not come up with new entities in which vertebral clefts are of major diagnostic value.     

Effect of catecholamine depletion on myocardial infarct size in dogs: role of catecholamines in ischemic preconditioning

OBJECTIVES: Cardioprotective adaptation to brief periods of ischemia and reperfusion is termed ischemic preconditioning (PC). Limitation of infarct size by preconditioning is associated with marked slowing of ischemic metabolism. The cause of metabolic slowing has not been determined but may involve either pro- or anti-adrenergic mechanisms. Hypothetically, adrenergic stimulation could signal the adaptive response. Alternatively, metabolic slowing during the sustained ischemic challenge could occur through a reduction in beta-adrenergic stimulation. This study was designed to test the role of cardiac norepinephrine (NE) in PC. METHODS: The effect of PC on myocardial infarct size was studied in control dogs and dogs depleted of catecholamines by pretreatment with reserpine (RES; 0.25 mg/kg i.v.). PC was induced by four cycles of 5 min of ischemia and 5 min of reperfusion. Infarcts were produced by 60 min of ischemia and 3 h of reperfusion. Cardiac NE depletion was verified by radioimmunoassay of tissue samples and by absence of hemodynamic response to a tyramine bolus (1.4 mg/kg) administered at the end of each experiment. Infarct size, expressed as percent of area at risk, was controlled for variation in collateral blood flow using analysis of covariance (ANCOVA). RESULTS: Adjusted mean infarct size was 25.5 +/- 3.2% in untreated controls vs. 19.1 +/- 3.3% in RES-treated controls (P = NS). PC limited infarct size in untreated dogs (7.4 +/- 1.8 vs. 25.5 +/- 3.2%; PC vs. control; P < 0.01) but not in RES-treated dogs (15.7 +/- 3.0% vs. 19.1 +/- 3.3%; RES + PC vs. RES; P = NS). Infarct size was larger in dogs with RES + PC than with PC alone, even though there was a trend toward a slight beneficial effect with RES alone. CONCLUSION: The cardioprotective effect of ischemic preconditioning cannot be explained entirely as an anti-adrenergic effect. On the contrary, adrenergic receptor stimulation may be required for the full expression of ischemic preconditioning in canine myocardium.     

Signatures: A language extension for improving type abstraction and subtype polymorphism in C++

C++ uses inheritance as a substitute for subtype polymorphism. We give examples where this makes the type system too inflexible. We then describe a conservative language extension that allows a programmer to define an abstract type hierarchy independent of any implementation hierarchies, to retroactively abstract over an implementation, and to decouple subtyping from inheritance. This extension gives the user more of the flexibility of dynamic typing while retaining the efficiency and security of static typing. With default implementations and views flexible mechanisms are provided for implementing an abstract type by different concrete class types. We first show how the language extension can be implemented in a preprocessor to a C++ compiler, and then detail and analyse the efficiency of an implementation we directly incorporated in the GNU C++ compiler.