3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes ...mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as alpha-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidinoacetic acid 9 and diaminoguanidinoacetic acid analogue 7 were found to be equipotent to 2, leading eventually to the discovery of the significantly more potent diaminoguanidinoacetic acid regioisomers 52 and 53. Further attempts to modify the more active template represented by 52 led only to reductions in antidiabetic activity. Each of the new active analogues displayed the same resistance to creatine-like metabolism as 2. Further testing of 7, 9, and 53 in obese diabetic ob/ob mice confirmed that weight loss is induced selectively from adipose tissue, similar to the lead 1. Administration of 53 to insulin-resistant rhesus monkeys led to reductions in both fasting and post-prandial plasma glucose levels with concomitant reductions in plasma insulin levels, suggesting that the compound improved the action of endogenous insulin. Compounds 7 and 53 were selected for further preclinical development.
This paper outlines the rationale and design of the Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) weight loss project, in which detailed biologic profiling of three hundred and ...fifty obese individuals (body mass index (BMI): 30–50 kg/m
2) will be conducted as they lose weight via seven distinct interventions. These profiles will be compared to those of fifty normal, healthy, control participants (BMI: 18.5–24.9 kg/m
2). The interventions include the following: Roux-en-Y gastric bypass surgery, dietary interventions of differing macronutrient composition and diverse pharmacologic interventions. Outcome variables include eight conventional metabolites and CRP measured by standard clinical chemistry techniques, twenty hormones of energy balance and fuel homeostasis measured by radioimmunoassay (RIA) or by enzyme-linked Immunosorbent assay (ELISA), ten pro- and anti-inflammatory cytokines measured using Luminex xMAP® technology, one hundred and one intermediary metabolites measured by targeted mass-spectrometry-based methods, and physiologic variables such as body composition measured by dual energy X-ray absorptiometry (DEXA), air displacement plethysmography, and abdominal computerized tomography (CT), insulin sensitivity measured by intravenous glucose tolerance test (IV-GTT) and metabolic rate measured by indirect calorimetry. Results from this study will expand our knowledge of the biology of obesity and weight regulation and may lead to targeted strategies for its treatment and control.
PKS B1322-110 is a radio quasar that is located only 8.5' in angular separation from the bright B star Spica. It exhibits intra-day variability in its flux density at GHz frequencies attributed to ...scintillations from plasma inhomogeneities. We have tracked the rate of scintillation of this source for over a year with the Australia Telescope Compact Array, recording a strong annual cycle that includes a near-standstill in August and another in December. The cycle is consistent with scattering by highly anisotropic plasma microstructure, and we fit our data to that model in order to determine the kinematic parameters of the plasma. Because of the low ecliptic latitude of PKS B1322-110, the orientation of the plasma microstructure is poorly constrained. Nonetheless at each possible orientation our data single out a narrow range of the corresponding velocity component, leading to a one-dimensional constraint in a two-dimensional parameter space. The constrained region is consistent with a published model in which the scattering material is associated with Spica and consists of filaments that are radially oriented around the star. This result has a 1% probability of arising by chance.
Normal-weight bulimic patients have disturbed appetite, mood, and neuroendocrine function and often respond to antidepressants. Since these findings suggest abnormalities in brain monoaminergic ...pathways, the authors measured CSF monoamine concentrations in 27 normal-weight bulimic patients and 14 volunteers. Bulimic patients had a significantly lower mean CSF norepinephrine concentration. Levels of CSF 5-HIAA, the major serotonin metabolite, and CSF HVA, the major dopamine metabolite, were normal, although more frequent binge-eating in bulimic subjects was associated with a significantly lower CSF HVA level. Whether trait- or state-related, monoaminergic disturbances are part of this disorder's neurobiological syndrome. The lower CSF norepinephrine concentration suggests bulimia is not simply a variant of affective disorders.
One hundred and ten outpatients with either acute or chronic low‐back pain completed the McGill Pain Questionnaire, Beck Depression Inventory, State‐Trait Anxiety Inventory, and Life Experiences ...Survey. Acutes and chronics did not differ on dimensions of pain, but significant correlations between pain dimensions and depression and state anxiety were found for chronics. Both groups showed elevated state anxiety; chronics also evidenced mild depression. Combined scores on depression, anxiety, and negative life change predicted sensory and affective pain for the pooled sample. These results confirm the role of psychological variables in the experience of clinical pain and underscore the highly affective nature of chronic pain.
Some patients with radiologic findings of neurogenic arthropathy or multiple fractures do not exhibit overt neurologic signs. Results of nerve conduction velocity, computer-assisted sensory ...examination, periosteal nociception, and morphometric and graded teased-fiber evaluation of cutaneous nerves allowed us to recognize a mild neuropathic abnormality. Neurogenic arthropathy and subclinical neuropathy were also found in relatives. In three kinships, the underlying disorder was probably hereditary sensory neuropathy type 1 and in several others, it was recessively inherited sensory neuropathy. These arthropathies were often painful, and overt loss of superficial and deep pain sensation was not a prominent or necessary condition. An interplay of multiple factors including insensitivity, trauma, obesity, activity, abuse, personality, mental subnormality, and metabolic joint and bone disease are probably involved in the development of the bony lesions and thus provide further evidence that environmental factors affect expression of human mutant genes for inherited neuropathy.
Examined the relationship between sex‐role orientation and the Type A behavior pattern. Eighty undergraduates were classified as high or low on masculinity and femininity on the basis of Bem Sex Role ...Inventory (BSRI) scores. Three two‐way (masculinity × femininity) ANOVAs were performed on student Jenkins Activity Survey (JAS) scores for pooled Ss, for males, and for females; each yielded a main effect for masculinity. JAS scores were correlated positively with BSRI Masculinity scores and not correlated with BSRI Femininity scores across pooled Ss, across males, and across females. These results are discussed in terms of their research and treatment implications.
