Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment

OBJECTIVE: To observe the chronic effects of human growth hormone (hGH) and AOD9604 (a C-terminal fragment of hGH) on body weight, energy balance, and substrate oxidation rates in obese (ob/ob) and lean C57BL/6Jmice. In vitro assays were used to confirm whether the effects of AOD9604 are mediated through the hGH receptor, and if this peptide is capable of cell proliferation via the hGH receptor. METHOD: Obese and lean mice were treated with hGH, AOD or saline for 14 days using mini-osmotic pumps. Body weight, caloric intake, resting energy expenditure, fat oxidation, glucose oxidation, and plasma glucose, insulin and glycerol were measured before and after treatment. BaF-BO3 cells transfected with the hGH receptor were used to measure in Vitro I-125-hGH receptor binding and cell proliferation. RESULTS: Both hGH and AOD significantly reduced body weight gain in obese mice. This was associated with increased in vivo fat oxidation and increased plasma glycerol levels (an index of lipolysis). Unlike hGH, however, AOD9604 did not induce hyperglycaemia or reduce insulin secretion. AOD9604 does not compete for the hGH receptor and nor does it induce cell proliferation, unlike hGH. CONCLUSIONS: Both hGH and its C-terminal fragment reduce body weight gain, increase fat oxidation, and stimulate lipolysis in obese mice, yet AOD9604 does not interact with the hGH receptor. Thus, the concept of hGH behaving as a pro-hormone is further confirmed. This data shows that fragments of hGH can act in a manner novel to traditional hGH-stimulated pathways.

Specific manipulative therapy treatment for chronic lateral epicondylalgia produces uniquely characteristic hypoalgesia

The treatment of lateral epicondylalgia, a widely-used model of musculoskeletal pain in the evaluation of many physical therapy treatments, remains somewhat of an enigma. The protagonists of a new treatment technique for lateral epicondylalgia report that it produces substantial and rapid pain relief, despite a lack of experimental evidence. A randomized, double blind, placebo-controlled repeated-measures study evaluated the initial effect of this new treatment in 24 patients with unilateral, chronic lateral epicondylalgia. Pain-free grip strength was assessed as an outcome measure before, during and after the application of the treatment, placebo and control conditions. Pressure-pain thresholds were also measured before and after the application of treatment, placebo and control conditions. The results demonstrated a significant and substantial increase in pain-free grip strength of 58% (of the order of 60 N) during treatment but not during placebo and control. In contrast, the 10% change in pressure-pain threshold after treatment, although significantly greater than placebo and control, was substantially smaller than the change demonstrated for pain-free grip strength. This effect was only present in the affected limb. The selective and specific effect of this treatment technique provides a valuable insight into the physical modulation of musculoskeletal pain and requires further investigation. (C) 2001 Harcourt Publishers Ltd.

Saturable dose-response relationships for melphalan in melanoma treatment by isolated limb infusion in the nude rat

Nude rats bearing melanomas on their hindlimbs were treated by isolated limb infusion (ILI) with increasing doses (7.5-400 mug/ml) of melphalan. The response of tumours to treatment at the end of the observation period was graded, according to diameter, as complete response (CR), partial response (PR), no change (NC) or progressive disease (PD). No linear relationship between the dose of melphalan and the tumour response was observed. All doses above a threshold of 15 mug/ml achieved a PR or CR. The achievement of CR was not related to increased dose. Two major implications arise from this work. Firstly, the typically two-to three-fold increase in cytotoxic drug concentration given in high dose chemotherapy compared with standard drug concentration may not be sufficient to produce the expected increase in tumour response and possibly survival, and the controversial results of high dose chemotherapy in different studies may thus be explained. Secondly, since an increase in melphalan dose above a certain threshold does not greatly increase tumour response, the use of combination therapies would seem to be more likely to be effective than increased chemotherapeutic drug doses in achieving better tumour responses.