The effect of ergometer design on rowing stroke mechanics.

The effect of rowing ergometer design upon power delivery and coordination patterns of the rowing stroke was analyzed for 14 elite rowers. Rowers were tested in three ergometer conditions: the fixed stretcher Concept2c ergometer, the Concept2c ergometer mounted on sliding rails, and the sliding stretcher RowPerfect ergometer. Ergometers were instrumented to measure the external force generated at the handle and the foot stretcher and a nine-segment inverse dynamics model used to calculate joint and overall power delivery. Peak power generation and absorption at the knee joint was significantly greater, and total power delivered to the ergometer delayed on the fixed stretcher ergometer when compared to the sliding stretcher ergometers. No differences were found in the mechanical energy delivered to the handle of the three ergometers; however, greater joint mechanical energy production of the lower limb reduced mechanical efficiency when rowing the Concept2c fixed ergometer. The fixed foot stretcher on the Concept2c fixed ergometer acts to increase the inertial forces that the rower must overcome at the catch, increasing the moment and power output at the knee, and affecting the coordination pattern during the recovery phase.

Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone.

BACKGROUND AND PURPOSE: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib. EXPERIMENTAL APPROACH: Cardiovascular effects of the CETP inhibitors torcetrapib and anacetrapib were evaluated in animal models. KEY RESULTS: Torcetrapib evoked an acute increase in blood pressure in all species evaluated whereas no increase was observed with anacetrapib. The pressor effect of torcetrapib was not diminished in the presence of adrenoceptor, angiotensin II or endothelin receptor antagonists. Torcetrapib did not have a contractile effect on vascular smooth muscle suggesting its effects in vivo are via the release of a secondary mediator. Treatment with torcetrapib was associated with an increase in plasma levels of aldosterone and corticosterone and, in vitro, was shown to release aldosterone from adrenocortical cells. Increased adrenal steroid levels were not observed with anacetrapib. Inhibition of adrenal steroid synthesis did not inhibit the pressor response to torcetrapib whereas adrenalectomy prevented the ability of torcetrapib to increase blood pressure in rats. CONCLUSIONS AND IMPLICATIONS: Torcetrapib evoked an acute increase in blood pressure and an acute increase in plasma adrenal steroids. The acute pressor response to torcetrapib was not mediated by adrenal steroids but was dependent on intact adrenal glands.

Cricket fast bowling performance and technique and the influence of selected physical factors during an 8-over spell.

The aims of this study were to determine the influence of an 8-over spell on cricket fast bowling technique and performance (speed and accuracy), and to establish the relationship of selected physical capacities with technique and performance during an 8-over spell. Fourteen first-grade fast bowlers with a mean age of 23 years participated in the study. Physical capacities assessed were abdominal strength, trunk stability, selected girth and skinfold measures. During the delivery stride, bowlers were filmed from an overhead and lateral perspective (50 Hz) to obtain two-dimensional data for transverse plane shoulder alignment and sagittal plane knee joint angle respectively. Ball speed was measured by a radar gun and accuracy by the impact point of each delivery on a zoned scoring target at the batter's stumps. Shoulder counter-rotation did not change significantly between overs 2 and 8 for all bowlers, but was significantly related to a more front-on shoulder orientation at back foot impact. When the front-on fast bowlers (n = 5) were isolated for analysis, shoulder counter-rotation increased significantly between overs 2 and 8. Ball speed remained constant while accuracy showed some non-significant variation during the spell. Shoulder counter-rotation was significantly related to accuracy scores during the second half of the 8-over spell. Chest girth and composition and body composition were significantly related to ball release speed at various times during the spell.

Postural control during stance in paraplegia: effects of medially linked versus unlinked knee-ankle-foot orthoses.

OBJECTIVE: To investigate the effect of medially linking knee-ankle-foot orthoses (KAFOs) on postural stability and sway during (1) quiet standing and (2) functional activities for persons with spinal cord injury (SCI). DESIGN: A randomized, mixed design, with the factors being activity (quiet standing and two function-mimicking tasks), SCI (present or not), and type of orthosis used in SCI group (linked or unlinked KAFO). PARTICIPANTS: Nine men with T5 to T12 paraplegia, 8 of whom had complete lesions and 1 with some sacral sparing (American Spinal Injury Association grade B) without proprioception, matched to 9 able-bodied men. MAIN OUTCOME MEASURES: Mean amplitude of sway and sway path in anteroposterior and mediolateral directions, derived from center of pressure measurements on a force platform. RESULTS: All men with SCI were able to stand unsupported and perform function-mimicking activities in medially linked KAFOs; however, when wearing unlinked KAFOs only 5 could maintain balance during quiet stance and 3 could maintain balance during activity. Significant differences were found between linked and unlinked KAFOs; side-to-side mean amplitude of sway was less and sway path was greater for SCI subjects when they wore the linked KAFOs. CONCLUSION: Medial linkage of bilateral KAFOs provides an effective strategy to improve stability and increase postural control for persons with SCI, facilitating performance of functional activities during standing without upper limb support.

C32-O-phenalkyl ether derivatives of the immunosuppressant ascomycin: a tether length study.

A tether length study of C32-O-phenalkyl ether derivatives of ascomycin was conducted wherein it was determined that a 2-carbon tether provides optimum in vitro immunosuppressive activity. Oxygen-bearing substituents along the 2-carbon tether can further increase the potency of this design.

Potent immunosuppressive C32-O-arylethyl ether derivatives of ascomycin with reduced toxicity.

The synthesis of C32-O-arylethyl ether derivatives of ascomycin that possess equivalent immunosuppressant activity but reduced toxicity, compared to FK-506, is described.

32-Indolyl ether derivatives of ascomycin: three-dimensional structures of complexes with FK506-binding protein.

32-Indole ether derivatives of tacrolimus and ascomycin retain the potent immunosuppressive activity of their parent compounds but display reduced toxicity. In addition, their complexes with the 12-kDa FK506-binding protein (FKBP) form more stable complexes with the protein phosphatase calcineurin, the molecular target of these drugs. We have solved the three-dimensional structures of the FKBP complexes with two 32-indolyl derivatives of ascomycin. The structures of the protein and the macrolide are remarkably similar to those seen in the complexes with tacrolimus and ascomycin. The indole groups project away from the body of the complex, and multiple conformations are observed for the linkage to these groups as well as for a nearby peptide suggesting apparent flexibility in these parts of the structure. Comparison of these structures with that of the ternary complex of calcineurin, FKBP, and tacrolimus suggests that the indole groups interact with a binding site comprising elements of both the calcineurin alpha- and beta-chains and that this interaction is responsible for the increased stability of these complexes.

A tacrolimus-related immunosuppressant with biochemical properties distinct from those of tacrolimus.

BACKGROUND: Tacrolimus (FK506) is an immunosuppressive drug 50-100 times more potent than cyclosporine (CsA), the current mainstay of organ transplant rejection therapy. Despite being chemically unrelated, CsA and tacrolimus exert their immunosuppressive effects through the inhibition of calcineurin (CaN), a critical signaling molecule during T-lymphocyte activation. Although numerous clinical studies have proven the therapeutic efficacy of drugs within this class, tacrolimus and CsA also have a strikingly similar profile of unwanted side effects. METHOD: Our objective has been to identify a less toxic immunosuppressant through the modification of ascomycin (FK520). Quantitative in vitro immunosuppression and toxicity assays have demonstrated (see the accompanying article, p. 18) that we achieved our goal with L-732,531 (indolyl-ascomycin; indolyl-ASC), a 32-O-(1-hydroxyethylindol-5-yl) ascomycin derivative with an improved therapeutic index relative to tacrolimus. RESULTS: We report that the attributes of indolyl-ASC may result from its distinctive biochemical properties. In contrast to tacrolimus, indolyl-ASC binds poorly to FK506 binding protein 12 (FKBP12), the major cytosolic receptor for tacrolimus and related compounds. However, the stability of the interaction between the FKBP12-indolyl-ASC complex and CaN is much greater than that of the FKBP12-tacrolimus complex. These distinguishing properties of indolyl-ASC result in the potent inhibition of CaN within T lymphocytes but may lower the accumulation of the drug at sites of toxicity. CONCLUSIONS: Indolyl-ASC may define those properties needed to increase the therapeutic efficacy of a macrolactam immunoregulant for treating both human autoimmune disease and organ transplant rejection.

A tacrolimus-related immunosuppressant with reduced toxicity.

BACKGROUND: Tacrolimus (FK506) has potent immunosuppressive properties reflecting its ability to block the transcription of lymphokine genes in activated T cells through formation of a complex with FK506 binding protein-12, which inhibits the phosphatase activity of calcineurin. The clinical usefulness of tacrolimus is limited, however, by severe adverse effects, including neurotoxicity and nephrotoxicity. Although this toxicity, like immunosuppression, appears mechanistically related to the calcineurin inhibitory action of the drug, a large chemistry effort has been devoted to search for tacrolimus analogs with reduced toxicity but preserved immunosuppressive activity that might have enhanced therapeutic utility. METHODS: Here, we report on the identification of such an analog, which was synthetically derived from ascomycin (ASC), the C21 ethyl analog of tacrolimus, by introducing an indole group at the C32 position. The profile of biological activity of indolyl-ASC was characterized in rodent models of immunosuppression and toxicity. RESULTS: Indolyl-ASC was found to exhibit an immunosuppressive potency equivalent to that of tacrolimus in T-cell activation in vitro and in murine transplant models, even though indolyl-ASC bound about 10 times less to intracellular FK506 binding protein-12 than tacrolimus or ASC. Further evaluation of indolyl-ASC revealed that it is threefold less potent than tacrolimus in inducing hypothermia, a response that may reflect neurotoxicity, and in causing gastrointestinal transit alterations in mice. Moreover, indolyl-ASC was at least twofold less nephrotoxic than tacrolimus upon 3-week oral treatment in rats. CONCLUSIONS: Altogether, these data indicate a modest but definite improvement in the therapeutic index for indolyl-ASC compared with tacrolimus in rodent models.

Pedal forces produced during neuromuscular electrical stimulation cycling in paraplegics.

This study investigated forces applied to the pedal of a cycle ergometer by paraplegic subjects undergoing neuromuscular electrical-stimulation-induced leg exercise. The patterns of force application were compared with those of able-bodied subjects cycling under voluntary muscle control in order to investigate the effectiveness of the muscle stimulation parameters. Results show that paraplegic subjects applied significantly larger peak forces than the able-bodied subjects because of the short duration of neuromuscular stimulation. Able-bodied subjects were able to achieve the same average workload by applying smaller forces over a greater percentage of each crank revolution. It is suggested that the large forces produced by paraplegic subjects contribute to the low efficiency reported by previous studies, and that increasing the range of angles over which muscles are stimulated may provide a means to increase the efficiency of cycling for paraplegic individuals.

[3H]paraherquamide binding to Caenorhabditis elegans. Studies on a potent new anthelmintic agent.

Paraherquamide was identified recently as a potent anthelmintic agent. In this paper we describe the identification and characterization of a specific, high-affinity paraherquamide binding site in a membrane preparation isolated from the free-living nematode, Caenorhabditis elegans. [3H] Paraherquamide bound specifically to C. elegans membranes with an apparent dissociation constant, Kd, of 263 nM. A series of paraherquamide analogs were examined, and their relative affinity for the paraherquamide binding site correlated with their nematocidal activity. Phenothiazines were the only other class of anthelmintics tested which inhibited specific [3H]paraherquamide binding. These results suggest that the anthelmintic activity of paraherquamide and phenothiazine is mediated via an interaction with a common binding site.

Carbon Dioxide laser in the treatment of cutaneous disorders.

Experienced gained with the Carbon Dioxide Laser over a two year period is documented. This laser modality has been used successfully for many indications. We believe it is the treatment of choice for conditions such as resistant verrucae, extensive actinic cheilitis or labial leukoplakia, and for the cosmetic removal of widespread facial tumours, some keloid scars and rhinophyma.