Issues in measuring change in motor function in children with cerebral palsy: a special communication

Assessing clinical change in motor function in children with cerebral palsy is a complex measurement task. Whereas a variety of methods have been developed to quantify specific aspects of gross motor behavior (eg, gait analysis, electrophysiological tests, energy-consumption techniques), systematic measurement of overall gross motor function is a more difficult problem. This special communication reviews the structural and performance characteristics required of a well-developed, valid, and responsive clinically based evaluative measure. We discuss several recent approaches used to assess responsiveness and critically examine clinical measures used in randomized controlled trials of physical therapy for children with cerebral palsy. It is argued that the creation and validation of responsive evaluative measures is essential if we are to assess accurately whether our treatments do more good than harm.     

Feasibility of penumbra compensating filters for conformal prostate radiotherapy

Radiation therapy beams demonstrate a gradual dose fall off at the field edges, due to factors affecting the physical penumbra and transport of radiation. Adequate target coverage requires an increase in field size larger than the target volume itself for a uniform dose to be delivered to that target volume. A method is presented for the design and fabrication of penumbra compensating filters (PCFs) which essentially sharpen the penumbra on a field-by-field basis and are used in conjunction with custom shielding blocks. We have explored the feasibility of using PCFs to reduce the field margins required for our four-field conformal prostate treatments. The penumbra compensation is designed based on a profile measured along the direction perpendicular to the blocked field edge that shows the greatest 50% to 95% isodose distance for a typical conformal prostate patient. Rigid foam material is milled and filled with a low melting point alloy material to create a filter which provides dose compensation in the field periphery of the custom shielding block. The accuracy of our methodology has been established using film dosimetry. By employing PCFs, the reduction in the rectal margin ranges from approximately 4 mm in the posterior region to 13 mm in the superior-posterior region, as compared with the shielding blocks alone. The reduction in bladder margin ranges from approximately 4 mm in the superior-anterior region to 10 mm in the superior region. Dose-volume histograms for an idealized cylindrical rectum indicate a substantial reduction in the volume treated to high doses. The calculated normal tissue complication probability values were 8.7% and 10.5% with and without PCFs included in the blocked fields respectively. The advantages of using PCFs, compared with multileaf collimator based techniques, are discussed.     

Potential of Recombinant Human Growth Hormone in HIV-Associated Adipose Redistribution Syndrome

HIV infection recently has been complicated by the emergence of a rare metabolic dysmorphic disorder characterised by fat atrophy, redistribution and accumulation in the setting of hyperlipidaemia and, on occasion, hyperglycaemia. The disorder, sometimes referred to as HIV-associated Adipose Redistribution Syndrome (HARS), has a prevalence rate of about 50 to 60% and seems temporally related to the advent of highly active antiretroviral therapy, especially the usage of protease inhibitors. Various studies also implicate the nucleoside analogues stavudine, didanosine and lamivudine in the pathogenesis of HARS, especially fat atrophy. It is uncertain whether the changes described in HARS represent a single syndrome or a group of related syndromes. Reports have noted differences between morphologic and metabolic changes. More recently, it has been suggested that fat atrophy and fat accumulation may also be separate entities. There are several potential pathogenic theories for HARS that implicate both protease inhibitors and nucleoside analogues as causative agents. However, long term HIV infection rather than any specific agent or class of agent may be the source. Recombinant human growth hormone (rhGH) is a mammalian cell-derived product, which has been useful in a variety of human disorders ranging from pituitary dwarfism to septic shock. It has anabolic, immunological and metabolic properties that restore normal functioning to many aberrant disease pathways. The lipolytic properties of rhGH have been especially beneficial in the diminution of localised fat accumulation in the dorsocervical area (buffalo humps) and truncal region. This has been observed in various reports where rhGH has been administered at doses of 5 to 6 mg/day in patients with HARS for periods ranging from 3 months to >2 years. Relapses after discontinuation of rhGH occurred in most patients. Adverse effects included carpal tunnel syndrome, facial swelling, arthralgias and myalgias and worsening or onset of hyperglycaemia. The small uncontrolled studies conducted to date suggest that the most notable effect of rhGH treatment is the reduction of truncal adiposity and buffalo humps and that the agent has little effect on restoring the adiposity of the appendicular muscles, buttocks or face. Although most patients with HARS have associated hyperlipidaemia, rhGH has no notable effect on serum cholesterol and triglyceride levels. However, blood glucose levels can increase and pre-existent diabetes mellitus may worsen. A short term confirmatory placebo-controlled trial in patients with HARS is urgently needed, as are comparative trials using other anabolic agents such as oxandrolone and testosterone.     

Pancreastatin: multiple actions on human intermediary metabolism in vivo, variation in disease, and naturally occurring functional genetic polymorphism

RATIONALE: The chromogranin A (CHGA) fragment pancreastatin (human CHGA250-301) impairs glucose metabolism, but the role of human pancreastatin in vivo remains unexplored. METHODS: We studied brachial arterial infusion of pancreastatin (CHGA273-301-amide at approximately 200 nm) on forearm metabolism of glucose, free fatty acids, and amino acids. Plasma pancreastatin was measured in obesity or type 2 diabetes. Systematic discovery of amino acid variation was performed, and the potency of one variant in the active carboxyl terminus (Gly297Ser) was tested. RESULTS: Pancreastatin decreased glucose uptake by approximately 48-50%; the lack of change in forearm plasma flow indicated a metabolic, rather than hemodynamic, mechanism. A control CHGA peptide (catestatin, CHGA352-372) did not affect glucose. Insulin increased glucose uptake, but pancreastatin did not antagonize this action. Pancreastatin increased spillover of free fatty acids by about 4.5- to 6.4-fold, but not spillover of amino acids. Insulin diminished spillover of both free fatty acids and amino acids, but these actions were not reversed by pancreastatin. Plasma pancreastatin was elevated approximately 3.7-fold in diabetes, but was unchanged during weight loss. Proteolytic cleavage sites for pancreastatin in vivo were documented by matrix-assisted laser desorption ionization/time of flight mass spectrometry. Three pancreastatin variants were discovered: Arg253Trp, Ala256Gly, and Gly297Ser. The Gly297Ser variant had unexpectedly increased potency to inhibit glucose uptake. CONCLUSIONS: The dysglycemic peptide pancreastatin is specifically and potently active in humans on multiple facets of intermediary metabolism, although it did not antagonize insulin. Pancreastatin is elevated in diabetes, and the variant Gly297Ser had increased potency to inhibit glucose uptake. The importance of human pancreastatin in vivo as well as its natural variants is established.     

Hypoglycemia and cardiac arrest in a critically ill patient on strict glycemic control

Glycemic control in critically ill patients has become a subject of considerable interest since the publication of studies showing reduced morbidity and mortality in patients when blood glucose was maintained within a relatively low and narrow range (4.4 to 6.1 mM/L). We describe a patient who developed cardiac asystole while being given a concentrated glucose solution to treat severe hypoglycemia after administration of insulin. The mechanism in this patient appears to be hyperkalemia from the rapid administration of a concentrated glucose solution.     

Dose- and schedule-dependent activation and drug synergism between thymidine and 5-aza-2'-deoxycytidine in a human promyelocytic leukemia cell line

The ability of thymidine (dThd) to enhance the metabolism and cytotoxicity of subsequent administered 5-aza-2'-deoxycytidine (5-aza-dCyd) was studied in L1210 cells and in the human promyelocytic leukemic cell line, HL-60. Exposure of L1210 cells to 0.1 mM dThd for 5 h resulted in an increase in the total intracellular and acid-precipitable accumulation of 5-aza-dCyd. Higher dThd concentrations and longer exposure intervals resulted in smaller increments in 5-aza-dCyd accumulation. In contrast, in HL-60 cells, a 24-hr exposure in 1 mM dThd resulted in the greatest intracellular accumulation of 5-aza-dCyd, 3.3 times more accumulation than in control cells. There was also a 4-fold increase in the acid-precipitable accumulation and nearly a 3-fold increase in DNA incorporation of 5-aza-dCyd in HL-60 cells exposed to the same dThd schedule. High-pressure liquid chromatographic analysis demonstrated a greater than 3-fold increase in the intracellular amounts of 5-aza-dCyd metabolites eluting in the triphosphate region in these human cells under identical conditions. Shorter dThd incubation exposure intervals (6 hr) and lower dThd concentration (0.1 mM) produced smaller increments in these studies. Both growth and clonogenic assays of HL-60 cells demonstrated a dose- and schedule sequence-dependent synergism between dThd and 5-aza-dCyd.     

Neurodevelopmental Therapy and Upper-Extremity Inhibitive Casting for Children with Cerebral Palsy

The purpose of this research was to study the effect of intensive neurodevelopmental therapy (NDT) and upper-extremity inhibitive casting, separately or in combination, on hand function, quality of upper-extremity movement and range of motion of 73 children with spastic cerebral palsy aged 18 months to eight years. There was no significant difference between intensive or regular therapy and casting or no casting for hand function, between intensive and regular NDT, or between intensive NDT plus casting and the other groups for quality of movement and range of motion. Casting led to increased quality of movement and wrist extension after six months. Casting with NDT improved the quality of upper-extremity movement and range of motion. There appear to be no immediate benefits from intensive therapy alone.