High rate of autonomic neuropathy in Cornelia de Lange Syndrome.

BACKGROUND: Cornelia de Lange Syndrome (CdLS) is a rare congenital disorder characterized by typical facial features, growth failure, limb abnormalities, and gastroesophageal dysfunction that may be caused by mutations in several genes that disrupt gene regulation early in development. Symptoms in individuals with CdLS suggest that the peripheral nervous system (PNS) is involved, yet there is little direct evidence. METHOD: Somatic nervous system was evaluated by conventional motor and sensory nerve conduction studies and autonomic nervous system by heart rate variability, sympathetic skin response and sudomotor testing. CdLS Clinical Score and genetic studies were also obtained. RESULTS: Sympathetic skin response and sudomotor test were pathological in 35% and 34% of the individuals with CdLS, respectively. Nevertheless, normal values in large fiber nerve function studies. CONCLUSIONS: Autonomic nervous system (ANS) dysfunction is found in many individuals with Cornelia de Lange Syndrome, and could be related to premature aging.

A GH receptor antisense oligonucleotide inhibits hepatic GH receptor expression, IGF-I production and body weight gain in normal mice.

Diabetic retinopathy and acromegaly are diseases associated with excess action of GH and its effector IGF-I, and there is a need for improved therapies. We have designed an optimised 2'-O-(2-methoxyethyl)-modified phosphorothioate oligodeoxynucleotide, ATL 227446, and demonstrated its ability to suppress GH receptor mRNA in vitro. Subcutaneous injections of ATL 227446 reduced GH receptor mRNA levels, GH binding activity and serum IGF-I levels in mice after seven days of dosing. The reduction in serum IGF-I could be sustained for over ten weeks of dosing at therapeutically relevant levels, during which there was also a significant decrease in body weight gain in antisense-treated mice relative to saline and mismatch control-treated mice. The findings indicate that administration of an antisense oligonucleotide to the GH receptor may be applicable to human diseases in which suppression of GH action provides therapeutic benefit.

Physical activity and determinants of physical activity in obese and non-obese children.

OBJECTIVE: To compare the physical activity (PA) patterns and the hypothesized psychosocial and environmental determinants of PA in an ethnically diverse sample of obese and non-obese middle school children. DESIGN: Cross-sectional study. SUBJECTS: One-hundred and thirty-three non-obese and 54 obese sixth grade children (mean age of 11.4+/-0.6). Obesity status determined using the age-, race- and gender-specific 95th percentile for BMI from NHANES-1. MEASUREMENTS: Objective measurements were collected of PA over a 7-day period using the CSA 7164 accelerometer: total daily counts; daily moderate (3-5.9 METs) physical activity (MPA); daily vigorous physical activity (> or =6 METs; VPA); and weekly number of 5, 10 and 20 min bouts of moderate-to-vigorous physical activity (> or =3 METs, MVPA). Self-report measures were collected of PA self-efficacy; social influences regarding PA, beliefs about PA outcomes; perceived PA levels of parents and peers, access to sporting and/or fitness equipment at home, involvement in community-based PA organizations; participation in community sports teams; and hours spent watching television or playing video games. RESULTS: Compared to their non-obese counterparts, obese children exhibited significantly lower daily accumulations of total counts, MPA and VPA as well as significantly fewer 5, 10 and 20 min bouts of MVPA. Obese children reported significantly lower levels of PA self-efficacy, were involved in significantly fewer community organizations promoting PA and were significantly less likely to report their father or male guardian as physically active. CONCLUSIONS: The results are consistent with the hypothesis that physical inactivity is an important contributing factor in the maintenance of childhood obesity. Interventions to promote PA in obese children should endeavor to boost self-efficacy perceptions regarding exercise, increase awareness of, and access to, community PA outlets, and increase parental modeling of PA.

[Retroperitoneal cystic lymphangioma]. / Linfangioma cístico retroperitonial.

The lymphangioma is a rare disease, more frequently reported in children and just occasionally in the adult patient. The lymphangioma is considered a benign neoplasm of embryonic origin of the lymphatic vessels. Its habitual location is in the cervical and axillary area; it is rarely found in the abdominal cavity and exceptionally in the retroperitonio. In this latter location, the lesion habitually is asymptomatic. The clinical diagnosis of the retroperitoneal cystic lymphangioma is not often due to its rarity and the absence of clinical expression. The size of the lesion is more important than its location to the symptomatology development. The findings of the abdominal ultrasonography and computerized tomography of the abdomen usually show a cystic lesion and its location. The treatment is surgical and it consists of the resection of the cyst or group of cysts once the liquid accumulation in its interior may be responsible for the development of some important complications of this disease. The cure is obtained when the lesion is completely resected also with the resection of eventual adhesive structures. The relapse may take place when the resection is incomplete. A case of retroperitoneal lymphangioma in a female adult patient as incidental finding of abdominal ultra-sonography is described. It is discussed the clinical picture, the radiologic diagnosis, the treatment and the prognostic of this unusual disease.

Ischemic stroke in the young: evaluation and age comparison of patients six months to thirty-nine years.

Ischemic stroke in the young is uncommon, but we currently evaluate at least one young stroke patient at our institutions each week. We undertook this chart review of strokes in patients between the ages of 6 months and 39 years to review all conditions associated with, and thus possibly contributory to, the stroke. We also compare younger and older age groups to observe if age-dependent factors exist. Of 100 total ischemic strokes, 22 were in persons 6 months to 18 years and 78 were in persons 19 to 39 years. Seventy-five percent of strokes were associated with a condition known or postulated to increase stroke risk. Some of these conditions are well accepted as causes for stroke, such as some forms of heart disease, whereas others are only postulated, such as the hypercoagulable states. Taken as a whole, associated conditions were approximately equally divided between infectious/inflammatory, structural, and presumed hypercoagulable conditions. Strokes in the first two decades of life were more commonly associated with infectious/inflammatory conditions, whereas strokes in the next two decades more commonly had structural or presumed hypercoagulable associated conditions. Since many strokes remain unexplained, it would be valuable to determine the significance, if any, of conditions less well known as risk factors for stroke.

Comparison of the density and distribution of brain D-1 and D-2 dopamine receptors in Buffalo vs. Fischer 344 rats.

In vitro autoradiography was used to compare the D-1 and D-2 receptor densities in brains from Buffalo (BUFF) and Fischer 344 (F344) rats. The latter strain has been proposed as a model for human attention deficit disorder with hyperactivity (ADDH). The radioligands [3H]-SCH 23390 and [3H]-sulpiride were used to selectively identify dopamine D-1 and D-2 receptors, respectively. Certain forebrain structures from F344 rats have a higher density of D-2 receptors, but similar numbers of D-1 receptors compared to BUFF rats. Scatchard analysis of D-2 binding (in caudate-putamen) revealed a Bmax of 10.52 +/- 1.62 fmol/mg tissue and Kd of 12.72 +/- 0.93 nM in F344 rats and 3.00 +/- 0.57 and 3.87 +/- 0.58, respectively in BUFF rats (n = 3). These results support the hypothesis that high D-2 levels are correlated with certain behavioral traits, e.g., high levels of spontaneous activity. A similar increase in D-2 receptors may be responsible for some of the behavioral manifestations of ADDH in children.

A venom peptide with a novel presynaptic blocking action.

The venom of the fish-eating marine mollusc, Conus geographus, contains several neurotoxic peptides having different targets. A novel peptide has recently been isolated from the venom of C. geographus by Drs B. M. Olivera and W. R. Gray and colleagues in our department (in preparation). We report here that this peptide, designated omega CgTX (omega C. geographus toxin), irreversibly blocks nerve stimulus-evoked release of transmitter at the frog skeletal neuromuscular junction. Experiments indicate that the toxin acts by preventing action potential. Consistent with this is the demonstration that omega CgTX also irreversibly attenuates the Ca2+ component of the action potential in dorsal root ganglion (DRG) neurones from embryonic chick. omega CgTX thus provides a unique and potentially powerful probe for exploring the presynaptic terminal.

Ca2+-dependent slow action potentials in normal and dystrophic mouse skeletal muscle.

Slowly rising action potentials (APs), previously described in amphibian skeletal muscle, were examined in skeletal muscle of normal and dystrophic mice (129/ReJ strain). A standard two-microelectrode recording technique was used. Muscles were bathed in a solution that was Cl- free (methanesulfonate substituted), high in K+ (20 mM), and contained 15 mM tetraethylammonium. The slow APs were elicited under conditions in which the fast Na+ channels were voltage inactivated (by partial depolarization) and in which the external Na+ concentration was only 10 mM. Increases in external Ca2+ concentration produced increases in slow AP amplitude and duration. Mn2+ (4 mM), La3+ (4 mM), and detubulation with osmotic shock blocked the slow APs. When slow APs were generated at 30-s intervals, their amplitude stayed constant. When they were generated at 15-s intervals, their amplitude decreased progressively and then fell to zero by the 11th stimulus. The Ca antagonists verapamil (10(-5) M) and bepridil (10(-5) M) caused this decrease in amplitude to occur more quickly. Voltage inactivation of the slow APs occurred between -45 and -10 mV. Slow APs recorded from dystrophic muscle fibers were decreased in amplitude and duration compared with those in normal fibers, and there was a reduced incidence of occurrence; 96% of the fibers in normal muscle exhibited slow APs compared with only 46% of dystrophic muscle fibers. In summary, slow Ca2+ APs in mammalian muscle are similar to those in cardiac and amphibian skeletal muscle, and these slow APs are depressed in dystrophic skeletal muscle.

Effects of pH on membrane resistance in normal and dystrophic mouse skeletal muscle fibers.

Membrane cable properties of skeletal muscle fibers of dystrophic mice (Rej-129) and their littermate controls were examined using a conventional two-microelectrode recording technique. Fibers from dystrophic mice had a decreased membrane resistivity (Rm) compared with those from normal mice (517 +/- 27 vs 642 +/- 34 omega - cm2), while the internal resistivities (Ri) did not differ significantly. The increase in membrane specific conductance was due to an increased Cl- conductance (gCl) (2304 vs 1346 microseconds/cm2 for normal fibers), although the K+ conductance (gK) was actually decreased (234 vs 369 microseconds/cm2 for normal fibers). With changes in pH, membrane conductances of normal and dystrophic skeletal muscle fibers varied differently, mainly due to differences in effects on the Cl- conductance. This contrast may be due to altered regulation of internal pH in dystrophic muscle.

Membrane alterations in skeletal muscle fibers of dystrophic mice.

Skeletal muscle fibers from dystrophic mice and littermate controls (ReJ-129) were characterized electrically and then injected with an intracellular marker. In this way they could be identified for examination with an electron microscope to correlate the relative time course of electrical and ultrastructural alterations resulting from the dystrophic process. On the average, dystrophic muscle fibers displayed decreased membrane potentials (-59 +/- 1.2 vs -79 +/- 0.7 mV for normals), decreased specific membrane resistivity (517 +/- 27 vs 642 +/- 34 omega-cm2 for normals), and depressed action potential (AP) maximum rates of rise (+Vmax) (352 +/- 9 vs 417 +/- 9 V/s for normals) and amplitudes (92 +/- 1.2 vs 102 +/- 1.0 mV for normals) at an experimentally polarized membrane potential of -90 mV. Membrane resistivity and AP +Vmax were decreased even in those fibers from dystrophic muscles that displayed normal ultrastructure (classified visually and by ratio of sarcoplasmic reticulum to total cell volume). These findings support the membrane hypothesis of muscular dystrophy that membrane lesions are the primary lesion in the disease process.

Effect of the calcium antagonists bepridil (CERM-1978) and verapamil on Ca++-dependent slow action potentials in frog skeletal muscle.

The calcium slow channels found in cardiac and smooth muscle are blocked by calcium-antagonistic agents. In the present study, the effects of the Ca++-antagonistic drugs bepridil and verapamil on the slow action potentials (APs) found in the frog skeletal muscle were examined. Slow APs were induced in Cl-- free (acetate substituted), Na+-free (sucrose substituted), high K+ (25 mM)media. A conventional two-microelectrode recording technique was used. Amplitude of the slow APs increases linearly with log [Ca]o with a slope of 28.2 mV/decade, suggesting that Ca++ is the major inward current carrier because this value approaches the theoretical slope of 29 mV/decade (at 21 degrees C) predicted by the Nernst equation for a divalent cation. Duration also increases with increases in [Ca]o. The slow APs were abolished by glycerol shock treatment, which disconnects the T-tubules from the surface membrane, suggesting that the slow APs originate in the T-tubules. Verapamil and bepridil depress the amplitude of the slow APs in a use-dependent manner at concentrations of 5 X 10-9 to 1 X 10-6 M and abolish the slow APs at 5 X 10-6 M. These drugs also decrease the rates of rise of the slow APs. Bepridil decreases the duration of the slow APs, whereas verapamil has little effect, suggesting that bepridil, in addition to blocking the slow channels, might also increase gk. Thus, the slow channels found in the T-tubular system of frog skeletal muscle have some of the same properties of slow channels in vascular smooth muscle and cardiac muscle.

Influence of acoustic experience on the ontogeny of frequency generalization gradients in the chicken.

The role of auditory experience in the ontogeny of perceptual coding was investigated in hatching chickens. In Experiment 1, auditory frequency generalization gradients were determined by using a habituation-generalization paradigm and an orienting response. One-day and 3-4 day chicks were habituated to 800-Hz tones and then tested at five frequencies ranging from 800 to 1,000 Hz. One-day chicks displayed reliably flatter generalization gradients than 3-4-day chicks. In Experiment 2 an auditory deprivation method is described in which an ear impression compound was injected into the external ear. This method (a) is fully calibrated and provides approximately 40 dB of attenuation across a .125- to 4.0-kHz range, (b) appears to be fully reversible, and (c) is applicable prior to normal auditory experience as well as at subsequent stages. In Experiment 3, this method was used to investigate the effects of auditory deprivation on the "perceptual sharpening" described in Experimental 1. Chicks were deprived from Embryonic Day 18 1/2 to 3-4 days posthatch, at which time normal, deprived, and sham-operated chicks were tested as in Experiment 1. The generalization gradients of the deprived chicks were significantly flatter than those of the 3-4 day normal and sham-operated chicks and were similar to those of 1-day chicks. This effect cannot be attributed to (a) operative procedures, (b) changes in auditory thresholds, or (c) changes in response rate with age or condition. Thus the perceptual sharpening normally occurring between 1 and 3-4 days posthatch fails to occur during that time in the absence of a normal acoustic environment.