Neurotrophins in the ventral tegmental area: Role in social stress, mood disorders and drug abuse.

This review discusses the impact of neurotrophins and other trophic factors, including fibroblast growth factor and glial cell line-derived neurotrophic factor, on mood disorders, weight regulation and drug abuse, with an emphasis on stress- and drug-induced changes in the ventral tegmental area (VTA). Neurotrophins, comprising nerve growth factor, brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4/5 play important roles in neuronal plasticity and the development of different psychopathologies. In the VTA, most research has focused on the role of BDNF, because other neurotrophins are not found there in significant quantities. BDNF originating in the VTA provides trophic support to dopamine neurons. The diverse intracellular signaling pathways activated by BDNF may underlie precise physiological functions specific to the VTA. In general, VTA BDNF expression increases after psychostimulant exposures, and enhanced BDNF level in the VTA facilitates psychostimulant effects. The impact of VTA BDNF on the behavioral effects of psychostimulants relies primarily on its action within the mesocorticolimbic circuit. In the case of opiates, VTA BDNF expression and effects seem to be dependent on whether an animal is drug-naïve or has a history of drug use, only the latter of which is related to dopamine mechanisms. Social defeat stress that is continuous in mice or intermittent in rats increases VTA BDNF expression, and is associated with depressive and social avoidance behaviors. Intermittent social defeat stress induces persistent VTA BDNF expression that triggers psychostimulant cross-sensitization. Understanding the cellular and molecular substrates of neurotrophin effects may lead to novel therapeutic approaches for the prevention and treatment of substance use and mood disorders.

Sound production in the pygmy sculpin Cottus paulus (Cottidae) during courtship and agonistic behaviours.

A field study examined sound production in the pygmy sculpin Cottus paulus, a threatened species found only in Coldwater Spring (Coosa River drainage), Alabama where the study was conducted. Two distinct call types are made during both courtship and agonistic encounters: a single knock and a knock train. The duration of the knock train significantly differs between contexts, while the signal structure stays the same. Knock trains are longer when the intended audience is a female, while short and abrupt when intended for a male intruder.

Evolution of acoustic signals in Cyprinella: degree of similarity in sister species.

Signal structure and behavioural context were examined in two sister species, the Tallapoosa shiner Cyprinella gibbsi and the tricolor shiner Cyprinella trichroistia, with two more distantly related species, the Ocmulgee shiner Cyprinella callisema and the whitetail shiner Cyprinella galactura, in order to test the hypothesis that more closely related species would share components of signals not shared with more distant relatives, and to look at the degree of divergence. The species examined differed in number and type of signal components, contexts and frequency under which calls were produced. While all species produced pulses arranged into pulse bursts, C. gibbsi and C. trichroistia shared unique call types, chirps and rattles, and C. galactura and C. callisema both produced the knock call type. The sister species shared more components of their call repertoire with each other than with the more distantly related C. galactura and C. callisema and clustered together based on courtship call similarity.

Antigen selection for future anti-Trichuris vaccines: a comparison of cytokine and antibody responses to larval and adult antigen in a primary infection.

Trichuriasis, caused by the whipworm Trichuris trichiura, is endemic in tropical and subtropical areas, affecting approximately 1 billion people. Child anthelminthic treatment programmes are being implemented but repeated treatments are costly, may prevent the development of acquired immunity and can lead to the development of drug resistant parasites. Thus, the development of a vaccine which would lead to the acquisition of immunity at an earlier age and reduce community faecal egg output would be beneficial. Development of subunit vaccines requires the identification of protective antigens and their formulation in a suitable adjuvant. Trichuris muris is an antigenically similar laboratory model for T. trichiura. Subcutaneous vaccination with adult excretory-secretory products (ES) protects susceptible mouse strains from T. muris. Larval stages may contain novel and more relevant antigens which when incorporated in a vaccine induce worm expulsion earlier in infection than the adult worm products. This study finds negligible difference in the cellular and humoral immune response to T. muris adult and third stage larva(e) (L3) ES during a primary T. muris infection, but identifies high molecular weight proteins in both adult and L3 ES as potential vaccine candidates.

Mutations responsible for Larsen syndrome cluster in the FLNB protein.

BACKGROUND: A gene for Larsen syndrome was recently described, and mutations were reported in five cases. OBJECTIVE: To test whether mutations in this gene, FLNB, could explain the disease in our independent collection of sporadic and dominant Larsen syndrome cases; and to test whether mutations occurred in a non-random pattern. RESULTS: Missense mutations were found in each of five cases. Four of the five were new; one was reported in a sporadic case in the original Larsen syndrome study of five cases. All mutations from the two studies were compiled. Clustered mutations were observed within three filamin B protein domains: the calponin homology 2 domain, repeat 14, and repeat 15. This suggested that as few as five (of the total of 46) coding exons of FLNB could be screened to detect Larsen syndrome mutations. Four of these exons were screened in a sixth (sporadic) case and a previously reported G1691S substitution mutation detected. CONCLUSIONS: Mutations in FLNB may be responsible for all cases of Larsen syndrome. They appear to occur in specific functional domains of the filamin B protein. This should simplify diagnostic screening of the FLNB gene. Analyses in larger patient series are warranted to quantify this. The study confirmed the extreme variability in clinical presentation and the presence of unaffected carriers. A molecular screen would be valuable for diagnosis and genetic counselling.

Isolates of Trichuris muris elicit different adaptive immune responses in their murine host.

The J and S isolates of Trichuris muris have different infection profiles in C57BL/6 mice; J worms are expelled, S worms survive to chronicity. Building on this, the ability of the J and S isolates to survive, and the quality of the immune response induced was explored in three different strains of mouse. The resistant BALB/c mouse mounted a strong Th2 response against both isolates, which were quickly expelled. The susceptible AKR host mounted a Th1 response and retained both isolates. Despite equivalent worm exposure, mesenteric lymph node cells from AKR mice infected with the S isolate produced significantly higher levels of IL-12 and the intestinal mastocytosis was reduced. IgG1 and IgG2a from S-infected AKR mice recognized low molecular weight antigens not recognized by J-infected mice. Differential expulsion kinetics was observed in the slower-responding C57BL/6 strain; J worms were expelled but S isolate worms were retained. Survival of the S isolate was again associated with elevated IL-12 and decreased Th2 responses. In resistant mouse strains, the outcome of infection is thus dominantly influenced by host genetics. However, in the slower-responding host, isolate-derived factors may play a role in shaping the quality of the adaptive immune response, thus influencing parasite survival.

Late open reduction internal fixation of lateral condyle fractures.

To study the effects of late open reduction of lateral condyle fracture (LCF) on avascular necrosis (AVN), amount of displacement, and improvement, the records of 11 children with an open capitellar physis and a malunion or a nonunion treated >3 weeks after injury were reviewed. Preoperative and postoperative displacement amounts were recorded. Radiographs were reviewed for AVN, lateral overgrowth, or fishtail deformity. There were no cases of AVN. Three patients had occasional pain. Four patients had displacement of >10 mm before surgery. In fractures with >1 cm of displacement, fragment position was minimally improved surgically, but final alignment and range of motion were good. These fractures showed more radiographic deformities at the time of late open reduction. The risk of AVN with late open reduction of LCF at >3 weeks is reduced if no tissue is stripped off the fracture fragment posteriorly. Even children without anatomic reduction had functional arms with little or no pain.

Efficacy of perioperative halo-gravity traction in the treatment of severe scoliosis in children.

SUMMARY: Perioperative halo traction was used in the treatment of severe scoliosis in 19 children. Diagnoses included neuromuscular, idiopathic, and congenital scoliosis. Traction was transferable between the bed and a walker or wheelchair. Thirteen patients had prior spinal surgery, and most required osteotomy. Traction was used for 6 to 21 weeks. All patients underwent spinal fusion surgery after traction, with instrumentation used in 15 patients. Improvement was achieved in all patients. The Cobb angle improved 35% from an average 84 degrees before traction (range 63 degrees -100 degrees ) to 55 degrees preceding fusion. Trunk decompensation improved in all patients. Trunk height increased 5.3 cm in traction. Response to traction did not correlate with diagnosis, patient age, or prior surgery. There were no neurologic complications. Perioperative halo-gravity traction improves trunk balance and frontal and sagittal alignment in children with severe spinal deformity. Surgical fusion was enhanced by the improved alignment, and neurologic injury was avoided.

Outcome of ultrasonographic hip abnormalities in clinically stable hips.

A retrospective review was performed of 192 newborn hips in 112 patients referred for hip evaluation. The average age at presentation was 12.7 days, with average radiographic follow-up of 15.9 months. Inclusion criteria for our study were a normal physical examination of the hip without evidence of instability and an ultrasound examination that was considered abnormal. Pavlik harness treatment was chosen at the discretion of the treating physician. At final follow-up, dysplasia was defined as greater than two standard deviations above the mean acetabular index (AI) for age. Group I consisted of 43 hips that had Pavlik treatment, and group II consisted of 149 hips that did not receive treatment. There was no difference in these two groups with respect to risk factors for dysplasia or the initial abnormalities seen on ultrasound evaluation, although patients in group I had less coverage of the femoral head during stress maneuvers. No hip in group I and two (1.3%) hips in group II were considered dysplastic (AI > 2 SD) at final radiographic follow-up (p > 0.10). There was no correlation between the severity of the ultrasound abnormality at birth and the subsequent presence of dysplasia (p > 0.10). The two hips considered dysplastic on radiograph were not being actively treated. When the hip examination of a newborn hip younger than 1 month is normal, a screening ultrasound does not appear to predict accurately subsequent hip dysplasia. In this specific setting, an initial screening ultrasound may be too sensitive and does not appear warranted.

Back pain during orthotic treatment of idiopathic scoliosis.

The incidence and etiology of back pain during orthotic management of idiopathic scoliosis was determined for 303 patients treated from 1980 through 1990 for a minimum of 1 year. All patients denied back pain before orthotic prescription. Thirty-four (11%) patients reported back pain after institution of brace treatment. A family history of scoliosis (p = 0.014) and vigorous sports activities (p < 0.001) were correlated with pain. Seventeen of 34 patients with pain showed >10 degrees of curve progression during bracing, whereas 67 of 269 patients without pain progressed (p = 0.002). Four patients with pain and 11 without were eventually found to have an underlying pathology (spondylolysis/listhesis). No other underlying pathologies were found. Night pain or a left thoracic curve pattern were not correlated with a serious underlying etiology. Back pain occurring after institution of brace treatment for idiopathic scoliosis is often associated with curve progression and is poorly correlated with a serious underlying pathology.

Ethanol ingestion prolongs orthostatic intolerance in hyperthermic humans.

BACKGROUND: Both ethanol ingestion and hyperthermia contribute to orthostatic intolerance (OI). HYPOTHESIS: Since ethanol has been cited as a major risk factor for hyperthermia-related deaths, we hypothesized that ethanol exacerbates OI induced by hyperthermia. METHODS: There were seven subjects (four males, three females) rendered hyperthermic (esophageal temperature = 39 degrees C) in a 40 degrees C water bath on two separate days: Condition 1) Control (juice ingestion); and Condition 2) Ethanol [ethanol (1 ml x kg(-1) body mass) and juice ingestion]. To test for OI, 5-min supine periods were followed by 5-min 63 degrees head-up tilts prior to and following immersion. BPs, heart rate and esophageal temperatures were monitored throughout the experiments. RESULTS: For first and second post-immersion tilts, mean arterial BP (MAP) during tilting increased by 5.9 +/- 3.6 (SE) and 9.8 +/- 2.6 mm Hg in the control condition, while it decreased by 7.9 +/- 5.8 and 0.6 +/- 4.3 mm Hg in the ethanol condition. This gave significantly lower MAP (ethanol vs. control) of 63.6 +/- 3.1 vs. 71.8 +/- 4.5 mm Hg (p < 0.05) for the first and 79.6 +/- 2.3 vs. 86.7 +/- 4.4 mm Hg (p < 0.05) for the second post-immersion tilts. These values were all significantly less (p < 0.05) than normothermic tilted values of 94.7 +/- 4.7 mm Hg in the ethanol and 93.6 +/- 2.9 mm Hg in the control condition. Prior to warm water immersion, subjects tolerated all head-up tilts. In the control condition, only one subject experienced orthostatic intolerance following the first post-heating tilt and no intolerance was experienced following 30 min post-heating. However, during the ethanol condition, 4 subjects experienced orthostatic intolerance following the first tilt with episodes of intolerance lasting as long as 80 min (8 supine/tilt cycles). CONCLUSION: Ethanol ingestion prolonged and increased the magnitude of OI in hyperthermic subjects. This may at least partly explain why ethanol is a major risk factor in hyperthermia-related deaths.

Gait analysis and muscle strength in children with congenital pseudarthrosis of the tibia: the effect of treatment.

Twelve patients with healed congenital pseudarthrosis of the tibia underwent gait analysis and muscle strength testing to determine the functional result of treatment. Six children younger than 4 years of age presented with pseudarthroses (early onset), and six children first fractured at older than 4 years of age (delayed onset). Four children with amputations as final treatment for congenital pseudarthrosis were studied for comparison. The early-onset group had undergone an average of 4.2 surgeries and all required transankle fixation. The delayed-onset group had undergone an average of 1.5 surgeries, with one child requiring fixation across the ankle. Lack of ankle push-off and foot drop occurred in the early-onset group. Terminal stance phase ankle power generation was greatly diminished in the early-onset group. Total mechanical work performed by the affected limb, when compared to the uninvolved contralateral limb, was symmetric in delayed-onset patients and reduced by 68% in early-onset patients and by 85% in amputees. Gastrocsoleus strength was reduced by 40%. Gait and muscle strength of patients with "healed" congenital pseudarthrosis of the tibia are markedly disturbed. Early onset of disease, early surgery, and transankle fixation lead to an inefficient gait comparable to that of amputees.

Clonidine decreases vasoconstriction and shivering thresholds, without affecting the sweating threshold.

PURPOSE: This study was conducted to test the hypothesis that clonidine produces a dose-dependent increase in the sweating threshold and dose-dependent decreases in vasoconstriction and shivering thresholds. METHODS: Six healthy subjects (two female) were studied on four days after taking clonidine in oral doses of either 0 (control), 3, 6 or 9 micrograms.kg-1. The order followed a balanced design in a double-blind fashion. Oesophageal temperature and mean skin temperature (from 12 sites) were measured. Subjects were seated in 37 degrees C water which was gradually warmed until sweating occurred (sweat rate increased above 50 g.m-2.h-1). The water was then cooled gradually until thresholds for vasoconstriction (onset of sustained decrease in fingertip blood flow) and shivering (sustained elevation in metabolism) were determined. Thresholds were then referred to as the core temperature, adjusted to a designated mean skin temperature of 33 degrees C. RESULTS: High dose clonidine similarly decreased the adjusted core temperature thresholds for vasoconstriction by 1.16 +/- 0.30 degrees C and for shivering by 1.63 +/- 0.23 degrees C (P < 0.01). The dose response effects were linear for both cold responses with vasoconstriction and shivering thresholds decreasing by 0.13 +/- 0.05 and 0.19 +/- 0.09 degree C.microgram-1 respectively (P < 0.0001). The sweating threshold was unaffected by clonidine, however the interthreshold range between sweating and vasoconstriction thresholds increased from control (0.19 +/- 0.48 degree C) to high dose clonidine (1.31 +/- 0.54 degrees C). CONCLUSION: The decreases in core temperature thresholds for cold responses and increased interthreshold range are consistent with the effects of several anaesthetic agents and opioids and is indicative of central thermoregulatory inhibition.

The prevalence of back pain in children who have idiopathic scoliosis.

A retrospective study of 2442 patients who had idiopathic scoliosis was performed to determine the prevalence of back pain and its association with an underlying pathological condition. Five hundred and sixty (23 per cent) of the 2442 patients had back pain at the time of presentation, and an additional 210 (9 per cent) had back pain during the period of observation. There was a significant association between back pain and an age of more than fifteen years, skeletal maturity (a Risser sign of 2 or more), postmenarchal status, and a history of injury. There was no association with gender, family history of scoliosis, limb-length discrepancy, magnitude or type of curve, or spinal alignment. At the latest follow-up evaluation, 324 (58 per cent) of the 560 patients who had had back pain at presentation had no additional symptoms. Forty-eight (9 per cent) of the 560 patients who had back pain had an underlying pathological condition: twenty-nine patients had spondylolysis or spondylolisthesis, nine had Scheurmann kyphosis, five had a syrinx, two had a herniated disc, one had hydromyelia, one had a tethered cord, and one had an intraspinal tumor. A painful left thoracic curve or an abnormal neurological finding was most predictive of an underlying pathological condition, although only eight of the thirty-three patients who had such findings were found to have such a condition. When a patient with scoliosis has back pain, a careful history should be recorded, a thorough physical examination should be performed, and good-quality plain radiographs should be made. If this initial evaluation reveals normal findings, a diagnosis of idiopathic scoliosis can be made, the scoliosis can be treated appropriately, and non-operative treatment can be initiated for the back pain. It is not necessary to perform extensive diagnostic studies to evaluate every patient who has scoliosis and back pain.

Intense exercise increases the post-exercise threshold for sweating.

We demonstrated previously that esophageal temperature (T(es)) remains elevated by approximately 0.5 degrees C for at least 65 min after intense exercise. Following exercise, average skin temperature (T(avg)) and skin blood flow returned rapidly to pre-exercise values even though T(es) remained elevated, indicating that the T(es) threshold for vasodilation is elevated during this period. The present study evaluates the hypothesis that the threshold for sweating is also increased following intense exercise. Four males and three females were immersed in water (water temperature, T(w) = 42 degrees C) until onset of sweating (Immersion 1), followed by recovery in air (air temperature, T(a) = 24 degrees C). At a T(a) of 24 degrees C, 15 min of cycle ergometry (70% VO2max) (Exercise) was then followed by 30 min of recovery. Subjects were then immersed again (T(w) = 42 degrees C) until onset of sweating (Immersion 2). Baseline T(es) and T(skavg) were 37.0 (0.1) degrees C and 32.3 (0.3) degrees C, respectively. Because the T(skavg) at the onset of sweating was different during Exercise [30.9 (0.3) degrees C] than during Immersion 1 and Immersion 2 [36.8 (0.2) degrees C and 36.4 (0.2) degrees C, respectively] a corrected core temperature, T((es) (calculated)), was calculated at a single designated skin temperature, T((sk)(designated)), as follows: T((es)(calculated)) = T(es) + [beta/(1-beta)][T(skavg)-T((sk)(designated))]. The T((sk)(designated)) was set at 36.5 degrees C (mean of Immersion 1 and Immersion 2 conditions) and beta represents the fractional contribution of T(skavg) to the sweating response (beta for sweating = 0.1). While T((es)(calculated)) at the onset of sweating was significantly lower during exercise [36.7 (0.2) degrees C] than during Immersion 1 [37.1 (0.1) degrees C], the threshold of sweating during Immersion 2 [37.3 (0.1) degrees C] was greater than during both Exercise and Immersion 1 (P < 0.05). We conclude that intense exercise decreases the sweating threshold during exercise itself, but elicits a subsequent short-term increase in the resting sweating threshold.

Efficacy of forced-air and inhalation rewarming by using a human model for severe hypothermia.

We recently developed a nonshivering human model for severe hypothermia by using meperidine to inhibit shivering in mildly hypothermic subjects. This thermal model was used to evaluate warming techniques. On three occasions, eight subjects were immersed for approximately 25 min in 9 degrees C water. Meperidine (1.5 mg/kg) was injected before the subjects exited the water. Subjects were then removed, insulated, and rewarmed in an ambient temperature of -20 degrees C with either 1) spontaneous rewarming (control), 2) inhalation rewarming with saturated air at approximately 43 degrees C, or 3) forced-air warming. Additional meperidine (to a maximum cumulative dose of 2.5 mg/kg) was given to maintain shivering inhibition. The core temperature afterdrop was 30-40% less during forced-air warming (0.9 degree C) than during control (1.4 degrees C) and inhalation rewarming (1.2 degrees C) (P < 0.05). Rewarming rate was 6- to 10-fold greater during forced-air warming (2.40 degrees C/h) than during control (0.41 degree C/h) and inhalation rewarming (0.23 degree C/h) (P < 0.05). In nonshivering hypothermic subjects, forced-air warming provided a rewarming advantage, but inhalation rewarming did not.

Inhibition of shivering increases core temperature afterdrop and attenuates rewarming in hypothermic humans.

During severe hypothermia, shivering is absent. To simulate severe hypothermia, shivering in eight mildly hypothermic subjects was inhibited with meperidine (1.5 mg/kg). Subjects were cooled twice (meperidine and control trials) in 8 degrees C water to a core temperature of 35.9 +/- 0.5 (SD) degrees C, dried, and then placed in sleeping bags. Meperidine caused a 3.2-fold increase in core temperature afterdrop (1.1 +/- 0.6 vs. 0.4 +/- 0.2 degree C), a 4.3-fold increase in afterdrop duration (89.4 +/- 31.4 vs. 20.9 +/- 5.7 min), and a 37% decrease in rewarming rate (1.2 +/- 0.5 vs. 1.9 +/- 0.9 degrees C/h). Meperidine inhibited overt shivering. Oxygen consumption, minute ventilation, and heart rate decreased after meperidine injection but subsequently returned toward preinjection values after 45 min postimmersion. This was likely due to the increased thermoregulatory drive with the greater afterdrop and the short half-life of meperidine. These results demonstrate the effectiveness of shivering heat production in attenuating the postcooling afterdrop of core temperature and potentiating core rewarming. The meperidine protocol may be valuable for comparing the efficacy of various hypothermia rewarming methods in the absence of shivering.