Neurobehavioral and neurochemical effects of perinatal arsenite exposure in Sprague-Dawley rats.

Exposure to relatively high levels of inorganic arsenic (iAs) is associated with detrimental effects on human health, including cancer and diabetes. The effects of lower-level exposures are less clear, and gaps in the literature exist as to the effects of iAs exposure on neurodevelopment. The current study assessed the effects of perinatal iAs exposure on rodent neurodevelopment and behavior. Pregnant Sprague-Dawley (SD) rats were exposed to arsenite (AsIII) via oral gavage on gestational days (GD) 6 through 21, and pups were directly dosed via gavage on postnatal days (PND) 1 through 21. Dams and offspring received the same doses: 0.00, 0.10, 1.50, or 3.75 mg/kg/day. Male and female offspring underwent a battery of behavioral assessments from weaning until PND 180. Brain arsenic levels increased in a dose-dependent manner at both PND 1 and 21. Results from the behavioral tests show that pre- and postnatal AsIII exposure did not adversely affect offspring weight gain, adolescent motor and cognitive functions, or adult motor and cognitive functions in the SD rat. There were no differences in concentration of several brain proteins associated with blood-brain barrier permeability, dopamine functions, and inflammation.

Minimal effects from a single exposure to sevoflurane in adult male and female Sprague-Dawley rats.

Many people undergo procedures requiring general anesthesia each day and adverse cognitive effects have been reported in response to that anesthesia. Postoperative Cognitive Dysfunction (POCD) may occur in as many as 80% of adults during the first post-surgical week and can have lasting effects. Here, the cognitive and motor effects of sevoflurane exposure in Sprague-Dawley rats was examined along with body weights, blood oxygen saturation, heart rate, and body temperature. Male and female rats were exposed to 2.5% sevoflurane or medical grade air for one hour at postnatal day 115. Beginning the following day, rats began a series of behavioral tests examining locomotor activity, motor coordination, novel object recognition, and spatial learning and memory in a water maze. Blood oxygen saturation, heart rate, and body temperature were not affected by the sevoflurane exposure. A slight effect on locomotor activity was detected, but no effects on motor coordination, novel object recognition, or spatial learning and memory were observed. Brain weights following behavioral testing did not differ. The results reported here along with existing literature suggest sevoflurane is largely without effects on later cognition in adult rodents when exposure is of a relatively short duration and at a relatively low concentration.

Effects of intravenous and oral di(2-ethylhexyl) phthalate (DEHP) and 20% Intralipid vehicle on neonatal rat testis, lung, liver, and kidney.

The highest human exposures to the plasticizer di(2-ethylhexyl) phthalate (DEHP) occur through intravenous (iv) exposure from medical procedures. Rodent toxicity studies, mainly using oral exposures, have identified male reproductive toxicity after developmental exposure to DEHP as the primary concern. Other organs are also affected by DEHP and route may influence the degree of target organ involvement. Cammack et al. (2003) reported a critical study focused on testicular toxicity using oral and iv exposures of neonatal Sprague-Dawley rats to 60, 300, or 600 mg/kg body weight/day DEHP in Intralipid vehicle. The present study followed the same dosing paradigm and included assessment of additional organs to evaluate the potential utility of this design for DEHP alternatives. Reduction of testis weight was observed in all DEHP treatment groups and germ cell and Sertoli cell toxicity was observed at the two highest doses with both routes. Lung granulomas occurred in all iv DEHP groups, possibly related to increased fat particle size in DEHP lipid emulsions. Lung alveolar development was inhibited after both oral and iv high dose DEHP. Toxicity of oral Intralipid vehicle was observed in germ and Sertoli cells. The lack of such effects after iv vehicle exposure suggested that this may be a gut-mediated effect.

Developmental neurotoxicity of inorganic arsenic exposure in Sprague-Dawley rats.

High levels of inorganic arsenic (iAs) exposure are associated with severe health effects. Less clear are effects of lower exposure levels on neurodevelopment. Relative to maternal intake, there is limited lactational transfer of arsenic in humans or rodents, yet there are few rodent studies which directly exposed preweaning animals. To more clearly determine iAs developmental neurotoxicity, 28 pregnant Sprague-Dawley rats were exposed to arsenate (AsV) via drinking water (0, 23.6, 47.7, 71.0 ppm) (n = 5-7/group) from gestational day (GD) 6 through GD 22 with targeted doses of 0, 2.33, 4.67, 7.00 mg/kg/day, respectively. Offspring were dosed by gavage daily with the same mg/kg AsV dose as intended for their dam from postnatal day (PND) 1 to 21. Gestational water intake was reduced at all AsV doses, but returned to control levels on lactational day (LD) 1 when control water was returned. Gestational body weight was reduced only at the highest dose on GD 22 and lactational body weight was unaffected. Food intake was unaffected. iAs exposure did not alter offspring body weight (PNDs 1-21) or age at fur development and bilateral ear opening. Incisor eruption, however, was significantly delayed in offspring of the 4.67 and 7.00 mg/kg groups. Further, all iAs groups were significantly delayed in bilateral eye opening. Righting reflex (PNDs 3-6) was unaffected, while slant board performance (PNDs 8-11) was significantly poorer at the highest dose. Brains of culled pups (PND 1) showed dose-dependent increases of iAs. There were no significant AsV-related effects on PND 21 brain regional concentrations of dopamine, DOPAC, HVA, 5-HT or 5-HIAA. These hazard identification results will guide the study designs of developmental iAs exposure at human-relevant levels essential for risk-assessment.

The Convergence of Vasculopathy and Vasculitis: Computer Mapping Analysis of 2 Renal Biopsies in a Patient with both Systemic Sclerosis and ANCA-Related Vasculitis.

Scleroderma vasculopathy and ANCA (antineutrophil cytoplasmic antibodies)-associated glomerulonephritis have rarely been reported to occur simultaneously in one patient. Herein, we report a patient who presented with a classic constellation of clinical and laboratory findings of systemic scleroderma and was subsequently found to be positive for p-ANCA. Two renal biopsies, performed 5 months apart, demonstrated typical changes of the two entities in both acute and "healed" phases, which were analyzed by computer mapping techniques. The two renal biopsies were serially sectioned and stained routinely, and with CD31 and CD34 as endothelial markers. The slides were digitized, aligned and analyzed. Each glomerular tuft was sequentially studied in terms of total area (µm2) and each biopsy was individually profiled. All arterial vessels were sequentially studied with whole vessel and luminal areas delineated and ratios calculated. The initial biopsy contained 32 glomeruli almost all with extensive fibrinoid necrosis and destruction of the capillary network. The arterial vessels (interlobular and arcuate) showed intimal edema with luminal occlusion. CD31/CD34 stains showed variable endothelial intactness but demonstrated the luminal size shifts. The second biopsy had 37 glomeruli that were either segmentally or globally sclerotic with no active changes. The vessels were now normally patent. Each glomerular tuft and arterial vessel in both biopsies was analyzed as a serial section histogram documenting these changes. These studies depict the rare occurrence of two entities together, the scleroderma kidney vasculopathy and the glomerulonephritis of ANCA-associated vasculitis syndrome both in an acute and healing phase, profiled by computer mapping techniques.

Developmental treatment with ethinyl estradiol, but not bisphenol A, causes alterations in sexually dimorphic behaviors in male and female Sprague Dawley rats.

The developing central nervous system may be particularly sensitive to bisphenol A (BPA)-induced alterations. Here, pregnant Sprague Dawley rats (n = 11-12/group) were gavaged daily with vehicle, 2.5 or 25.0 µg/kg BPA, or 5.0 or 10.0 µg/kg ethinyl estradiol (EE2) on gestational days 6-21. The BPA doses were selected to be below the no-observed-adverse-effect level (NOAEL) of 5 mg/kg/day. On postnatal days 1-21, all offspring/litter were orally treated with the same dose. A naïve control group was not gavaged. Body weight, pubertal age, estrous cyclicity, and adult serum hormone levels were measured. Adolescent play, running wheel activity, flavored solution intake, female sex behavior, and manually elicited lordosis were assessed. No significant differences existed between the vehicle and naïve control groups. Vehicle controls exhibited significant sexual dimorphism for most behaviors, indicating these evaluations were sensitive to sex differences. However, only EE2 treatment caused significant effects. Relative to female controls, EE2-treated females were heavier, exhibited delayed vaginal opening, aberrant estrous cyclicity, increased play behavior, decreased running wheel activity, and increased aggression toward the stimulus male during sexual behavior assessments. Relative to male controls, EE2-treated males were older at testes descent and preputial separation and had lower testosterone levels. These results suggest EE2-induced masculinization/defeminization of females and are consistent with increased volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) at weaning in female siblings of these subjects (He, Z., Paule, M. G. and Ferguson, S. A. (2012) Low oral doses of bisphenol A increase volume of the sexually dimorphic nucleus of the preoptic area in male, but not female, rats at postnatal day 21. Neurotoxicol. Teratol. 34, 331-337). Although EE2 treatment caused pubertal delays and decreased testosterone levels in males, their behaviors were within the range of control males. Conversely, BPA treatment did not alter any measured endpoint. Similar to our previous reports (Ferguson, S. A., Law, C. D. Jr and Abshire, J. S. (2011) Developmental treatment with bisphenol A or ethinyl estradiol causes few alterations on early preweaning measures. Toxicol. Sci. 124, 149-160; Ferguson, S. A., Law, C. D. and Abshire, J. S. (2012) Developmental treatment with bisphenol A causes few alterations on measures of postweaning activity and learning. Neurotoxicol. Teratol. 34, 598-606), the BPA doses and design used here produced few alterations.

Developmental treatment with bisphenol A or ethinyl estradiol causes few alterations on early preweaning measures.

Because bisphenol A (BPA) exposure is nearly ubiquitous, increased knowledge of its potential effects on development will enable better risk assessment and regulatory guidance. Here, Sprague-Dawley rats were reared in low exogenous estrogen environments. After breeding at adulthood, dams were gavaged on gestational days (GDs) 6-21 with vehicle (VEH), 2.5 or 25.0 µg/kg/day BPA, or 5.0 or 10.0 µg/kg/day ethinyl estradiol (EE2). Offspring were orally treated on postnatal days (PNDs) 1-21 with the same dose the dam received. Relative to the VEH group, dams of both EE2-treated groups weighed less throughout gestation and lactation. PND 1 absolute anogenital distance and anogenital index were unaltered by any treatment. Ages at fur development and eye and ear opening were unaffected by any treatment. Despite a significant treatment effect, no group was significantly different from VEH in PNDs 3-6 righting latencies; although males had shorter latencies and all latencies decreased with age. PNDs 8-11 slant board behavior was unaffected by any treatment; however, males had shorter turning latencies and latencies decreased with age. Preweaning body weights of BPA- and EE2-treated groups as well as naive controls were less than VEH. No treatment affected PND 21 whole or regional brain weights or levels of estradiol, testosterone, corticosterone, T3, T4, luteinizing hormone, ghrelin, or leptin. These results add to the literature indicating that developmental BPA treatment at these doses has no effects on gestational or lactational body weight, offspring anogenital distance, preweaning behaviors or hormone levels, and whole and regional brain weights measured at weaning.

Treatment of congenital hemiparesis with pediatric constraint-induced movement therapy.

To determine efficacy of pediatric Constraint-Induced Movement therapy, 20 children with congenital hemiparesis (ages 2 to 6 years) were randomly assigned to receive the treatment or usual care. Controls crossed over to the therapy after 6 months. Children receiving the therapy first exhibited emergence of more new classes of motor patterns and skills (eg, crawling, thumb-forefinger prehension; 6.4 vs 0.02, P < .0001, effect size d = 1.3), and demonstrated significant gains in spontaneous use of the more affected arm at home (2.2 vs 0.1, P < .0001, d = 3.8) and in a laboratory motor function test. Depending on the measure, benefits were maintained (range, no loss to 68% retention over 6 months). When controls crossed over to the therapy, they exhibited improvements as great as or greater than those receiving therapy first. Thus, Constraint-Induced Movement therapy appears to be efficacious for young children with hemiparesis consequent to congenital stroke.

Approach-specific multi-grid anatomical modeling for neurosurgery simulation with public-domain and open-source software.

We present on-going work on multi-resolution sulcal-separable meshing for approach-specific neurosurgery simulation, in conjunction multi-grid and Total Lagrangian Explicit Dynamics finite elements. Conflicting requirements of interactive nonlinear finite elements and small structures lead to a multi-grid framework. Implications for meshing are explicit control over resolution, and prior knowledge of the intended neurosurgical approach and intended path. This information is used to define a subvolume of clinical interest, within some distance of the path and the target pathology. Restricted to this subvolume are a tetrahedralization of finer resolution, the representation of critical tissues, and sulcal separability constraint for all mesh levels.

Ssecrett and NeuroTrace: interactive visualization and analysis tools for large-scale neuroscience data sets.

Data sets imaged with modern electron microscopes can range from tens of terabytes to about one petabyte. Two new tools, Ssecrett and NeuroTrace, support interactive exploration and analysis of large-scale optical-and electron-microscopy images to help scientists reconstruct complex neural circuits of the mammalian nervous system.

Medial pectoral nerve to musculocutaneous nerve neurotization for the treatment of persistent birth-related brachial plexus palsy: an 11-year institutional experience.

OBJECT: Medial pectoral nerve (MPN) to musculocutaneous nerve (MCN) neurotization for recovery of elbow flexion by biceps reinnervation is a valid option following traumatic injury to the upper brachial plexus. A major criticism of the application of this technique in infants is the smaller size of the MPN and mismatch of viable axons. We describe our institutional experience utilizing this procedure and critically examine functional outcomes. METHODS: Office charts and hospital records of children from over an 11-year period beginning January 1997 were reviewed. Of the 53 children of various ages undergoing brachial plexus exploration for traumatic injury of any nature, 20 underwent MPN to MCN neurotization as a part of an overall procedure in the first year of life to treat birth-related brachial plexus palsy and had at least 9 months' follow-up. Medial pectoral nerve to MCN neurotization was chosen if the results of clinical examination and intraoperative electrophysiological evidence were consistent with medial cord function. Functional recovery was defined as the ability of the child to bring their hand to their mouth. RESULTS: Sixteen patients (80%) gained functional recovery. The median age at surgery was 7 months. Median time to first clinic visit documenting recovery was 11.5 months and median overall follow up was 21.5 months. Preoperative hand function was a useful predictor of recovery of elbow flexion. CONCLUSIONS: Medial pectoral nerve to MCN neurotization is a valid surgical option for the reinnervation of the biceps muscle for birth-related brachial plexus palsy when the hand is functional preoperatively. Useful elbow flexion can be expected in the majority of these children.

Pediatric CI therapy for stroke-induced hemiparesis in young children.

In this laboratory we have developed a set of techniques that randomized controlled studies and a multisite randomized controlled trial have shown can substantially reduce the motor deficit of adult patients with mild to severe chronic strokes. Equivalent results have been obtained with adult patients after traumatic brain injury and brain resection. The basic technique, termed Constraint-Induced Movement therapy or CI therapy was derived directly from basic research with monkeys with mature motor systems and with monkeys given surgical intervention either on their day of birth or prenatally by intrauterine surgical procedures. We report here the results of two randomized controlled trials of CI therapy with young children with asymmetric upper extremity motor deficits of varied etiologies from 8 months to 8 years of age in one study and with children with hemiparesis consequent to prenatal, perinatal, or early antenatal stroke from 2 to 6 years old in a second study. The procedures used with children are very similar to those used with adults and diverge simply to make the basic techniques age-appropriate. All forms of CI therapy for the upper extremity to date involve 3 main elements: (1) intensive training of the more affected extremity, (2) prolonged restraint of the less affected extremity, (3) a 'transfer package' of techniques to induce transfer of therapeutic gains achieved in the laboratory to the life situation. The results in children with cerebral palsy are considerably better than those obtained in adults. Marked changes were observed in the quality of movement in the laboratory scored by masked observers from videotape; actual amount of use of the more affected arm in the life situation; active range of motion; and emergence of new classes of behaviour never performed before, such as in individual cases, fine thumb-forefinger grasp, supination, and use of the more affected extremity in crawling with palmar placement and rhythmic alteration. In the second experiment, the control group, after receiving usual and customary care for 6 months, was crossed over to receive CI therapy and exhibited results that were as good as those for the children receiving CI therapy first. Retention of treatment gains was approximately 70% at 6 months after the end of treatment. For some children there was no decrement in retention while for others there was a marked drop-off. One of the important factors contributing to good retention was the compliance of parents with the recommended post-treatment regimen. When retention is poor, brush-up periods may be of value. In the first experiment children were treated for 6 hr/day for 21 consecutive days, while in the second experiment treatment occurred only on the weekdays of the 3-wk treatment period (15 days). The results were at least as good with 15 days of treatment as with 21 consecutive days, thereby allowing the protocol to be fit into the usual therapist work week and making it more practical and less expensive for clinical use. CI therapy does not make movement normal in children with cerebral palsy with asymmetric upper extremity motor disorders. However, as carried out in this laboratory, it can produce a substantial improvement in a majority of cases.

Scheduled oral analgesics and the need for opiates in children following partial dorsal rhizotomy.

OBJECT: Postoperative epidural morphine is commonly used to control pain in children following dorsal rhizotomy for spasticity. The authors report their experience in using a regimen of scheduled minor analgesic drugs to manage postoperative pain, with the goal of avoiding opiate use following a spinal intradural procedure. METHODS: Postoperative pain scores were analyzed in a group of 22 children who underwent a partial dorsal rhizotomy. According to a preestablished standard regimen for postoperative pain control after dorsal rhizotomy, in each patient an intraoperative epidural catheter was placed for the potential infusion of postoperative morphine. Additionally, this cohort underwent a scheduled regimen of acetaminophen (10 mg/kg) and ibuprofen (10 mg/kg), alternating every 2 hours. For comparison, a retrospective chart review was performed in 20 patients with rhizotomies completed prior to the use of this oral analgesic protocol. Only one patient received a postoperative dose of morphine epidurally. None of the remaining patients required postoperative epidural morphine for pain control. Pain scores were significantly lower in this group compared with a retrospective review of patients treated according to the standard regimen. Length of hospital stay was shorter in these patients and antiemetic requirements were lower. CONCLUSIONS: A regimen of minor analgesic therapy, when given in alternating doses every 2 hours immediately after partial dorsal rhizotomy for spasticity and throughout hospitalization, significantly reduced postoperative pain scores, hospitalization, and antiemetic requirements in these patients.

Intensive pediatric constraint-induced therapy for children with cerebral palsy: randomized, controlled, crossover trial.

A randomized crossover trial of a new form of pediatric rehabilitation was conducted with 18 children with hemiparesis. Half were randomly assigned to receive pediatric constraint-induced therapy involving constraint of the functional upper extremity and intensive therapy with the hemiparetic upper extremity. Controls received conventional physical and occupational therapy and then were crossed over to receive pediatric constraint-induced therapy. Pediatric constraint-induced therapy produced significantly greater gains than conventional rehabilitation services.

Acquired Chiari I malformation following baclofen pump placement in a child. Case report.

The authors present a case of a child suffering from shunt-treated hydrocephalus and spastic quadriplegia who underwent surgery for placement of a baclofen pump. Magnetic resonance (MR) imaging performed prior to pump placement demonstrated no hindbrain herniation. Afterward, however, the patient exhibited symptoms of brainstem compression, and MR imaging revealed a significant Chiari I malformation along with a fully functioning ventriculoperitoneal shunt. Posterior fossa decompression was performed, and the patient's symptoms abated. The authors believe this to be the first report of an acquired Chiari I malformation in a patient with a baclofen pump. Clinicians should consider Chiari I malformation as a rare but severe complication of baclofen pump placement.