Sex differences in choice-based thermal nociceptive tests in adult rats.

Interest in the role of sex as a biological variable has increased, including a mandate for the study of both sexes in NIH-funded research. As sex differences exist in both human chronic pain conditions and rodent models of nociception, it is critical to understand the impact of sex in nociceptive assays. Choice-based thermal nociceptive tests permit the study of avoidance responses to thermal stimuli compared to traditional nociceptive assays, which measure nocifensive reactions. However, to date no comparison of male and female responses to choice-based tests has been published. Herein, we examined the effect of sex on two choice-based thermal nociceptive tests, the thermal gradient test and the temperature place preference test, in adult rats. The activation of a 10 °C-to-47 °C thermal gradient results in an increase in time spent in the 10 °C zone in females, compared to a reduction in males. Additionally, in a temperature place preference test pairing a surface temperature of 22 °C with either 5 °C, 10 °C, 47 °C, or 50 °C, females appeared to have overall greater tolerance for non-ambient temperatures. Males spent less than 50% of their time in every non-22 °C zone, whereas in females this was only observed when testing 5 °C and 50 °C. Together, these results suggest that male rats show more avoidance behavior than females to both hot and cold non-ambient temperatures when given free access to multiple zones, including at milder temperatures than those typically used to evoke a nociceptive response in traditional hot and cold plate tests.

Surprising interobserver and intra-observer variability in pediatric testicular ultrasound volumes.

INTRODUCTION: Testicular volume (TV) can be obtained by either scrotal ultrasound (SU) or orchidometer. Scrotal ultrasound allows for a more objective measurement; however, the interobserver and intra-observer variability of TV measurements has not been rigorously studied. OBJECTIVE: The authors measured intra-observer and interobserver variability of SU TV measurements in pediatric patients to assess the reliability and reproducibility of SU. Special attention was paid to how often a 20% discrepancy in TV was noted as this has previously been utilized as an indication for varicocelectomy. DESIGN: Patients with an indication for SU or undergoing an ultrasound for another reason were prospectively recruited. Two different urologic specific ultrasound technicians (A and B) performed SU to assess interobserver variability. A second measurement was taken by technician A within 90 days to assess intra-observer variability (A vs A1). The technicians were blinded to other ultrasound results. RESULTS: Fourteen patients (28 testes, 56 volume measurements) were included in the intra-observer group and 17 patients (34 testes, 68 volume measurements) in the interobserver group. The mean time to repeat intra-observer ultrasound measurements (range) was 46 days (23-84). Mean age (range) in the intra-observer group was 14.3 years (11-19) and 14.1 years (11-19) in the interobserver group. Indication for ultrasound was varicocele (n = 6), scrotal pain (4), hydronephrosis (3), hydrocele (2), epididymal cyst (2), posterior urethral valves (1), and testis asymmetry (1). Utilizing Bland-Altman analysis and plots, variability was seen in both intra-observer and interobserver measurements. The mean values for testicular sizes for technician A and technician B were 13.0 ± 9.7 cm3 vs 13.8 ± 9.9 cm3, respectively. The mean values for TV measurement for technician A's first and second measurements (A, A1) were 14.3 ± 9.7 cm3 and 14.8 ± 8.9 cm3, respectively. An errant 20% difference in TV measurements for the same testis was seen in 25% (7 of 28) of intra-observer measurements and 35% (12 of 34) of interobserver measurements. These 20% differences were more common with a lower body mass index (odds ratio, OR = 0.74, p = 0.01) in the interobserver group, and lower TV was a predictor in the intra-observer group (OR: 0.82, p = 0.009). CONCLUSIONS: Variability exists in both interobserver and intra-observer measurements of TV by dedicated urologic ultrasonographers, and greater than 20% of differences in measured TV in same testicles occurred in over 25% of cases. Caution should be exercised in basing operative decisions and scientific studies on limited measurements of TV.

Role of maternal elimination diets and human milk IgA in the development of cow's milk allergy in the infants.

BACKGROUND: The role of maternal avoidance diets in the prevention of food allergies is currently under debate. Little is known regarding the effects of such diets on human milk (HM) composition or induction of infant humoral responses. OBJECTIVE: To assess the association of maternal cow's milk (CM) avoidance during breastfeeding with specific IgA levels in HM and development of cow's milk allergy (CMA) in infants. METHODS: We utilized HM and infant serum samples from a prospective birth cohort of 145 dyads. Maternal serum and HM samples were assessed for casein and beta-lactoglobulin (BLG)-specific IgA and IgG by ELISA; 21 mothers prophylactically initiated a strict maternal CM avoidance diet due to a sibling's history of food allergy and 16 due to atopic eczema or regurgitation/vomiting seen in their infants within the first 3 months of life. Infants' sera were assessed for casein and BLG-specific IgG, IgA and IgE; CMA was confirmed by an oral food challenge. The impact of HM on BLG uptake was assessed in transcytosis assays utilizing Caco-2 intestinal epithelial cell line. RESULTS: Mothers avoiding CM had lower casein- and BLG-specific IgA in HM than mothers with no CM restriction (P = 0.019 and P = 0.047). Their infants had lower serum casein- and BLG-specific IgG(1) (P = 0.025 and P < 0.001) and BLG-specific IgG(4) levels (P = 0.037), and their casein- and BLG-specific IgA levels were less often detectable than those with no CM elimination diet (P = 0.003 and P = 0.007). Lower CM-specific IgG4 and IgA levels in turn were associated with infant CMA. Transcytosis of BLG was impaired by HM with high, but not low levels of specific IgA. CONCLUSIONS: Maternal CM avoidance was associated with lower levels of mucosal-specific IgA levels and the development of CMA in infants. CLINICAL RELEVANCE: HM IgA may play a role in preventing excessive, uncontrolled food antigen uptake in the gut lumen and thereby in the prevention of CMA.

KLF8 promotes human breast cancer cell invasion and metastasis by transcriptional activation of MMP9.

Epithelial to mesenchymal transition (EMT) and extracellular matrix degradation are critical for the initiation and progression of tumor invasion. We have recently identified Krüppel-like factor 8 (KLF8) as a critical inducer of EMT and invasion. KLF8 induces EMT primarily by repressing E-cadherin transcription. However, how KLF8 promotes invasion is unknown. Here, we report a novel KLF8-to- matrix metalloproteinase (MMP)9 signaling that promotes human breast cancer invasion. To identify the potential KLF8 regulation of MMPs in breast cancer, we established two inducible cell lines that allow either KLF8 overexpression in MCF-10A or knockdown in MDA-MB-231 cells. KLF8 overexpression induced a strong increase in MMP9 expression and activity as determined by quantitative real-time PCR and zymography. This induction was well correlated with the MMP inhibitor-sensitive Matrigel invasion. Conversely, KLF8 knockdown caused the opposite changes that could be partially prevented by MMP9 overexpression. Promoter-reporter assays and chromatin and oligonucleotide precipitations determined that KLF8 directly bound and activated the human MMP9 gene promoter. Three-dimensional (3D) glandular culture showed that KLF8 expression disrupted the normal acinus formation, which could be prevented by the MMP inhibitor, whereas KLF8 knockdown corrected the abnormal 3D architecture, which could be protected by MMP9 overexpression. KLF8 knockdown promoted MDA-MB-231 cell aggregation in suspension culture, which could be prevented by MMP9 overexpression. KLF8 knockdown inhibited the lung metastasis of MDA-MB-231 cells in nude mice. Immunohistochemical staining strongly correlated the co-expression of KLF8 and MMP9 with the patient tumor invasion, metastasis and poor survival. Taken together, this work identified the KLF8 activation of MMP9 as a novel and critical signaling mechanism underlying human breast cancer invasion and metastasis.

Sodium channel currents in rat hippocampal NG2 glia: characterization and contribution to resting membrane potential.

We have recently reported that most of NG2 glycoprotein expressing glial cells, or NG2 glia, in rat hippocampus persistently express sodium channel currents (I(Na)) during development, but little is known about its function. We report here that hippocampal NG2 glia recorded in either acute slices or freshly isolated preparations from postnatal days (P) 7-21 rats express low density I(Na) (9.5-15.7 pA/pF) that is characterized by a fast activation and rapid inactivation kinetics with a tetrodotoxin (TTX) IC(50) value of 39.3 nM. The I(Na) expression correlated with a approximately 25 mV more depolarized resting membrane potential (RMP) as compared with non-I(Na)-expressing GLAST(+) astrocytes in situ at the same age. In the presence of the sodium channel blocker TTX (0.1 microM), these depolarized RMPs were negatively shifted by an average of 19 mV and 16 mV for I(Na)-expressing glia recordings from in situ and freshly isolated preparations, respectively. The I(Na) expressing glia actually showed a positive RMP (+12 mV) in the absence of potassium conductance that was inhibited to 0 mV by 0.1 microM TTX. Analysis of the I(Na) activation/inactivation curves yields an I(Na) "window current" at -40+/-20 mV, implying a persistent I(Na) component being active around the NG2 glia RMP of approximately -45 mV. According to the constant-field equation analysis, this active I(Na) component leads to a pNa/pK ratio of 0.14 at RMP which is approximately threefold higher than astrocytes (0.05). These results indicate that a TTX sensitive I(Na) component in NG2 glia contributes significantly to the depolarized NG2 glia RMP in the developing brain.

Longitudinal outcome of Parkinson's disease patients with psychosis.

OBJECTIVES: To examine the long-term outcome of PD patients with psychosis requiring antipsychotic therapy; to explore predictors of mortality, nursing home placement, dementia, and persistent psychosis; and to compare outcomes of those with persistent psychosis vs those whose psychosis resolved. METHODS: Baseline data available from 59 patients enrolled in the PSYCLOPS (PSychosis and CLOzapine in PD Study) trial included age, age at onset of PD, duration of PD and psychosis, character of psychosis, medications, living setting, and scores for Mini-Mental State Examination (MMSE), Unified Parkinson's Disease Rating Scale, Hoehn and Yahr Scale, and Clinical Global Impression Scale. Longitudinal data were collected 26 months later regarding four outcomes: death, nursing home placement, diagnosis of dementia, and persistence of psychosis. Logistic regression was used to explore whether any baseline characteristics were associated with an increased likelihood of one of these outcomes. RESULTS: At baseline, 56% of patients had an MMSE score of <25, 12% were in a nursing home, 95% had hallucinations, and 60% had paranoia. On follow-up, 25% were dead, nursing home placement occurred in 42%, psychosis was persistent in 69%, and dementia was diagnosed in 68%. Select baseline characteristics predicted individual outcomes: Nursing home placement was associated with the presence of paranoia and older age; persistent psychosis was associated with younger age at onset of PD and longer disease duration; dementia was associated with older age at PD onset and lower initial MMSE score; no characteristics predicted death. Whether psychosis persisted or not had no significant effect on the development of the other three outcomes. The prevalence of hallucinations at follow-up was not different between groups currently receiving antipsychotics vs those on no treatment. CONCLUSIONS: Psychosis in PD requiring antipsychotic therapy is frequently associated with death, nursing home placement, development and progression of dementia, and persistence of psychosis. Still, it appears the prognosis has improved with atypical antipsychotic therapy based on the finding that 28% of NH patients died within 2 years compared with 100% in a previous study done prior to availability of this treatment.

Diuretic renogram clearance half-times in the diagnosis of obstructive uropathy: effect of age and previous surgery.

Diuretic renography with radiotracers has been used successfully to diagnose obstruction in patients with hydronephrosis. Controversy persists with regard to the best approach for the interpretation of renogram curves: visual analysis or a quantitative index, i.e. the clearance half-time. The latter is often reported to be in the intermediate or non-diagnostic range. It is important to measure the incidence of equivocal half-times in various subsets of patients with hydronephrosis in order to determine in which settings the measurement of this index may be clinically useful. We performed a retrospective study of diuretic renograms performed at our institution between 1997 and 2000 for the evaluation of suspected uretero-pelvic junction (UPJ) obstruction. Vigorous intravenous hydration, exceeding current guidelines, was employed in these patients. Three hundred and seventy-seven renogram curves in 205 patients were analysed. Patients were divided into three groups: >1 year of age; 20 min) or intermediate (half-time, 10-20 min). In patients >1 year of age, 37% of 101 renograms showed normal half-times before furosemide, 20% showed normal half-times after furosemide, 44% showed prolonged half-times and none (0%) showed an intermediate half-time. In patients 1 year. Caution is advised when interpreting this finding in this age group. The measurement of washout was less useful in patients who had undergone a corrective procedure, because of the high rate of 'indeterminate' and 'abnormal' values in spite of successful surgery. Vigorous intravenous hydration, exceeding current standards, may have contributed to the lower incidence of intermediate half-times than reported previously.

Influence of diagnostic and therapeutic doses on thyroid remnant ablation rates.

Radioiodine ablation of thyroid tissue after subtotal thyroidectomy has been shown to decrease recurrence in certain subsets of patients with well-differentiated thyroid cancer. In a substantial percentage of cases (20-30%), initial ablation of the thyroid remnant fails, necessitating a second treatment. The factors associated with ablation failure are not fully understood. In particular, it is not certain whether the use of doses higher than 3.70 GBq would result in any additional benefit, or whether there is a 'stunning' effect of the diagnostic dose of 131I on the subsequent ablation rate. A retrospective analysis was performed of all patients (n=389) with well-differentiated thyroid cancer treated at our institution between 1992 and 2001. Remnant ablation success was determined by a whole-body radioiodine scan. The following factors, thought to be associated with thyroid remnant ablation, were studied by logistic regression analysis: age, gender, tumour histology, stage, pre-therapy neck uptake of 131I, diagnostic dose, ablation dose, time between diagnostic and therapeutic dose (T1), time between therapeutic administration and the first follow-up whole-body scan (T2) and the thyroid-stimulating hormone (TSH) level measured at the time of therapy. Follow-up whole-body scans were available in 214 patients. We found no association with age, gender, histology, TSH level, neck uptake, diagnostic dose and successful ablation. The therapeutic dose was the only variable found to be associated with success (odds ratio, 1.96 per 1.85 GBq increment; 95% confidence interval, 1.11-3.46). Our results confirm the presence of a significant percentage of ablation failures (24.4%) despite the use of high ablative doses (3.70-7.40 GBq). Higher therapeutic doses are associated with higher rates of successful ablation, even when administered to patients with more advanced stages. Using our protocol, higher diagnostic doses were not associated with higher rates of ablation failure.

Long-term comparative experience with tolcapone and entacapone in advanced Parkinson's disease.

The objective of this study was to compare the long-term tolerability and efficacy of tolcapone and entacapone in patients with fluctuating Parkinson's disease (PD). Tolcapone and entacapone are two currently available catechol- O -methyltransferase inhibitors that have demonstrated efficacy in the treatment of advanced PD. There are little published data on long-term experience and no direct comparisons. We compared the results of two separate, simultaneous, long-term open label extensions, one for tolcapone and the other for entacapone. The inclusion/exclusion criteria were similar. Data were collected prospectively at 6, 12, 24, and 36 months. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS) total score, subscores, items 32 (duration of dyskinesia) and 39 (duration of "off" time), and levodopa dose. The two groups were compared using a Mann-Whitney U test for change from baseline and analysis of variance. Tolerability was defined as the ability of patients to maintain therapy and was compared using a Kaplan-Meier analysis. Eleven patients enrolled in the entacapone study and 14 in the tolcapone study. The tolcapone group had more severe disease with significantly higher UPDRS motor score, duration of "off," and levodopa dose requirement. Tolcapone was more effective in lowering UPDRS motor and complication subscores, duration of "off" time, and levodopa doses. UPDRS motor scores and change in levodopa dose in the tolcapone group remained below baseline level for 36 months; however, they were above baseline in the entacapone group from 6 months on. Tolerability was the same for both treatments. Tolcapone appears to have greater and longer efficacy with regard to motor symptoms, "off" time, and change in levodopa requirements than entacapone. These findings indicate that tolcapone continues to have a place in the treatment of advanced PD. However, the risks associated with this drug, particularly hepatic injury, and the requirement for rigorous blood monitoring, need to be considered when choosing an appropriate treatment for patients with advanced PD.

Outcome of adolescent trauma admitted to an adult surgical intensive care unit versus a pediatric intensive care unit.

BACKGROUND: Institutional protocol designates the adult trauma service as the primary manager of all adolescent traumas (age 14-18 years) unless admission to the pediatric intensive care unit (PICU) occurs. In the PICU, primary care becomes the responsibility of the pediatric intensivist, with trauma service as a consultant. The purpose of this study was to identify differences in the management of adolescent trauma between the pediatric intensivist in the PICU, and the adult trauma team in the surgical intensive care unit (SICU). METHODS: From January 1993 to January 1998, the medical records of all adolescent trauma patients requiring intensive care unit (ICU) management were reviewed. Depending on bed availability, patients younger than 16 were admitted to the PICU, and those 16 or older to the SICU. Demographic data obtained were age, sex, race, mechanism of injury, length of stay (LOS), ICU length of stay, days on mechanical ventilation, intubation, tracheotomy, intracranial pressure monitor, and Swan-Ganz catheter placement. Home discharge, rehabilitation placement, and death were recorded. Morbidity was measured using Injury Severity Score methodology, Pediatric Trauma Score, and Pediatric Risk of Mortality. RESULTS: One hundred nine completed records were reviewed (SICU, n = 58; PICU, n = 51). There was no statistical difference in sex, race, mechanism of injury, ICU LOS, tracheotomy, and intracranial pressure monitor placements. There was no difference in morbidity, as measured by Injury Severity Score, Pediatric Trauma Score, and Pediatric Risk of Mortality score or in outcome measurements (death, rehabilitation placement). SICU patients were older (SICU, 16.9 +/- 1.0 years; PICU, 15.4 +/- 1.0 years; p < or = 0.1 Mann-Whitney U test), more likely to be intubated (SICU, n = 42; PICU, n = 24; p < or = 0.05 Fisher's exact test), more likely to have pulmonary artery catheter placement (SICU, n = 7; PICU, n = 0), and had longer LOS (SICU, 12.2 +/- 10.6; PICU, 9.8 +/- 14.1; p < or = 0.03 Mann-Whitney U test). CONCLUSION: Adolescent trauma patients admitted to the PICU were less likely to be intubated or have a Swan-Ganz catheter placed. They had decreased LOS and days of mechanical ventilation. There was no difference in outcome measurements.

Preoperative risk assessment for gastrostomy tube placement in head and neck cancer patients.

BACKGROUND: The presentation and definitive surgical treatment of head and neck malignancies have varying impact on postoperative recovery and return of swallowing function, which heretofore has not been well defined. METHODS: We performed a retrospective chart review of 142 patients who underwent extirpative surgery for head and neck cancer. RESULTS: Factors significantly associated with the need for long-term postoperative nutritional support (p < .05) included heavy alcohol use, tongue base involvement and surgery, pharyngectomy, composite resection, reconstruction with a myocutaneous flap, radiation therapy, tumor size, and moderately-to-poorly differentiated histology. Heavy alcohol users were at an absolute risk for gastrostomy tube dependence; patients who underwent radiation therapy, flap reconstruction, tongue base resection, and pharyngectomy were at a two to sevenfold increased risk for gastrostomy tube dependence, respectively. CONCLUSIONS: High-risk patients based on these criteria should receive a feeding gastrostomy at the time of their initial surgical therapy.

Tamoxifen inhibits nitrotyrosine formation after reversible middle cerebral artery occlusion in the rat.

Tamoxifen (TAM), a widely used non-steroidal anti-estrogen, has recently been shown to be neuroprotective in a rat model of reversible middle cerebral artery occlusion (rMCAo). Tamoxifen has several potential mechanisms of action including inhibition of the release of excitatory amino acids (EAA) and nitric oxide synthase (NOS) activity. The question addressed in this study was whether TAM reduces ischemia-induced production of nitrotyrosine, considered as a footprint of the product of nitric oxide and superoxide, peroxynitrite. In rat brain, 2 h rMCAo produced a time-dependent increase in nitrotyrosine content in the cerebral cortex, as measured by Western blot analysis. Compared with vehicle, TAM significantly reduced nitrotyrosine levels in the ischemic cortex at 24 h. The neuronal (n)NOS inhibitor, 7-nitroindazole also tended to reduce nitrotyrosine, but this reduction was not statistically significant. Immunostaining for nitrotyrosine was seen in cortical neurons in the MCA territory and this immunostaining was reduced by TAM. In vitro, TAM and the calmodulin inhibitor trifluoperazine inhibited, with similar EC(50) values, the activity of recombinant nNOS as well as NOS activity in brain homogenates, measured by conversion of [(3)H]arginine to [(3)H]citrulline. There was marginal inhibition of recombinant inducible (i)NOS activity up to 100 microM TAM. These data suggest that TAM is an effective inhibitor of Ca(2+)/calmodulin-dependent NOS and the derived peroxynitrite production in transient focal cerebral ischemia and this may be one mechanism for its neuroprotective effect following rMCAo.

Acute treatment with tamoxifen reduces ischemic damage following middle cerebral artery occlusion.

Inhibitors of cell-swelling-activated anion channels, including the antiestrogenic compound tamoxifen (TAM), have been shown to attenuate the increase in excitatory amino acids (EAA) during ischemia. Since TAM enters the CNS we tested whether it provides protection from damage due to reversible middle cerebral artery occlusion (rMCAo) in rats. TAM (5 mg/kg, i.v.) infused 25 min before ischemia, potently reduced the total volume of the infarct from 328 +/- 34 mm3 to 41 +/- 21 mm3, a reduction of 87%, as measured by TTC staining. It was equally effective when infused starting at 1 h after reperfusion, i.e. 3 h after initiation of rMCAo. Protection of neurons was also found histologically. TAM had no effect on CBF as measured by hydrogen clearance. This appears to be the first report of a marked neuroprotective effect of TAM. Further studies are needed to determine whether its effects are due to inhibition of EAA release and/or other potential neuroprotective sites of action.

Comparison of power-assisted adenoidectomy vs adenoid curette adenoidectomy.

OBJECTIVE: To compare the safety and efficacy of power-assisted adenoidectomy (PAA) vs adenoid curette adenoidectomy (ACA). DESIGN: A prospective randomized study. SETTING: Children's hospital of a tertiary care medical center. PATIENTS: Ninety patients (aged 1-13 years) underwent PAA, and 87 patients (aged 1-12 years) underwent ACA. MAIN OUTCOME MEASURES: The parameters evaluated were operative time, blood loss, completeness and depth of resection, injuries to surrounding structures, short- and long-term complications, surgeon satisfaction with the procedure, and parents' assessment of the patient's postoperative recovery period. RESULTS: The PAA was 20% faster (P<.001) and had 27% less blood loss (P<.001) than the ACA. It provided a more complete resection(P<.001) and better control of the depth of resection (P<.05). Surgeon satisfaction was greater with PAA (P<.001). There was no difference in the recovery period or parent satisfaction. One patient in the PAA group returned to the operating room for control of postoperative bleeding, and 1 child in the ACA group returned to the hospital for postoperative dehydration. CONCLUSION: The PAA provides a faster, dryer, more complete, and more surgically satisfying resection than the ACA.

Workforce demand for neurosurgeons in the United States of America: a 13-year retrospective study.

OBJECT: The workforce demand for neurosurgeons was quantified by a review and an analysis of journal recruitment advertisements published over the past 13 years. METHODS: A retrospective analysis of recruitment advertisements from July 1985 through June 1998 was performed by examining issues of the Journal of Neurosurgery and Neurosurgery. Advertisement information that appeared in each journal during the last 3 years was collected from alternating months (July to May); information that appeared prior to that time was collected from alternating recruitment years back to 1985. The authors examined the following workforce parameters: practice venue, subspecialization, and practice size. They found no significant decrease in neurosurgical recruitment advertisements. There was an average of 102.7+/-22.4 (standard deviation) advertised positions per year during the most recent 3 years compared with 92.6+/-17.9 advertised positions per year during the preceding decade. Similarly, there has been no decline in advertised positions either in academic (33+/-6.1/year for the most recent 3 years compared with 32.8+/-5.9/year for 1985-1995) or private practice (69.7+/-21.6/year for the most recent 3 years compared with 59.8+/-13.4/year for 1985-1995). A shift in demand toward subspecialty neurosurgery was observed. During the past 3 years, 31.2+/-5.9% of advertised positions called for subspecialty expertise, compared with 18.5+/-2.8% for the preceding decade (p < 0.05). The largest number of subspecialty advertisements designated positions for spine and pediatric neurosurgeons. Private practice advertisements increasingly sought to add neurosurgeons to group practices. CONCLUSIONS: Contrary to previous reports and a prevailing myth, our data show no decrease in workforce demand for neurosurgeons in the United States over the past 3 years compared with the prior decade. A shift toward subspecialist recruitment, particularly for spine neurosurgeons, has been demonstrated in both academic and private practice venues.

Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokinate and an anion channel blocker.

BACKGROUND AND PURPOSE: Increased activation of excitatory amino acid (EAA) receptors is considered a major cause of neuronal damage. Possible sources and mechanisms of ischemia-induced EAA release were investigated pharmacologically with microdialysis probes placed bilaterally in rat striatum. METHODS: Forebrain ischemia was induced by bilateral carotid artery occlusion and controlled hypotension in halothane-anesthetized rats. During 30 minutes of ischemia, microdialysate concentrations of glutamate and aspartate were measured in the presence of a nontransportable blocker of the astrocytic glutamate transporter GLT-1, dihydrokinate (DHK), or an anion channel blocker, 4,4'-dinitrostilben-2,2'-disulfonic acid (DNDS), administered separately or together through the dialysis probe. RESULTS: In control striata during ischemia, glutamate and aspartate concentrations increased 44+/-13 (mean+/-SEM) times and 19+/-5 times baseline, respectively, and returned to baseline values on reperfusion. DHK (1 mmol/L in perfusate; n=8) significantly attenuated EAA increases compared with control (glutamate peak, 9. 6+/-1.7 versus control, 15.4+/-2.6 pmol/ microL). EAA levels were similarly decreased by 10 mmol/L DHK. DNDS (1 mmol/L; n=5) also suppressed EAA peak increases (glutamate peak, 5.8+/-1.1 versus control, 10.1+/-0.7 pmol/ microL). At a higher concentration, DNDS (10 mmol/L; n=7) further reduced glutamate and aspartate release and also inhibited ischemia-induced taurine release. Together, 1 mmol/L DHK and 10 mmol/L DNDS (n=5) inhibited 83% of EAA release (glutamate peak, 2.7+/-0.7 versus control, 10.9+/-1.2 pmol/ microL). CONCLUSIONS: These findings support the hypothesis that both cell swelling-induced release of EAAs and reversal of the astrocytic glutamate transporter are contributors to the ischemia-induced increases of extracellular EAAs in the striatum as measured by microdialysis.

Scintigraphic detection of breast cancer xenografts with Tc-99m natural and recombinant human alpha-fetoprotein.

Because adenocarcinoma of the breast expresses receptors for alpha-fetoprotein (AFP), we studied Tc-99m AFP as a radiopharmaceutical to detect breast cancer. The biodistribution of Tc-99m radiolabeled natural human AFP (full length) and recombinant domain III (DIII) of human AFP was compared to Tc-99m sestamibi and Tl-201 in a murine model of human breast cancer. Estrogen receptor positive (MCF7, T-47D) and estrogen receptor negative (MDA-MB-231, BT-20) human breast cancer xenografts were grown subcutaneously in the lateral thorax region of immunosuppressed mice (ICR SCID). Quantitative comparisons of percent-injected dose per gram of tissue (%ID/gram) and tumor to thigh ratio (T/Th) were performed at 0-60 minutes and at 24 hours following injection. For most tumors, T/Th for AFP and DIII was significantly greater than T/Th for Tc-99m sestamibi and Tl-201. In all breast cancers (BT-20, MCF7, MDA-MB-231, T-47D), Tc-99m AFP T/Th increased from 60 minutes to 24 hours, suggesting good tumor retention of this radiopharmaceutical. DIII and AFP had significantly higher %ID/gram than either Tl-201 or Tc-99m sestamibi when considered across all tumor types at both 60 minutes and 24 hours. The data suggests that localization of Tc-99m AFP in human breast cancer xenografts is initially rapid, increases with time, and is superior to Tc-99m sestamibi and Tl-201. Given its high uptake by breast cancer cells, its low non-tumor localization and its rapid renal excretion, these Tc-99m AFP preparations may be useful agents to detect human breast carcinoma.

Clinical comparison of tardive and idiopathic cervical dystonia.

It has been suggested that tardive cervical dystonia may be clinically indistinguishable from the idiopathic form and that the diagnosis rests solely on documenting an exposure to dopamine antagonist medications. To investigate this, we performed a retrospective evaluation of patient records on 102 patients with idiopathic and 20 patients with tardive cervical dystonia seen in our Movement Disorder Clinic over the past 8 years. Several clinical and demographic variables were compared and a number of differences were observed. The presence of extracervical involvement, retrocollis, and spasmodic head movements were individually found to be predictive of tardive cervical dystonia. Torticollis, laterocollis, and trick maneuvers were predictive of idiopathic cervical dystonia. Head tremor (42.2%) and family history of dystonia (9.8%) were present only in the idiopathic group. Cervical muscle hypertrophy was significantly more common in the idiopathic group (100% versus 75%). No difference was found between the two groups in their response to treatment with botulinum toxin A. These results indicate that clinical differences between idiopathic and tardive cervical dystonia exist. These differences may help to distinguish them in the clinical setting, improve diagnostic accuracy, and support the existence of a causal relationship between exposure to dopamine antagonist medications and chronic dystonia.

Effect of hyperventilation, mannitol, and ventriculostomy drainage on cerebral blood flow after head injury.

Therapies to lower intracranial pressure (ICP) after traumatic brain injury (TBI) include hyperventilation (HV), intravenous mannitol (IM), and cerebrospinal fluid drainage from a ventriculostomy (DV). To determine the effects of these therapies on cerebral blood flow (CBF), fiberoptic oximetry was used to measure jugular venous O2 saturation (SjvO2) as an index of the CBF to cerebral metabolic rate for O2 (CMRO2) ratio after IM (25 g IV for more than 5 min), DV (3 min), or HV (increase respiratory rate by 4) therapy for elevated ICP. Assuming CMRO2 is constant, changes in SjvO2 reflect changes in CBF. Continuous measurements of SjvO2, ICP, blood pressure, arterial O2 saturation, and end-tidal CO2 were obtained in 22 patients with a Glasgow Coma Scale score of 5.3 +/- 0.4 (mean +/- SD) in the first 5 days after TBI. Therapy was initiated a total of 196 times when ICP was > 15 mm Hg for > 5 minutes, and measurements made at 20 minutes after treatment were compared with those made just before. After DV, ICP fell in 90% of the observations by 8.6 +/- 0.7 mm Hg (mean +/- SEM, n = 119); after IM, ICP fell in 90% of the observations by 7.4 +/- 0.7 mm Hg (n = 43); and after HV, ICP fell in 88% of the observations by 6.3 +/- 1.2 mm Hg (n = 14). In patients where ICP fell, SjvO2 increased by 2.49 +/- 0.7% saturation (from 68.0 +/- 1.3%) with IM, but only by 0.39 +/- 0.4% saturation (from 67.2 +/- 0.9%) with DV.(ABSTRACT TRUNCATED AT 250 WORDS)

Orbital fractures in children.

OBJECTIVE: To determine if the pattern of orbital fractures may be influenced by the changing craniofacial ratio of the growing child, as the orbit is the boundary between the face and the cranium. DESIGN: Retrospective case series of 40 patients between the ages of 1 year and 16 years with orbital fractures. SETTING: The Albany (NY) Medical Center Hospital, a tertiary level 1 trauma center. OUTCOME MEASURES: The sex, age, site, and mechanism of injury, associated injury, and treatment methods for children admitted to the Albany Medical Center Hospital with orbital fractures between July 1986 and June 1992. RESULTS: Fourteen children had fractures of the orbital roof, 10 children had fractures of the orbital floor, 14 children had mixed fractures, and two children had fractures of the medial wall. The mean age (4.8 +/- 3.3 years) of the 14 patients with roof fractures was significantly less than the mean age (12.0 +/- 4.2 years) of the 26 children with other orbital fractures. Logistic regression demonstrated that the age at which the probability of lower orbital fractures exceeds the probability of orbital roof fractures is 7.1 +/- 1.0 years. Orbital roof fractures had a significantly greater likelihood of associated neurocranial injuries. The need for surgical repair was significantly lower among children with roof fractures as well as among children 7 years of age and younger. CONCLUSIONS: Orbital roof fractures are a type of skull fracture that occur primarily in younger children as a consequence of the proportionally larger cranium and the lack of frontal sinus pneumatization. Lower orbital fractures are a type of facial fracture that occur primarily in older children as a consequence of the increased vulnerability of the face due to growth and the pneumatization of the paranasal sinuses.