Cervical medullary syndrome secondary to craniocervical instability and ventral brainstem compression in hereditary hypermobility connective tissue disorders: 5-year follow-up after craniocervical reduction, fusion, and stabilization.

A great deal of literature has drawn attention to the "complex Chiari," wherein the presence of instability or ventral brainstem compression prompts consideration for addressing both concerns at the time of surgery. This report addresses the clinical and radiological features and surgical outcomes in a consecutive series of subjects with hereditary connective tissue disorders (HCTD) and Chiari malformation. In 2011 and 2012, 22 consecutive patients with cervical medullary syndrome and geneticist-confirmed hereditary connective tissue disorder (HCTD), with Chiari malformation (type 1 or 0) and kyphotic clivo-axial angle (CXA) enrolled in the IRB-approved study (IRB# 10-036-06: GBMC). Two subjects were excluded on the basis of previous cranio-spinal fusion or unrelated medical issues. Symptoms, patient satisfaction, and work status were assessed by a third-party questionnaire, pain by visual analog scale (0-10/10), neurologic exams by neurosurgeon, function by Karnofsky performance scale (KPS). Pre- and post-operative radiological measurements of clivo-axial angle (CXA), the Grabb-Mapstone-Oakes measurement, and Harris measurements were made independently by neuroradiologist, with pre- and post-operative imaging (MRI and CT), 10/20 with weight-bearing, flexion, and extension MRI. All subjects underwent open reduction, stabilization occiput to C2, and fusion with rib autograft. There was 100% follow-up (20/20) at 2 and 5 years. Patients were satisfied with the surgery and would do it again given the same circumstances (100%). Statistically significant improvement was seen with headache (8.2/10 pre-op to 4.5/10 post-op, p < 0.001, vertigo (92%), imbalance (82%), dysarthria (80%), dizziness (70%), memory problems (69%), walking problems (69%), function (KPS) (p < 0.001). Neurological deficits improved in all subjects. The CXA average improved from 127° to 148° (p < 0.001). The Grabb-Oakes and Harris measurements returned to normal. Fusion occurred in 100%. There were no significant differences between the 2- and 5-year period. Two patients returned to surgery for a superficial wound infections, and two required transfusion. All patients who had rib harvests had pain related that procedure (3/10), which abated by 5 years. The results support the literature, that open reduction of the kyphotic CXA to lessen ventral brainstem deformity, and fusion/stabilization to restore stability in patients with HCTD is feasible, associated with a low surgical morbidity, and results in enduring improvement in pain and function. Rib harvest resulted in pain for several years in almost all subjects.

Resting connectivity predicts task activation in pre-surgical populations.

Injury and disease affect neural processing and increase individual variations in patients when compared with healthy controls. Understanding this increased variability is critical for identifying the anatomical location of eloquent brain areas for pre-surgical planning. Here we show that precise and reliable language maps can be inferred in patient populations from resting scans of idle brain activity. We trained a predictive model on pairs of resting-state and task-evoked data and tested it to predict activation of unseen patients and healthy controls based on their resting-state data alone. A well-validated language task (category fluency) was used in acquiring the task-evoked fMRI data. Although patients showed greater variation in their actual language maps, our models successfully learned variations in both patient and control responses from the individual resting-connectivity features. Importantly, we further demonstrate that a model trained exclusively on the more-homogenous control group can be used to predict task activations in patients. These results are the first to show that resting connectivity robustly predicts individual differences in neural response in cases of pathological variability.

Evaluation of tizanidine as a marker of canine CYP1A2 activity.

The dog CYP1A2 enzyme is likely an important contributor to the metabolism of veterinary drugs. Dog CYP1A2 is expressed in liver, plus it is inducible and polymorphic, creating the potential for intersubject differences in pharmacokinetics. Hence, the ability to probe dog CYP1A2 activity and inhibition is relevant toward veterinary drug development and drug-drug interaction assessment. Previous studies have relied on human probes with questionable specificity for CYP1A2, so it was hypothesized that recombinant CYP1A2 could be used to find a specific CYP1A2 substrate. Intrinsic clearance experiments demonstrated that tizanidine was a substrate of CYP1A2. Profiling of tizanidine metabolites generated by CYP1A2 identified the imidazole metabolite that was detectable in dog plasma. The imidazole metabolite was subsequently used to evaluate tizanidine as a CYP1A2 probe. Co-administration of the CYP1A inhibitor enrofloxacin with tizanidine significantly decreased (30%; n = 3) the formation of the imidazole metabolite vs. control experiments. As enrofloxacin is a weak inhibitor, further studies are required to confirm the sensitivity of tizanidine as an in vivo probe. However, tizanidine may be a more selective CYP1A2 probe than phenacetin when conducting in vitro studies due to the presence of other phenacetin-metabolizing enzymes in dog liver microsomes.

Inhibition of airway hyper-responsiveness by TRPV1 antagonists (SB-705498 and PF-04065463) in the unanaesthetized, ovalbumin-sensitized guinea pig.

BACKGROUND AND PURPOSE Airway sensory nerves play a key role in respiratory cough, dyspnoea, airway hyper-responsiveness (AHR), all fundamental features of airway diseases [asthma and chronic obstructive pulmonary disease (COPD)]. Vagally mediated airway reflexes such as cough, bronchoconstriction and chest tightness originate from stimulation of airway sensory nerve endings. The transient receptor potential vanilloid 1 receptor (TRPV1) is present on peripheral terminals of airway sensory nerves and modulation of its activity represents a potential target for the pharmacological therapy of AHR in airway disease. EXPERIMENTAL APPROACH As guinea pig models can provide some of the essential features of asthma, including AHR, we have established the model with some classical pharmacological agents and examined the effect of the TRPV1 antagonists, SB-705498 and PF-04065463 on AHR to histamine evoked by ovalbumin (OA) in unanaesthetized sensitized guinea pigs restrained in a double chamber plethysmograph. Specific airway conductance (sGaw) derived from the airflow was calculated as a percentage of change from baseline. KEY RESULTS Cetirizine and salbutamol significantly inhibited OA-evoked bronchoconstriction [sGaw area under the curve (AUC): 70 and 78%, respectively]. Atropine, SB-705498 and PF-04065463 significantly inhibited OA-evoked AHR to histamine in unanaesthetized, OA-sensitized guinea pigs (sGaw AUC: 94%, 57% and 73%, respectively). Furthermore, this effect was not related to antagonism of histamine's activity. CONCLUSION AND IMPLICATIONS These data suggest that TRPV1 receptors located on airway sensory nerves are important in the development of AHR and that modulation of TRPV1-receptor activity represents a potential target for the pharmacological therapy of AHR in airway disease.

Distinct right frontal lobe activation in language processing following left hemisphere injury.

Right hemisphere activation during functional imaging studies of language has frequently been reported following left hemisphere injury. Few studies have anatomically characterized the specific right hemisphere structures engaged. We used functional MRI (fMRI) with verbal fluency tasks in 12 right-handed patients with left temporal lobe epilepsy (LTLE) and 12 right-handed healthy controls to localize language-related activity in the right inferior frontal gyrus (RIFG). During the phonemic task, LTLE patients activated a significantly more posterior region of the right anterior insula/frontal operculum than healthy controls (P = 0.02). Activation of the left inferior frontal gyrus (LIFG) did not differ significantly between the two groups. This suggests that, following left hemisphere injury, language-related processing in the right hemisphere differs from that with a functionally normal left hemisphere. The localization of activation in the left and right inferior frontal gyri was determined with respect to the anatomical sub-regions pars opercularis (Pop), pars triangularis (Ptr) and pars orbitalis (Por). In the LIFG, both healthy controls (8 out of 12) and LTLE patients (9 out of 12) engaged primarily Pop during phonemic fluency. Activations in the RIFG, however, were located mostly in the anterior insula/frontal operculum in both healthy controls (8 out of 12) and LTLE patients (8 out of 12), albeit in distinct regions. Mapping the locations of peak voxels in relation to previously obtained cytoarchitectonic maps of Broca's area confirmed lack of homology between activation regions in the left and right IFG. Verbal fluency-related activation in the RIFG was not anatomically homologous to LIFG activation in either patients or controls. To test more directly whether RIFG activation shifts in a potentially adaptive manner after left hemisphere injury, fMRI studies were performed in a patient prior to and following anatomical left hemispherectomy for the treatment of Rasmussen's encephalitis. An increase in activation magnitude and posterior shift in location were found in the RIFG after hemispherectomy for both phonemic and semantic tasks. Together, these results suggest that left temporal lobe injury is associated with potentially adaptive changes in right inferior frontal lobe functions in processing related to expressive language.

Quantitative fMRI assessment of the differences in lateralization of language-related brain activation in patients with temporal lobe epilepsy.

Defining language lateralization is important to minimize morbidity in patients treated surgically for temporal lobe epilepsy (TLE). Functional magnetic resonance imaging (fMRI) offers a promising, noninvasive, alternative strategy to the Wada test. Here we have used fMRI to study healthy controls and patients with TLE in order to (i) define language-related activation patterns and their reproducibility; (ii) compare lateralization determined by fMRI with those from of the Wada test; and (iii) contrast different methods of assessing fMRI lateralization. Twelve healthy right-handed controls and 19 right-handed preoperative patients with TLE (12 left- and seven right-TLE) were studied at 3T using fMRI and a verbal fluency paradigm. A Wada test also was performed on each of the patients. Greater activation was found in several areas in the right hemisphere for the left-TLE group relative to controls or right-TLE patients. Relative hemispheric activations calculated based on either the extent or the mean signal change gave consistent results showing a more bihemispheric language representation in the left-TLE patients. There was good agreement between the Wada and fMRI results, although the latter were more sensitive to involvement of the nondominant right hemisphere. The reproducibility of the fMRI values was lowest for the more bihemispherically represented left-TLE patients. Overall, our results further demonstrate that noninvasive fMRI measures of language-related lateralization may provide a practical and reliable alternative to invasive testing for presurgical language lateralization in patients with TLE. The high proportion (33%) of left-TLE patients showing bilateral or right hemispheric language-related lateralization suggests that there is considerable plasticity of language representation in the brains of patients with intractable TLE.

RSD931, a novel anti-tussive agent acting on airway sensory nerves.

1 The anti-tussive effects, of the local anaesthetic, lidocaine and carcainium chloride (RSD931) have been investigated in guinea-pigs and rabbits. 2 Pre-treatment of guinea-pigs with aerosols of lidocaine or RSD931 at 0.1, 1.0 and 10 mg ml(-1) reduced the number of citric acid-induced coughs by 9.3, 32.6 and 40.9% (P>0.05) for lidocaine and by 25.3% (P>0.05), 40.4% (P>0.05) and 97.6% (P<0.01) for RSD931, respectively and increased the latency to onset of cough at 10.0 mg ml(-1) only. In addition, RSD931 at 10 mg ml(-1) reduced citric acid-evoked cough responses in rabbits (with prior exposure to ozone at 3 p.p.m. for 1 h) from 22.1+/-5.1 to 2.7+/-0.9 coughs (P<0.01). 3 Acute pre-treatment of guinea-pigs with aerosols of lidocaine or RSD931 at 10.0 and 30.0 mg ml(-1) reduced the number of capsaicin-evoked coughs by 42.2 and 10.3% (P>0.05) (lidocaine) and by 25% (P>0.05) and 76.9% (P<0.01) (RSD931), respectively. Lidocaine had little effect on the latency of cough onset at either 10.0 or 30.0 mg ml(-1), however, RSD at 30.0 mg ml(-1) significantly (P<0.05) prolonged the latency of cough onset. 4 RSD931 (10.0 mg ml(-1)) significantly (P<0.05-<0.01) reduced the spontaneous and histamine-evoked discharges in Adelta-fibres originating from airway, rapidly adapting stretch receptors (RARs) without affecting histamine-evoked bronchoconstriction. Lidocaine at 10.0 mg ml(-1) also significantly (P<0.05) inhibited the spontaneous and histamine-induced discharges of RARs without affecting histamine-evoked bronchoconstriction. 5 Aerosols of RSD931 (10.0 mg ml(-1)) caused a transient, but significant (P<0.05), activation of pulmonary C-fibre endings 2.5 min after administration started. RSD931 had no significant (P>0.05) effects on discharges in bronchial C-fibres originating from bronchial C-fibre endings, capsaicin-evoked discharges of either pulmonary or bronchial C-fibre endings or on capsaicin-evoked bronchoconstriction. In contrast, lidocaine (10.0 mg ml(-1)) significantly (P<0.05) inhibited spontaneous and capsaicin-induced discharges in both pulmonary and bronchial C-fibres respectively. Lidocaine also significantly (P<0.05) reduced capsaicin-evoked bronchoconstriction. 6 These studies suggest that the anti-tussive actions of RSD931 are mediated via inhibition of discharges in Adelta-fibres originating from airway RARs. The mechanism of action of RSD931 is distinct from that of the local anaesthetic lidocaine and RSD931 may represent a novel class of anti-tussive agent.

Interleukin-8 and anti-interleukin-8 autoantibodies in gingival crevicular fluid from patients with periodontitis.

Interleukin-8 (IL-8) is believed to play an important role in the pathogenesis of various forms of periodontitis. In addition, the anti-IL-8 autoantibody has been recently recognized as a potent modulator of IL-8 function. In the current study, the concentrations of IL-8 and its autoantibody in gingival crevicular fluid from patients with chronic generalized periodontitis were compared to those in gingival crevicular fluid from patients with refractory chronic periodontitis. Gingival crevicular fluids were collected from patients treated in a private periodontal clinic. Nine patients who were identified as having chronic generalized periodontitis and four with refractory chronic periodontitis were selected for the study. Patients included in the latter group had undergone supportive periodontal therapy for more than 10 years, and during that time had experienced many episodes of periodontal destruction. The gingival crevicular fluid concentrations of total protein, IL-8, free anti-IL-8 autoantibody and IL-8 bound to the autoantibody (anti-IL-8:IL-8 complexes) were examined. There were no differences in concentration of total protein, but significantly higher levels of IL-8 were detected in patients with chronic generalized periodontitis in comparison to patients with refractory chronic periodontitis (P < 0.05). In addition, anti-IL-8:IL-8 complexes were present in 90% of patients with chronic generalized periodontitis, but in only 50% of patients with refractory chronic periodontitis. The results suggest that elevated concentrations of free and complexed IL-8 can differentiate patients with chronic generalized periodontitis from patients with refractory chronic periodontitis.

Towards understanding language organisation in the brain using fMRI.

Functional magnetic resonance imaging (fMRI), which allows non-invasive mapping of human cognitive functions, has become an important tool for understanding language function. An understanding of component processes and sources of noise in the images is contributing to increased confidence in the reproductability of studies. This allows clinical applications, e.g., for pre-surgical lateralisation of language functions in patients with temporal lobe epilepsy. fMRI is a sensitive method for mapping regions involved in language functions. We recently have applied it to study the effect of word surface form on reading with a comparison of responses to Chinese characters or alphabetical Pinyin. Interpretation of fMRI activations must be made with caution; fMRI suggests task-associated activation, but does not independently confirm that such activity is necessary. However, complementary studies can be performed using transcranial magnetic stimulation (TMS), which can be used to interfere with brain activity in a specific region transiently for characterisation of the behavioural effects. We describe how TMS combined with fMRI has confirmed a role for the left inferior frontal cortex in semantic processing.

Resolution of subdiaphragmatic gas.

A woman experienced dehydration, nausea, and vomiting after laparoscopic ovarian cystectomy. Symptoms resolved with hydration and observation. Daily abdominal radiographs revealed persistence of subdiaphragmatic gas for 7 days. There were no signs of peritonitis at any time during the evaluation. When patients experience abdominal complaints after laparoscopy, a major concern is perforated bowel. Since subdiaphragmatic air can persist for up to 24 days, clinical decisions are generally made on the basis of other findings.

Air embolus associated with tubal insufflation.

A patient underwent laparoscopy for a rectovaginal mass, dysmenorrhea, and infertility. After CO(2) pneumoperitoneum was established the laparoscope was placed without difficulty. Before the procedure was completed, the tubes were insufflated with air through a 20-ml syringe attached to a Cohen cannula. Tubes were patent. No other intraabdominal manipulation was performed at that time. During tubal insufflation the patient's end-tidal CO(2) decreased to 18%, partial pressure of oxygen decreased to 83%, and pulse increased to 130/minute. The CO(2) pneumoperitoneum was released, and the woman stabilized spontaneously. The CO(2) pneumoperitoneum was again established, with no further difficulty. The time relationship with tubal insufflation and lack of recurrence on reestablishing pneumoperitoneum suggest that air embolization during tubal insufflation occurred.

Functional magnetic resonance imaging: clinical applications and potential.

Demonstration that contrast in magnetic resonance images can be generated based on differences in blood oxygenation has led to an explosion of interest in so-called functional magnetic resonance imaging (FMRI). FMRI can be used to map increases in blood flow that accompany local synaptic activity in the brain. The technique has proved remarkably sensitive and has been used to map a broad range of cognitive, motor and sensory processes in the brain entirely non-invasively. More recently, efforts have been made to extend this technique to the analysis of clinical problems. A major application is for presurgical localization of cerebral functions, e.g. in the surgical treatment of epilepsy. The technique also is beginning to provide information on functional consequences of abnormal brain development. Perhaps most exciting are applications to neurological impairments that are not associated with structural abnormalities, such as learning problems, dyslexia and movement disorders. It is possible that useful applications of FMRI may be found for directly mapping sites of action of CNS-active drugs. Although the extent of the potential clinical applications of this new brain mapping technique is not clear, the widespread availability of MRI scanners suggests that the technique should in some form soon become a routine tool in major neuroradiological centres.

Exfoliation of maxillary central incisors due to misapplication of orthodontic rubber bands.

The patient's problem consisted of a large diastema between the central incisors. The cost-cutting treatment plan recommended to the patient and his parents by the general dentist was to use orthodontic rubber bands to loop the teeth and close the diastema.

The effect of medroxyprogesterone acetate on angiogenesis in complex endometrial hyperplasia.

OBJECTIVE: To evaluate the effect of orally administered medroxyprogesterone acetate upon angiogenesis in the myometrium of patients with complex endometrial hyperplasia. METHODS: Microvessel counts in the myometrium of consecutive patients with complex endometrial hyperplasia, treated with oral medroxyprogesterone acetate prior to hysterectomy (n = 12), were compared with microvessel counts of consecutive control patients with complex endometrial hyperplasia without prehysterectomy medroxyprogesterone acetate treatment (n = 15). All specimens were stained immunohistochemically for factor VIII-related antigen as a sensitive and specific marker for vascular endothelium. Areas with the highest angiogenic intensity, within the myometrium immediately underlying complex endometrial hyperplasia, were selected. Three fields (x400) were selected for each slide, and the mean microvessel count per high-power field was calculated. Statistical analysis included factorial analysis of variance/covariance, and multiple regression analysis with P < 0.05 considered significant throughout. RESULTS: Microvessel counts of uterine specimens of patients with complex endometrial hyperplasia treated with oral medroxyprogesterone acetate were significantly lower than microvessel counts of control patients with complex endometrial hyperplasia without medroxyprogesterone acetate therapy (median 20, range 11-37 versus median 38, range 20-130, respectively, P < 0.001). CONCLUSION: Orally administered medroxyprogesterone acetate has a significant antiangiogenic effect upon myometrium immediately underlying complex endometrial hyperplasia.

A case of thyrotoxicosis with chorea: association with anti-phospholipid antibody.

We report a case of thyrotoxicosis associated with chorea and detectable anti-phospholipid antibodies in which a structural abnormality could not be detected on routine imaging but cerebral perfusion single photon emission computed tomography scans suggested a reversible alteration of basal ganglia perfusion. The pathophysiological mechanisms of phospholipid antibody causing chorea in thyrotoxicosis are discussed.

The role of central 5-HT receptors in the bronchoconstriction evoked by inhaled capsaicin in anaesthetised guinea-pigs.

The effects of intracisternal (i.c) injections of the 5-HT1A receptor agonists, buspirone and 8-OH-DPAT, and the antagonists WAY-100635; and (-)-pindolol, the 5-HT1B/1D receptor agonist sumatriptan and antagonist GR127935, the 5-HT2 receptor agonist DOI and the antagonist cinanserin, the 5-HT3 receptor antagonist granisetron, the alpha-adrenoceptor agonist clonidine and the antagonist idazoxan, the D2 receptor antagonists (-)-sulpiride and the 5-HT uptake inhibitor fluoxetine on capsaicin-evoked increase in tracheal inflation pressure (bronchoconstriction) were investigated in alpha-chloralose anaesthetised, neuromuscularly blocked, artificially ventilated guinea-pigs. Buspirone, 8-OH-DPAT and fluoxetine significantly potentiated while WAY-100635 (-)-pindolol and sumatriptan attenuated the evoked bronchoconstriction when applied i.c. Granisetron attenuated the response when applied i.v. but not when given i.c. The 5-HT2, alpha2-adrenoceptor and D2 dopamine receptor ligands did not have any significant effect on the evoked bronchoconstriction. Pretreatment i.v. with WAY-100635 alone had no effect on the capsaicin-evoked bronchoconstriction but blocked the potentiating action of i.c. buspirone. The effects of sumatriptan could be completely blocked by pretreatment i.v. with GR127935. Only DOI, in the presence (i.v.) of the peripheral acting 5-HT2 receptor antagonist BW501C67, caused a significant increase in baseline tracheal inflation pressure. It is concluded that activation of central 5-HT1A and 5-HT1B/1D receptors have opposing roles, facilitation and inhibition respectively, on the reflex activation of bronchoconstrictor vagal preganglionic neurones.

The effect of 15-HPETE on airway responsiveness and pulmonary cell recruitment in rabbits.

1. In the present study we have investigated the effect of 15-hydroperoxyeicosatetraenoic acid (15-HPETE) and 15-hydroxyeicosatetraenoic acid (15-HETE) on airway responsiveness to inhaled histamine in rabbits in vivo. 2. 15-HPETE increased airway responsiveness to histamine 24 h after tracheal instillation and this was associated with a cellular infiltration consisting mainly of neutrophils, as measured by bronchoalveolar lavage. The airway hyperresponsiveness induced by 15-HPETE was still present 72 h after tracheal instillation of 15-HPETE, but had returned to baseline values one week post challenge. The number of neutrophils in bronchoalveolar lavage remained significantly elevated compared to pre-challenge levels. In contrast to 15-HPETE, the major metabolite 15-HETE, failed to alter airway hyperresponsiveness to histamine despite the recruitment of neutrophils into the lung, suggesting that the effect of 15-HPETE was not secondary to the generation of this metabolite nor dependent on the influx of neutrophils. 3. Both capsaicin and atropine but not the peripherally acting mu-opioid receptor agonist, BW443C (H-Tyr-D-Arg-Gly-Phe(4-NO2)-Pro-NH4), attenuated 15-HPETE-induced hyperresponsiveness. The increased cellular infiltration induced by 15-HPETE was only attenuated by capsaicin. 4. The results of the present study suggest that the release of 15-HPETE into the airways could contribute to sensitization of afferent nerve endings analogous to the hyperalgesia induced by this mediator in skin.

Involvement of central 5-HT1A receptors in the reflex activation of pulmonary vagal motoneurones by inhaled capsaicin in anaesthetized cats.

1. The aim of the present experiments was to determine whether 5-HT1A receptors play a role in the control of the reflex activation of pulmonary vagal motoneurones. This was carried out by investigating the effects of intracisternal injections (i.c.) of the 5-HT1A receptor ligands, 8-OH-DPAT (50 micrograms kg-1), buspirone (200 micrograms kg-1), WAY-100635 (100 micrograms kg-1), methiothepin (200 micrograms kg-1) and (-)-pindolol (100 micrograms kg-1) and the 5-HT2 receptor antagonist, cinanserin (200 micrograms kg-1), on the reflex bronchoconstriction evoked by inhaled capsaicin aerosol in alpha-chloralose anaesthetized, neuromuscularly blocked and artificially ventilated cats. Recordings were made of heart rate, blood pressure and upper tracheal pressure. 2. Central application of all the 5-HT1A receptor antagonists (methiothepin, WAY-100635 and (-)-pindolol) attenuated the reflex bronchoconstriction in the upper trachea. However, the same dose of WAY-100635 given i.v. had no effect on this reflex bronchoconstriction. The 5-HT1A receptor agonist, 8-OH-DPAT (50 micrograms kg-1) given i.c., potentiated the capsaicin-evoked reflex bronchoconstriction, whereas buspirone (200 micrograms kg-1) i.c. had no effect. The 5-HT2 receptor antagonist, cinanserin (200 micrograms kg-1) also had no effect. 3. It is concluded that the reflex excitation of pulmonary vagal motoneurones by inhaled capsaicin in alpha-chloralose anaesthetized cats involves the activation of central 5-HT1A receptors.