Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1.

BACKGROUND AND PURPOSE: M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M(1) mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs. EXPERIMENTAL APPROACH: In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology. KEY RESULTS: Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration. CONCLUSIONS AND IMPLICATIONS: These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.

Functional consequences of reduction in NMDA receptor glycine affinity in mice carrying targeted point mutations in the glycine binding site.

We have used site-directed mutagenesis in conjunction with homologous recombination to generate two mouse lines carrying point mutations in the glycine binding site of the NMDAR1 subunit (Grin1). Glycine concentration-response curves from acutely dissociated hippocampal neurons revealed a 5- and 86-fold reduction in receptor glycine affinity in mice carrying Grin1(D481N) and Grin1(K483Q) mutations, respectively, whereas receptor glutamate affinity remained unaffected. Homozygous mutant Grin1(D481N) animals are viable and fertile and appear to develop normally. However, homozygous mutant Grin1(K483Q) animals are significantly lighter at birth, do not feed, and die within a few days. No gross abnormalities in CNS anatomy were detected in either Grin1(D481N) or Grin1(K483Q) mice. Interestingly, in situ hybridization and Western blot analysis revealed changes in the expression levels of NMDA receptor subunits in Grin1(D481N) mice relative to wild type that may represent a compensatory response to the reduction in receptor glycine affinity. Grin1(D481N) mice exhibited deficits in hippocampal theta burst-induced long-term potentiation (LTP) and spatial learning and also a reduction in sensitivity to NMDA-induced seizures relative to wild-type controls, consistent with a reduced activation of NMDA receptors. Mutant mice exhibited normal prepulse inhibition but showed increased startle reactivity. Preliminary analysis indicated that the mice exhibit a decreased natural aversion to an exposed environment. The lethal phenotype of Grin1(K483Q) animals confirms the critical role of NMDA receptor activation in neonatal survival. A milder reduction in receptor glycine affinity results in an impairment of LTP and spatial learning and alterations in anxiety-related behavior, providing further evidence for the role of NMDA receptor activation in these processes.

Transfection-mediated expression of human Hsp70i protects rat dorsal root ganglian neurones and glia from severe heat stress.

Considerable evidence suggests that the expression of heat shock proteins prior to a toxic insult (e.g. ischaemia, excitoxins, heat) can confer protection to neurones and glia. It is not certain which hsp(s) are involved in conveying these neuroprotective effects. Here we show that calcium phosphate-mediated transfection of dorsal root ganglia with an EF-1 alpha promoter-hsp70i expression vector significantly increased the survival of neurones and glia exposed to a severe heat stress. These data suggest that overexpression of hsp70i plays an important role in protecting neurones and glia from the denaturing effects of severe thermal stress. Inducing the expression of specific hsps may lead to the development of novel treatment strategies for CNS diseases.

Cortical function in progressive lower motor neuron disorders and amyotrophic lateral sclerosis: a comparative PET study.

OBJECTIVE: To compare cortical function at rest and during limb movement in patients with progressive lower motor neuron degeneration (LMND) and amyotrophic lateral sclerosis (ALS). METHODS: PET was used to measure regional cerebral blood flow (rCBF) in five patients with progressive LMND, six patients with classic ALS with a similar degree of motor impairment, and six age-matched control subjects; measurements were taken in the resting state and while subjects moved a joystick with their right hand. RESULTS: rCBF at rest in the primary sensorimotor cortex (SMC) was significantly (p < 0.001) lower in ALS patients than in control subjects or LMND patients. rCBF at rest did not differ significantly between LMND patients and controls. During joystick movement, ALS patients showed significantly (p < 0.001) greater rCBF increases than controls or LMND patients in the hand/arm area of the SMC bilaterally, the face area of the contralateral SMC, the second somatic sensory (SII) cortex bilaterally, and the contralateral premotor and supplementary motor cortices. LMND patients showed significantly (p < 0.001) greater rCBF increases than controls and ALS patients only in the anterior insular cortex bilaterally. CONCLUSIONS: The finding of reduced rCBF at rest, together with abnormal bilateral activation and altered somatotopy during movement, in the sensorimotor cortex of ALS but not LMND patients suggests that these abnormalities reflect loss of pyramidal neurons. Abnormal activation of perisylvian areas (insular and SII cortices) during limb movement in both LMND and ALS patients suggests that these may be accessory sensorimotor areas that are recruited nonspecifically in response to limb weakness.

Activity-dependent presynaptic autoinhibition by group II metabotropic glutamate receptors at the perforant path inputs to the dentate gyrus and CA1.

Pharmacological activation of metabotropic glutamate receptors (mGluRs) can inhibit synaptic transmission; however, relatively little evidence exists regarding the physiological conditions under which such autoreceptors are activated by synaptically released glutamate. Bath application of selective group II mGluR agonists profoundly inhibited field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of the perforant path inputs to both the mid-molecular layer of the dentate gyrus and the stratum lacunosum moleculare of the CA1. Application of the group II selective mGluR antagonist LY341495 resulted in an increase in the relative amplitude of a test fEPSP evoked 200 ms after a conditioning burst, but not after a single conditioning stimulus, in both pathways. Antagonist application also resulted in a marked increase in the relative amplitude of test population spikes evoked in the dentate gyrus following a conditioning burst. These observations are consistent with a presynaptic autoinhibitory action of group II metabotropic receptors that is revealed following burst stimulation of the pathway, consistent with their localisation in the preterminal zone. Activation of group II mGluRs during theta-gamma pattern discharge of projection neurones in the entorhinal cortex is likely to play an important role in the regulation of synaptic transmission and plasticity in the perforant pathway.

Brain-derived neurotrophic factor, acidic and basic fibroblast growth factors, insulin-like growth factor-I, and various antioxidants do not prevent the apoptotic death of developing septal cholinergic neurons following nerve growth factor withdrawal in vitro.

The degree to which growth factors act alone or in combination to influence neuronal survival during the development of the central nervous system is not well understood. In this study, we investigated whether multiple growth factors might interact to regulate the survival of developing basal forebrain cholinergic neurons in vitro, in the rat. We have previously shown that most embryonic septal cholinergic neurons grown in sandwich cultures in serum-free, completely defined medium are dependent on nerve growth factor during a critical period of their development, such that nerve growth factor withdrawal during this period results in the protein synthesis-dependent, apoptotic death of most, but not all, of these neurons. Here we report that brain-derived neurotrophic factor, acidic and basic fibroblast growth factors, and insulin-like growth factor-I applied individually in serum-free, completely defined medium, were not able either to support the development of septal cholinergic neurons from plating at embryonic day 16, or to prevent the cell death of these neurons induced by nerve growth factor withdrawal during days 14-18 after plating. We also found that the apoptotic death of developing septal cholinergic neurons induced by nerve growth factor withdrawal was not prevented by a number of antioxidants, with the exception of a high concentration (50 mM) of ascorbic acid. However, this effect of ascorbic acid was prevented when pH was buffered, and is likely to have been mediated via a proton-induced sustained neuronal depolarization. These findings suggest that in the absence of serum and other additives, brain-derived neurotrophic factor, acidic and basic fibroblast growth factors, and insulin-like growth factor-I do not interact with nerve growth factor to regulate the survival of septal cholinergic neurons during the developmental period spanned by this in vitro model. In addition, the findings suggest that the apoptotic death of septal cholinergic neurons induced by nerve growth factor withdrawal is not mediated by oxidative stress or free radical generation.

Ciliary neurotrophic factor supports p75NGFR-immunoreactive non-cholinergic, but not cholinergic, developing septal neurons in vitro.

Ciliary neurotrophic factor is known to exert both survival and differentiative actions on a number of neuronal populations of the peripheral and central nervous systems. In this study we have compared the trophic effects of ciliary neurotrophic factor and nerve growth factor on developing septal neurons of the rat in vitro. Fetal septal neurons were grown in vitro under glass coverslips in sandwich culture. Septal cultures grown for 14 days in the continual presence of nerve growth factor contain a population of cholinergic neurons that stain intensely for the low-affinity nerve growth factor receptor (p75NGFR), choline acetyltransferase and acetylcholinesterase. Without added nerve growth factor, few neurons stain for these markers. Ciliary neurotrophic factor addition for 14 days from plating in the absence of exogenous nerve growth factor results in the appearance of a population of neurons that stains for p75NGFR. This population is similar in number to that seen in nerve growth factor-treated cultures but is not immunoreactive for choline acetyltransferase and is significantly smaller in mean cross-sectional area. Delayed addition of nerve growth factor to ciliary neurotrophic factor-supported cultures at 14 days for a further seven days fails to induce choline acetyltransferase immunoreactivity in these p75NGFR-positive septal neurons. In cultures grown in the continual presence of nerve growth factor from plating, removal of nerve growth factor and addition of nerve growth factor antibodies at 14 days results in the death of over 80% of the cholinergic neurons after a further four days. Addition of ciliary neurotrophic factor during the period of nerve growth factor withdrawal appears to preserve a p75NGFR-positive, choline acetyltransferase-negative neuronal population. However, seven day re-addition of nerve growth factor to ciliary neurotrophic factor-treated, nerve growth factor-withdrawn cultures fails to induce choline acetyltransferase immunoreactivity in the ciliary neurotrophic factor-supported p75NGFR-positive septal neurons. Simultaneous treatment of cultures with both ciliary neurotrophic factor and nerve growth factor for 14 days from plating approximately doubles the number of p75NGFR-positive neurons relative to cultures treated with either ciliary neurotrophic factor or nerve growth factor alone, but the number of choline acetyltransferase-positive neurons in these cultures is not significantly greater than that found in cultures treated solely with nerve growth factor. These results suggest that ciliary neurotrophic factor does not support the survival and differentiation of developing septal cholinergic neurons in vitro, but can support the development of a p75NGFR-immunoreactive population of non-cholinergic septal neurons.

Nerve growth factor withdrawal induces the apoptotic death of developing septal cholinergic neurons in vitro: protection by cyclic AMP analogue and high potassium.

Nerve growth factor regulates the developmental programmed cell death of certain neurons in the peripheral nervous system. The functions of nerve growth factor in the central nervous system are less well characterized. Nerve growth factor withdrawal results in the protein synthesis-dependent death of a large percentage of developing septal cholinergic neurons in sandwich tissue culture. In this study double labelling techniques were used to demonstrate that septal cholinergic neurons subjected to nerve growth factor withdrawal exhibit condensed chromatin and fragmented nuclei, and are labelled intensely for fragmented DNA. These degenerative changes are characteristic of apoptotic cell death. Half of the cholinergic neurons were committed to die and could no longer be rescued by nerve growth factor reapplication following approximately 16.5 h of nerve growth factor deprivation, whereas half of the cholinergic neurons could no longer be rescued by cycloheximide addition after only 9 h of nerve growth factor deprivation, suggesting that nerve growth factor and cycloheximide effect rescue by distinct mechanisms. Addition of a cyclic AMP analogue or depolarization with high K+, but not the general nuclease inhibitor aurintricarboxylic acid, prevented the death of cultured septal cholinergic neurons subjected to nerve growth factor withdrawal. Furthermore, these agents are capable of rescuing cholinergic neurons subjected to a period of nerve growth factor withdrawal after which addition of cycloheximide is no longer protective. Thus, nerve growth factor, cyclic AMP and high K+ can effect rescue after inhibition of translation ceases to be protective. These findings suggest that under defined conditions in vitro, withdrawal of nerve growth factor from septal cholinergic neurons during a critical period of development results in the apoptotic death of these CNS neurons, which can be prevented at the post-translational level by nerve growth factor, cyclic AMP and high K+.

State-dependent NMDA receptor antagonism by Ro 8-4304, a novel NR2B selective, non-competitive, voltage-independent antagonist.

1. Subunit-selective blockade of N-methyl-D-aspartate (NMDA) receptors provides a potentially attractive strategy for neuroprotection in the absence of undesirable side effects. Here, we describe a novel NR2B-selective NMDA antagonist, 4-¿3-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-hydroxy-propoxy ¿-benzamide (Ro 8-4304), which exhibits >100 fold higher affinity for recombinant NR1(001)/NR2B than NR1(001)/NR2A receptors. 2. Ro 8-4304 is a voltage-independent, non-competitive antagonist of NMDA receptors in rat cultured cortical neurones and exhibits a state-dependent mode of action similar to that described for ifenprodil. 3. The apparent affinity of Ro 8-4304 for the NMDA receptor increased in an NMDA concentration-dependent manner so that Ro 8-4304 inhibited 10 and 100 microM NMDA responses with IC50s of 2.3 and 0.36 microM, respectively. Currents elicited by 1 microM NMDA were slightly potentiated in the presence of 10 microM Ro 8-4304, and Ro 8-4304 binding slowed the rate of glutamate dissociation from NMDA receptors. 4. These results were predicted by a reaction scheme in which Ro 8-4304 exhibits a 14 and 23 fold higher affinity for the activated and desensitized states of the NMDA receptor, respectively, relative to the agonist-unbound resting state. Additionally, Ro 8-4304 binding resulted in a 3 4 fold increase in receptor affinity for glutamate site agonists. 5. Surprisingly, whilst exhibiting a similar affinity for NR2B-containing NMDA receptors as ifenprodil, Ro 8-4304 exhibited markedly faster kinetics of binding and unbinding to the NMDA receptor. This spectrum of kinetic behaviour reveals a further important feature of this emerging class of NR2B-selective compounds.

Acute renal failure in a patient with Rosai-Dorfman disease.

Acute renal failure developed in a 57-year-old woman who had Rosai-Dorfman disease diagnosed 1 year previously on a cervical lymph node. Organ imaging showed diffuse masses infiltrating both kidneys. The renal biopsy showed a lymphoplasmacytic and histiocytic process extensively replacing the parenchyma, which is in keeping with Rosai-Dorfman disease of the kidneys. However, the typical lymphophagocytic cells were lacking. This case illustrates that diagnosis of Rosai-Dorfman disease in renal biopsy can be very difficult, requiring both exclusion of many benign and malignant lesions and a high index of suspicion for this condition. In particular, lymphoma was excluded based on the mixed polyclonal composition of inflammatory cells and the absence of atypical lymphoid proliferation. The renal function partially recovered after a course of therapy combining VP-16 (etoposide) and dexamethasone and remained stable over 4-year follow-up. This report emphasizes the importance of early diagnosis and intervention to safeguard renal function in extensive Rosai-Dorfman disease.

Obstructive sleep apnea syndrome in a family with Crouzon's syndrome.

Craniofacial anomalies are recognized causes of obstructive sleep apnea syndrome (OSAS) in children. Current literature is limited due to rarity of cases. Furthermore, the mechanism of upper airway obstruction is not clearly understood. We would like to report a family (father and 2 sons) who are suffering from Crouzon's syndrome. The two brothers (ages 1 and 3) were found to have significant obstructive sleep apnea syndrome (OSAS) with failure to thrive. Nasal continuous positive airway pressure (CPAP) markedly improved their OSAS and resulted in accelerated weight gain. The nasoendoscopy and magnetic resonance imaging (MRI) scan taken during natural sleep showed that choanal stenosis, maxillary hypoplasia, posteriorly displaced tongue, lengthened soft palate and adenoid tissues were important in the pathogenesis of upper airways obstruction in Crouzon's syndrome. Nasal CPAP improved airway obstruction by opening a narrow slit as demonstrated by MRI. Our results suggest that OSAS occurred in children with Crouzon's syndrome and that nasal CPAP was a useful treatment modality.

Deep venous thrombosis caused by femoral venous catheters in critically ill adult patients.

STUDY OBJECTIVES: To determine the frequency of and potential risk factors for catheter-related deep venous thrombosis (DVT) in critically ill adult patients. DESIGN: Prospective, controlled, observational cohort study. SETTING: A mixed medical and surgical ICU in a university hospital. PATIENTS: All adult patients undergoing femoral vein catheterization. INTERVENTIONS: None. MEASUREMENTS: ICU diagnosis, underlying disease, demographic data, type of catheter, complications during cannulation, use of anticoagulants, coagulation status, medications infused, and duration of catheterization were recorded. Compression and duplex Doppler ultrasound studies of both femoral veins were performed prior to insertion, at 12 h after insertion, and daily until catheter removal. Follow-up investigation was performed at 24 h and 1 week after removal. RESULTS: Of 140 cases entered into the study, 124 were evaluated. Fourteen patients developed iliofemoral vein DVTs. Two were clinically obvious. Twelve (9.6%) were line related (uncannulated leg normal) and two (1.6%) occurred only in the uncannulated leg (p = 0.011; relative risk, 6.0; confidence interval, 1.5 to 23.5). Line-related DVT can occur any time from the day after insertion to 1 week after removal. The incidence of catheter-related DVT was unrelated to number of insertion attempts, arterial puncture or hematoma, duration of catheterization, coagulation status, or type of infused medications. No other predisposing or protective factors were identified. Three of the 12 patients with catheter-related DVT died. In no patient was clinical pulmonary embolus suspected. CONCLUSION: Although the femoral route is convenient and has potential advantages, the use of femoral lines increases the risk of iliofemoral DVT. Catheter-related DVT may occur as soon as 1 day after cannulation and is usually asymptomatic. This increased risk should be carefully considered when the femoral route of cannulation is chosen.

The effect of lung injury and excessive lung fluid, on impedance cardiac output measurements, in the critically ill.

OBJECTIVES: To investigate the relationship between the attenuation of impedance cardiac output (IC(co)) measurements and lung fluid content in critically ill patients. DESIGN: Observational study. SETTING: Intensive Care Unit of a major teaching hospital in Hong Kong. PATIENTS: Twenty-four critically ill patients who required a pulmonary artery catheter. MEASUREMENTS AND MAIN RESULTS: Triplicate thermodilution cardiac output (TD(co)) and BoMed NCCOM3 (IC(co)) measurements were made simultaneously on a single occasion in each patient. Lung fluid accumulation was assessed by: (a) thoracic impedance (Zo), (b) radiological assessment of chest X-rays using an alveolar consolidation score (0-4) and (c) scoring the degree of hypoxia and use of positive end-expiratory pressure (PEEP). Offsets (TD(co)-IC(co))/TD(co), expressed as percentage, were compared with these indices of excess lung fluid. Patients were divided into those with sepsis (n = 13), fluid balance problems (n = 5) and cardiothoracic problems (n = 6). Mean cardiac output values were: 6.7 l/min TD(co) (range 3.6-12.9) and 5.2 l/min IC(co) (range 2.7-9.0). Overall the TD(co) and IC(co) values showed great variance, with a bias and limits of agreement of 1.49 +/- 4.16 l/min, or +/- 69%. In septic patients, increasing offset was correlated with decreases in Zo (r = 0.73, P = 0.005) and increases in alveolar consolidation score (r = 0.72, P = 0.005). CONCLUSIONS: The BoMed under-estimates cardiac output in critically ill patients. In septic patients the degree of attenuation of IC(co) can be related to the extent of lung injury and fluid accumulation within the thorax.

CT and MR imaging appearances of an extraosseous calcifying epithelial odontogenic tumor (Pindborg tumor).

We herein report a rare case of extraosseous calcifying epithelial odontogenic tumor with local aggressive behavior. CT and MR imaging showed the distinctive appearances of this histologic entity. We briefly discuss the radiologic features of calcifying epithelial odontogenic tumor and the relevant literature.

Head and neck lipomas: sonographic appearance.

PURPOSE: The diagnosis of cervical lipoma may not always be clinically apparent, in which case patients are frequently referred for sonography. The purpose of this study was to document the sonographic features of head and neck lipomas. METHODS: Twenty-five patients with soft-tissue masses in the neck had sonography as their initial imaging study. A lipoma was suspected on the basis of findings at clinical examination in only eight of these patients. Lipoma was confirmed by fine-needle aspiration cytology in 11 patients, by excision biopsy in five patients, by CT in two patients, and by clinical examination with clinical sonographic follow-up (6 months to 2 years) in seven cases. RESULTS: Lipomas were well-defined (88%), compressible (100%), elliptical masses with the longest diameter parallel to the skin surface. All contained multiple echogenic lines parallel to the skin surface with no evidence of posterior enhancement or attenuation and no flow on color Doppler sonography. Compared with adjacent muscle, 76% of all lipomas were hyperechoic, 8% isoechoic, and 16% hypoechoic. CONCLUSION: The characteristic sonographic appearance of head and neck lipomas is that of an elliptical mass parallel to the skin surface that is hyperechoic relative to adjacent muscle and that contains linear echogenic lines at right angles to the ultrasound beam.

Metastatic adenopathy from nasopharyngeal carcinoma: successful response to radiation therapy assessed by color duplex sonography.

BACKGROUND AND PURPOSE: Although the role of gray-scale sonography for neck nodes is well documented, it plays a limited role in the evaluation of nodal response to treatment. This preliminary limited study sought to determine color duplex sonographic changes in successfully treated metastatic nodes from nasopharyngeal carcinoma. METHODS: Fourteen patients with nodal metastases from nasopharyngeal carcinoma were studied. A pretreatment sonogram was obtained for all patients. Patients were divided into two groups of seven: in one group, repeat sonograms were obtained 8 weeks after completion of treatment; in the second group, sonograms were obtained 16 weeks after treatment. The features studied included distribution of intranodal vascularity, resistive and pulsatility indexes, and peak systolic velocity. In 11 patients, follow-up sonograms were obtained 1 year after treatment. RESULTS: The majority (90%) of malignant nodes from nasopharyngeal carcinoma have an increased central and peripheral vascularity, a high resistive index (0.8), and a high pulsatility index (1.8). After radiation therapy to the nodes, a reduction in intranodal vascularity and a statistically significant reduction in the resistive index (0.58 to 0.59) and pulsatility index (0.91 to 0.93) are found. Although a similar reduction in the peak systolic velocity is observed, it is not statistically significant. CONCLUSION: Our preliminary findings suggest that after radiation therapy for malignant nodes in nasopharyngeal carcinoma, a reduction in intranodal vascularity is found, and the resistive and pulsatility indexes may return to benign parameters as early as 8 weeks after completion of treatment.

Madelung disease: distribution of cervical fat and preoperative findings at sonography, MR, and CT.

PURPOSE: Our goal was to document the distribution of excess fat in the neck and to determine the preoperative role of sonography, CT, and MR imaging in patients with Madelung disease. METHODS: Eight patients with Madelung disease were examined preoperatively with sonography, CT, and MR imaging of the neck, and the extent to which each technique provided answers to the surgeons' questions--such as distribution of fat, course of the major vessels within the fat, and presence of tracheal compression and nonlipomatous lesions--was studied. RESULTS: Excess fat was seen predominantly in the posterior part of the neck (eight patients), under the trapezius (eight patients) and sternomastoid (six patients) muscles, in the supraclavicular fossa (five patients), between the paraspinal muscles (five patients), in the anterior part of the neck (suprahyoid in seven patients and infrahyoid in three patients), in the superior mediastinum (three patients), and in the prevertebral space (two patients). Excess fat deposition was also seen in the pretracheal space (one patient), extrapleural space (two patients), and over the cheeks (one patient), sites previously not described. CONCLUSION: As a preoperative investigative tool for Madelung disease, both MR imaging and noncontrast CT provide the surgeon with adequate information; sonography is less helpful.

A positron emission tomography study of frontal lobe function (verbal fluency) in amyotrophic lateral sclerosis.

Positron emission tomography (PET) was used to investigate the location of cerebral cortical and subcortical abnormalities in non-demented patients with amyotrophic lateral sclerosis (ALS). Involvement of the frontal lobes was investigated with a task of executive frontal lobe function (verbal fluency/word generation), using a PET activation paradigm. Two groups of ALS patients defined by the presence or absence of cognitive impairment were tested. ALS patients who had cognitive impairments showed a region of cortical and subcortical dysfunction which extended across a wide area of the frontal lobes, and included the insular cortex and thalamic nuclear complex. These findings support the notion that extra-motor involvement is relatively common in ALS and broadens concepts of selective vulnerability in ALS.

Nasolacrimal duct opacity on CT.

A retrospective analysis of 100 coronal sinus CT scans was performed to investigate the frequency of opacity of the nasolacrimal duct and determine if there was any correlation between the pattern of duct opacity and the presence of inflammatory sinus disease. The study showed that the nasolacrimal ducts are opaque in the majority of normal people and that there is no relationship to inflammatory sinus disease.