Recognising facial onset sensory motor neuronopathy syndrome: insight from six new cases.

Facial onset sensory and motor neuronopathy (FOSMN) was first described in 2006 as an apparently sporadic neurodegenerative disease. Thirty cases have been reported to date. We summarise six new cases, highlighting the key clinical aspects of FOSMN and how to differentiate it from motor neurone disease (amyotrophic lateral sclerosis). Typically, patients present with slowly evolving numbness of the face followed by bulbar and proximal (neck and arm) weakness. However, one of our patients presented with a motor syndrome and his abnormal blink reflex studies provided a useful diagnostic clue. This extends the spectrum of the syndrome and emphasises that FOSMN should be considered in the differential diagnosis of motor neurone disease. We discuss the pathophysiology, diagnosis, prognosis and management considerations of FOSMN.

A study of patients attending a multidisciplinary hypodontia clinic over a five year period.

AIM: To gather information about planned treatment, outcomes and type of patient attending a multidisciplinary hypodontia clinic over a five year period at Glasgow Dental Hospital and School. STUDY DESIGN: There were three parts to the study: (i) to report demographics of the patients with hypodontia attending the multidisciplinary clinic from its outset in February 2002 until February 2007; (ii) to report on both the treatment planned on the clinic and whether this was completed as intended; and (iii) to show the number of patients for whom implants were considered. METHODS: The existing hypodontia database was analysed, supplemented where required by data gathered retrospectively from patients' clinical records and radiographs. RESULTS: In the demographic component there were 108 patients seen between February 2002 and February 2007, 57% female patients with a mean age of 13 years. Ninety-one percent (n = 107) of patients were missing two or more teeth, with the most common missing teeth being upper lateral incisors. Orthodontic therapy was most frequently considered in treatment planning. Nineteen patients (23%) may require dental implants. CONCLUSIONS: The majority of the patients were female, adolescent and had a positive or suspected family history of hypodontia. Orthodontic therapy was most frequently considered in treatment planning. Nineteen patients may undergo surgery for placement of dental implants.

Combined proteasome and histone deacetylase inhibition in non-small cell lung cancer.

OBJECTIVE: Inhibitors of histone deacetylases are potent inducers of cell-cycle arrest and apoptosis in certain malignancies. We have previously demonstrated that chemotherapy activates the antiapoptotic transcription factor nuclear factor kappa B in non-small cell lung cancer and fails to induce significant levels of apoptosis. We hypothesize that nuclear factor kappa B inhibition with the proteasome inhibitor bortezomib (formerly known as PS-341) will sensitize non-small cell lung cancer cells to histone deacetylase inhibitor-mediated apoptosis. METHODS: Tumorigenic non-small cell lung cancer cells (A549, H358, and H460) were treated with bortezomib, followed by the histone deactylase inhibitor sodium butyrate. After treatment, nuclear factor kappa B transcriptional activity was measured by using a luciferase reporter assay and transcription of the nuclear factor kappa B-dependent gene IL8. Apoptosis was determined on the basis of caspase-3 activation and DNA fragmentation. Western blot analyses for the cell-cycle regulatory proteins p21 and p53 were performed, and cell-cycle alterations were determined by means of FACS analysis. Experiments were performed in triplicate, and statistical significance was determined by using unpaired t tests. RESULTS: Butyrate increased nuclear factor kappa B transcriptional activity 4-fold relative to that seen in control cells (P =.05) in all non-small cell lung cancer cell lines. Treatment with bortezomib reduced butyrate-induced activation of nuclear factor kappa B to baseline levels. The proteins p21 and p53 were stabilized after treatment with bortezomib, correlating with a G(2)/M cell-cycle arrest. Treatment with butyrate alone resulted in minimal apoptosis, but combined histone deacetylase and proteasome inhibition increased apoptosis 3- to 4-fold (P =.02). CONCLUSIONS: Combined molecular targeting of histone deacteylases and proteasomes synergistically induced apoptosis in non-small cell lung cancer. Pharmacologic nuclear factor kappa B suppression through proteasome inhibition, followed by treatment with histone deacetylase inhibitors, might represent a novel treatment strategy for patients with non-small cell lung cancer.

Flunitrazepam used in a case of poisoning.

A male was found in a drowsy condition after being given a cup of tea and a tablet by a neighbour. An ambulance was called, he was taken to hospital and attended the police station on release. A blood sample taken 9h after the incident contained eight times the normal therapeutic level for Flunitrazepam. No motive could be proved and the neighbour was charged with Administering Poison under the Offences against the Person Act of 1861.

Inhibition of nuclear factor kappaB chemosensitizes non-small cell lung cancer through cytochrome c release and caspase activation.

OBJECTIVE: Although we have previously shown that inhibition of nuclear factor kappaB sensitizes non-small cell lung cancer cells to chemotherapy-mediated cell death, the apoptotic pathways mediating this process are unknown. The purpose of this study was to determine whether chemosensitivity after the inhibition of nuclear factor kappaB in non-small cell lung cancer cells is a mitochondrial and caspase-mediated process and whether it is dependent on nuclear factor kappaB transcriptional activity. METHODS: Previously described H157 non-small cell lung cancer cells were treated with gemcitabine, and DNA fragmentation was determined. Caspase 3, 6, 7, 8, and 9 activity in cytoplasmic extracts was determined fluorometrically. The mitochondrial permeability index and cytosolic cytochrome c levels were also determined. The caspase inhibitor Boc-D, as well as nuclear factor kappaB-regulated gene products A1, c-IAP-2, and Bcl-X(L), were added to H157 cells lacking nuclear factor kappaB and the degree of apoptosis assessed. All experiments were performed in triplicate, and data significance was determined by means of analysis of variance. RESULTS: Non-small cell lung cancer cells lacking functional nuclear factor kappaB (H157I) underwent more apoptosis after chemotherapy than vector control cells (H157V). There was an increase in the mitochondrial permeability index and cytochrome c release after chemotherapy in the H157I cells. H157I cells also had more activation of caspases 3 and 9 than control cells. Inhibition of caspase activity or transfection with nuclear factor kappaB-regulated gene products rescued cell death after the inhibition of nuclear factor kappaB. CONCLUSION: Chemosensitization by means of inhibition of nuclear factor kappaB in non-small cell lung cancer cells occurs through increased cytochrome c release and caspase 3 and 9 activation. Inhibition of nuclear factor kappaB or its gene products in addition to chemotherapy warrants further study as a treatment strategy in patients with advanced-stage non-small cell lung cancer.

Inhibition of NF-kappaB sensitizes non-small cell lung cancer cells to chemotherapy-induced apoptosis.

BACKGROUND: Most non-small cell lung cancers (NSCLC) are chemoresistant. Identification and modulation of chemoresistance cell-signaling pathways may sensitize NSCLC to chemotherapy and improve patient outcome. The purpose of this study was to determine if chemotherapy induces nuclear factor-kappa B (NF-kappaB) activation in NSCLC in vitro and whether inhibition of NF-kappaB would sensitize tumor cells to undergo chemotherapy-induced apoptosis. METHODS: Non-small cell lung cancer cells were treated with gemcitabine, harvested, and nuclear extracts analyzed for NF-kappaB DNA binding by electrophoretic mobility shift assays. Additionally, NSCLC cells that stably expressed a plasmid encoding the superrepressor IkappaBalpha protein (H157I) or a vector control (H157V) were generated. These cells were then treated with gemcitabine and apoptosis determined by terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay. RESULTS: Chemotherapy induced NF-kappaB nuclear translocation and DNA binding in all NSCLC cell lines. H157I cells had enhanced cell death compared with H157V cells, suggesting that NF-kappaB is required for cell survival after chemotherapy. The observed cell death following the loss of NF-kappaB occurred by apoptosis. CONCLUSIONS: Inhibition of chemotherapy-induced NF-kappaB activation sensitizes NSCLC to chemotherapy-induced apoptosis in vitro. Novel treatment strategies for patients with advanced NSCLC may involve chemotherapy combined with inhibition of NF-kappaB-dependent cell-survival pathways.

Nitric oxide interacts with oxygen free radicals to evoke the release of adenosine and adenine nucleotides from rat hippocampal slices.

The present study examined some possible mechanisms underlying the previously demonstrated release of adenosine by nitric oxide (NO) donors. Perfusion with the NO-donor S-nitroso-N-acetyl penicillamine (SNAP; 300 microM) led to a significant increase in the release of [3H]purines from both unstimulated and electrically stimulated hippocampal slices prelabeled with [3H]adenine. The NO-donor also evoked the release of endogenous ATP and ADP from unstimulated slices and, when combined with electrical stimulation, the release of ATP, AMP and adenosine. The SNAP-induced [3H]purine release was calcium-dependent, but not affected by the glutamate receptor antagonists MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]-cyclohepten-5,10-imine;100 nM) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; 10 microM). Zaprinast (5 microM), an inhibitor of the cyclic GMP-dependent phosphodiesterase and 8-Br-cyclic GMP (0.01-1 mM) failed to evoke the release of purines, whereas generation of oxygen free radicals by xanthine plus xanthine oxidase did evoke purine release. Coperfusion of SNAP with the free radical scavengers superoxide dismutase (SOD; 60 microg/ml) and catalase (50 microg/ml) reduced or eliminated the ability of the NO-donor to enhance [3H]purine release, but the poly (ADP-ribosyl) synthetase (PARS) inhibitor benzamide (500 microM) did not affect it. These data indicate that NO interacts with superoxide, likely forming peroxynitrite, which subsequently acts to release adenosine and adenine nucleotides from hippocampal tissue.

Release of adenosine from rat hippocampal slices by nitric oxide donors.

In the present study we have used perfused hippocampal slices to examine the hypothesis that nitric oxide (NO) can evoke the release of adenosine from nervous tissue. ATP stores were labeled by incubation with [3H]adenine. Electrical field stimulation at 5 Hz for 5 min evoked the release of 3H-purines, and this was enhanced by the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Stimulation at 10 Hz for 15 min evoked a larger release of 3H-purines, which was enhanced in a concentration-dependent manner by both SNAP and sodium nitroprusside (SNP), with SNP being 100-fold less potent than SNAP. N-Acetylpenicillamine (N-AP) was without effect. SNAP had a markedly reduced, although significant, effect when given in the absence of field stimulation. Using HPLC it was found that SNAP enhanced the release of both endogenous and labeled adenosine in a concentration-dependent manner. At the highest concentration used (1 mM), SNAP increased electrically evoked release of endogenous adenosine 100-fold and unstimulated adenosine release eightfold. The ability of SNAP to enhance adenosine release was eliminated in the added presence of hemoglobin (10 microM), further supporting the proposal that the effects of SNAP were due to the liberation of NO. These data provide direct evidence that NO evokes a concentration-dependent release of adenosine from both stimulated and unstimulated nerves of the hippocampus. It is suggested that such NO-stimulated adenosine release may contribute to some of the reported effects of NO donors in the nervous system.

A1, but not A2A, adenosine receptors modulate electrically stimulated [14C]acetylcholine release from rat cortex.

Adenosine A1 receptors are known to be widely distributed in various regions of the brain. A2A receptors are enriched in the dopamine-rich areas of the brain, but are also present in rat cortex. Electrically stimulated, perfused rat cortical slices were used to examine the influence of interactions between A1 and A2A receptors on the release of acetylcholine (ACh) from cortical cholinergic nerves. The A1-selective agonist, N6-cyclopentyladenosine (CPA) caused a dose-dependent inhibition of ACh release, which was attenuated in the added presence of the A1-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 1 microM). The inhibitory effects of CPA were unaltered in the added presence of the A2-selective antagonist (E)-8-(3,4-dimethyloxystyryl)-1,3-dipropyl-7-methylxanthine (KF 17837; 1 microM). The A2A-selective agonist 2-[p-(carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680), over the concentration range 1 nM to 10 microM, did not significantly alter ACh release when given alone or in the presence of DPCPX or KF 17837. These data suggest that the A(2A) receptors previously identified in rat cortex are not functionally coupled to modulation of ACh release in this tissue. This does not exclude that these receptors may regulate the release of other neurotransmitters.

Alexithymia and overeating.

While obesity is a complex, multidetermined disorder, a significant subgroup of overeaters suffer from alexithymia, which contributes to weight gain and difficulties in losing weight. For these individuals, food is used to regulate tension and inner-feeling states. The authors advocate psychotherapy aimed toward helping clients differentiate feelings and develop the capacity for symbolization as the most effective treatment.

Inhibition of neurotransmitter release from enteric nerve endings by 2-[p-(carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido-adenosine (CGS-21680) and related adenosine analogs: lack of simple competition by antagonists.

Adenosine receptors on enteric nerves mediate inhibitory responses to adenosine and its analogs and contribute to the overall excitability of enteric nerves. In characterizing these receptors, the response of the electrically stimulated guinea pig ileum longitudinal muscle-myenteric plexus preparation to receptor-selective analogs of adenosine was investigated and the antagonism of such activity by selective antagonists quantitated. The A1-selective agonist N6-cyclopentyladenosine, the nonselective agonist 5'-N-ethylcarboxamidoadenosine and the 2-substituted uronamides, 2-[p-(carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine and 2-[-(4-fluorophenyl)-ethoxy]-5'-N-ethylcarboxamidoadenosine, both relatively A2-selective agonists, inhibited field-stimulated responses of the ileum with the potency rank order: N6-cyclopentyladenosine > 5'-N-ethylcarboxamidoadenosine >> 2-[p-(carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine approximately 2-[-(4-fluorophenyl)-ethoxy]-5'-N-ethylcarboxamidoadenosine. Antagonism of these responses by receptor-selective antagonists was quantitated using the Schild technique and, for 1,3-dipropyl-8-cyclopentylxanthine, the A1-selective antagonist, demonstrated simple competitive interaction with the responses to N6-cyclopentyladenosine yielding a linear Schild isobole with unit slope. In contrast, responses to the uronamides could not be antagonized in a simple competitive manner. The potency order of the selective agonists is compatible with the presence on enteric nerve endings of an A1 receptor but does not support the presence of the A2 subtype. Moreover, these data demonstrate that the putatively A2-selective adenosine analogs 2-[p-(carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine and 2-[-(4-fluorophenyl)-ethoxy]-5'-N-ethylcarboxamidoadenosine interact with 1,3-dipropyl-8-cyclopentylxanthine at enteric nerve adenosine receptors in a manner which is not compatible with simple competitive interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

PYY: a neuropeptide in the canine enteric nervous system.

This study re-examined the anatomical locations of PYY in the canine gastrointestinal tract. Immunohistochemical studies with two relatively selective PYY antisera demonstrated PYY-LI immunoreactivity in nerve cell bodies and nerve fibres in the intestinal and gastric myenteric plexus and the intestinal submucosal plexus and in nerve fibres of the intestinal deep muscular plexus. Immunoreactive PYY-LI was also present in ileal endocrine cells. All PYY-LI immunoreactivity was completely abolished by pre-incubation of the antibodies with synthetic PYY but was unaltered by pre-incubation with synthetic NPY. Individual synaptosomal preparations obtained from canine intestinal and gastric myenteric plexus, and intestinal deep muscular plexus and submucous plexus, contained considerable quantities of PYY-LI which, on reverse-phase HPLC, co-eluted with a synthetic canine/porcine PYY standard. In contrast, isolated myenteric ganglia from rat and guinea pig did not contain detectable amounts of PYY-LI. These studies demonstrate that PYY is not confined to distal intestinal endocrine cells in the dog but is also an enteric neuropeptide with maximal concentrations being present in the intestinal myenteric plexus.

Adenosine and 5-HT inhibit substance P release from nerve endings in myenteric ganglia by distinct mechanisms.

Release of substance P-like immunoreactivity (SP-LI) from dissociated enteric ganglia and the receptor-mediated prejunctional inhibition of this release were investigated with the use of a perifusion technique. SP-LI release was evoked by elevated extracellular K+ concentration and was inhibited, in a graded manner, by N6-cyclopentyl adenosine (CPA), an adenosine analogue with selectivity for adenosine A1 receptors. Similar inhibition of SP-LI release was obtained with 5-hydroxytryptamine (5-HT); incrementing concentrations, however, yielded a biphasic concentration-response relationship. The selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentyl-xanthine abolished the inhibition due to CPA, whereas the inhibitory action of 5-HT was sensitive to the 5-HT1A-selective antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine hydrobromide. Inhibition due to both agonists was insensitive to blockade by tetrodotoxin, suggesting a prejunctional locus for both adenosine and 5-HT1A receptors on the tachykininergic nerve endings. Pretreatment of ganglia with pertussis toxin had no effect on CPA-mediated inhibition of SP-LI release, whereas 5-HT-mediated inhibition was abolished. The findings demonstrate that adenosine and 5-HT receptors on enteric nerve endings are coupled to inhibition of tachykinin release through distinct mechanisms, putatively distinct G proteins.

Adenosine A1 receptors mediate inhibition of tachykinin release from perifused enteric nerve endings.

A perifused preparation of guinea pig myenteric nerve varicosities (synaptosomes) was used to determine the characteristics of evoked tachykinin release and the inhibition of such release by adenosine analogues. Release of substance P-like immunoreactivity (SP-LI) and neurokinin A-like immunoreactivity (NKA-LI) was evoked by elevated extracellular [K+] in a reversible and repeatable manner. This release was completely abolished in the absence of extracellular Ca2+. Perifusion in the presence of 5'-N-ethylcarboxamidoadenosine (NECA), a nonselective A1/A2 adenosine receptor agonist, decreased K(+)-evoked release of SP-LI and NKA-LI compared with that in the absence of the nucleoside. Similar decrements in peptide release were obtained with N6-cyclopentyl adenosine (CPA), a selective A1 agonist, and 2-[p-(2-carboxyethyl)]phenethylamino-5'-N-ethyl-carboxamidoadenosi ne (CGS 21680), a selective A2 agonist. Response to all nucleosides was graded. Potency order of adenosine analogues was CPA greater than NECA much greater than CGS 21680. Inhibition due to the nucleosides was diminished in the presence of the highly selective A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) while perifusion in the presence of DPCPX alone did not alter evoked release of either peptide. These findings provide direct measurements of inhibitory effects of adenine nucleosides on the release, from enteric nerve endings, of endogenous neuromediators SP and NKA. The findings also directly demonstrate the presence of functional adenosine receptors of the A1 subtype on enteric nerve endings coupled negatively to release of tachykinins. The presence of A2 receptors on enteric nerve endings is neither supported nor excluded.

Long-term prospective study of lumbosacral discectomy.

A long-term prospective study of 100 patients undergoing lumbosacral discectomy was carried out in an attempt to delineate the natural history of these patients and to assess the relative significance of preoperative factors as determinants of long-term outcome. Neurological findings were documented preoperatively and at 1 month, 1 year, and 5 to 10 years postoperatively. A questionnaire using subjective and objective data was given to patients at 1 year and 5 to 10 years postoperatively. An 83% long-term follow-up result was obtained. At a minimum of 5 years postoperatively, 62% of patients had complete relief of back pain and 62% had complete relief of leg pain; 96% were pleased that they had submitted to surgery and 93% were able to return to work. Nine percent reported that their back pain at 5 to 10 years was as severe as or worse than preoperatively and 11% reported that their leg pain was as severe as or worse than preoperatively. The reoperation rate was 18%. Preoperative factors found to be significantly associated with outcome at 1 year postoperatively were not significantly associated with outcome at 5 to 10 years postoperatively. The results of lumbosacral discectomy appear favorable as evaluated in this study. Preoperative factors useful as predictors of short-term outcome are much less reliable when considering the long-term results.

Third ventricle choroid plexus carcinoma.

Benign and malignant tumors of the choroid plexus in infancy are extremely uncommon. Diagnosis and management of a malignant tumor is described and the literature survey of the problem is presented.

Study of unaided cross-eyed stereopsis.

The learning of the skill of unaided cross-eyed stereopsis was investigated on a group of young adults. Both pictorial and random-dot stereograms were used; small stereograms were viewed at normal reading distance and large projected stereograms were viewed in an auditorium. The results suggest that this direct stereoscopic technique can be learned within a few minutes by almost everyone in the population represented by the test group. The calculated eye-convergence angles for various conditions of cross-eyed stereoscopic viewing indicate that little eye discomfort is caused by this factor when the stereograms are located at a sufficient distance from the viewers. The comments of subjects support this conclusion. The unexpected prevalence of the aptitude for this skill should have practical application in the unaided three-dimensional visualization of computer-generated stereograms.

Developmental and psychodynamic issues related to cases of childhood functional hearing loss.

The literature is scant regarding the details of the personality organizations of children exhibiting functional hearing losses. Projective data gleaned from five clinical cases of childhood functional hearing loss is presented. The core pathology involves a poorly consolidated image of the self. Threats to the continuity and cohesiveness of the self are avoided through a form of selective inattention.