Supranuclear eye movements and nystagmus in children: A review of the literature and guide to clinical examination, interpretation of findings and age-appropriate norms.

Abnormal eye movements in children, including nystagmus, present a significant challenge to ophthalmologists and other healthcare professionals. Similarly, examination of supranuclear eye movements and nystagmus in children and interpretation of any resulting clinical signs can seem very complex. A structured assessment is often lacking although in many cases, simple clinical observations, combined with a basic understanding of the underlying neurology, can hold the key to clinical diagnosis. As the range of underlying diagnoses for children with abnormal eye movements is broad, recognising clinical patterns and understanding their neurological basis is also imperative for ongoing management. Here, we present a review and best practice guide for a structured, methodical clinical examination of supranuclear eye movements and nystagmus in children, a guide to clinical interpretation and age-appropriate norms. We also detail the more common specific clinical findings and how they should be interpreted and used to guide further management. In summary, this review will encourage clinicians to combine a structured assessment and a logical interpretation of the resulting clinical signs, in order to recognise patterns of presentation and avoid unnecessary investigations and protracted delays in diagnosis and clinical care.

A novel orally administered trimebutine compound (GIC-1001) is anti-nociceptive and features peripheral opioid agonistic activity and Hydrogen Sulphide-releasing capacity in mice.

BACKGROUND: Trimebutine maleate, a noncompetitive spasmolytic agent with some affinity for peripheral µ- and κ-opioid receptors has been evaluated as a treatment in a limited number of patients undergoing sedation-free full colonoscopy. The efficiency of such treatment was comparable to sedation-based colonoscopies to relieve from pain and discomfort. METHODS: A new and improved trimebutine salt capable of releasing in vivo hydrogen sulphide (H2S), a gaseous mediator known to reduce nociception, has been developed. This drug salt (GIC-1001) is composed of trimebutine bearing a H2S-releasing counterion (3-thiocarbamoylbenzoate, 3TCB), the latter having the ability to release H2S. GIC-1001 has been tested here in a mouse model of colorectal distension. RESULTS: In mice, while orally given trimebutine (the maleate salt, non-H2 S-releaser) only slightly reduced the nociceptive response to increasing pressures of colorectal distension, oral administration of GIC-1001 (the H2S-releaser) was able to significantly reduce nociceptive response to all noxious stimuli, in a dose-dependent manner. This effect of GIC-1001 was significantly better than the effects of its parent compound trimebutine administered at equimolar doses. CONCLUSIONS: Taken together, these results demonstrated increased antinociceptive properties for GIC-1001 compared to trimebutine, suggesting that this compound would be a better option to relieve from visceral pain and discomfort induced by lumenal distension.

Internalizing behaviours in school-age children born very preterm are predicted by neonatal pain and morphine exposure.

BACKGROUND: Greater neonatal pain is associated with higher internalizing behaviours in very preterm infants at 18 months corrected age, but it is unknown whether this relationship persists to school age. Moreover, it is unclear whether morphine ameliorates or exacerbates the potential influence of neonatal pain/stress on internalizing behaviours. We examined whether neonatal pain-related stress is associated with internalizing behaviours at age 7 years in children born very preterm, and whether morphine affects this relationship. METHODS: One hundred one children born very preterm (≤32 weeks gestation) were seen at mean age 7.7 years. A parent completed the Parenting Stress Index and Child Behavior Checklist questionnaires. Neonatal pain-related stress (the number of skin-breaking procedures adjusted for clinical factors associated with prematurity) was examined in relation to internalizing behaviour, separately in subjects mechanically ventilated and exposed to both pain and morphine (n = 57) and those never mechanically ventilated, exposed to pain but not morphine (n = 44). RESULTS: In the non-ventilated group, higher skin-breaking procedures (p = 0.037) and parenting stress (p = 0.004) were related to greater internalizing behaviours. In the ventilated group, greater morphine exposure (p = 0.004) was associated with higher child internalizing scores. CONCLUSIONS: In very preterm children who undergo mechanical ventilation, judicious use of morphine is important, since morphine may mitigate the negative effects of neonatal pain on nociception but adversely affect internalizing behaviours at school age. Management of procedural pain needs to be addressed in very preterm infants in the neonatal intensive care unit, to prevent long-term effects on child behaviour.

Changing body position alters the location of the spinal cord within the vertebral canal: a magnetic resonance imaging study.

BACKGROUND: The influence of changes in body position relevant to neuraxial blockade on the location of the spinal cord and related neural structures has not been fully quantified. Our aim was to determine the changes, if any, that occur in the location of the spinal cord tip [equivalent to the tip of the conus medullaris (CM)] and nerve roots when an individual moves from the supine to the left lateral position with knees and hips flexed. METHODS: We used magnetic resonance imaging to determine movement of the spinal cord tip and associated structures in 30 adult volunteers. RESULTS: The tip shifted both anteriorly [average 6.3 mm, standard deviation (sd) 2.15 mm; P<0.001] and laterally towards the dependent side (average 1.63 mm, sd 1.19 mm; P<0.001). Although we observed anterior shift in all 30 volunteers, lateral movement did not occur in seven. Movement along the cranio-caudal axis was not statistically significant. CONCLUSIONS: Both the CM and associated nerve roots shift consistently and significantly anteriorly when moving from the supine to the lateral position with knees and hips flexed, which may provide a greater margin of safety during neuraxial blockade than might be predicted. However, the absence of significant cranial movement of the CM along the cranio-caudal axis still makes the spinal cord vulnerable to injury during lumbar neuraxial blockade.

Poly(N-vinylpyrrolidone)-block-poly(D,L-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation.

The majority of novel anticancer drugs developed to date are intended for parenteral administration. Paradoxically, most of these drugs are water-insoluble, delaying their clinical development. A common approach to confering water solubility to drugs is to use amphiphilic, solubilizing agents, such as polyethoxylated castor oil (e.g., Cremophor EL, CrmEL). However, these vehicles are themselves associated with a number of pharmacokinetic and pharmaceutical concerns. The present work is aimed at evaluating a novel polymeric solubilizer for anticancer drugs, i.e., poly(N-vinylpyrrolidone)-block-poly(D,L-lactide) (PVP-b-PDLLA). This copolymer self-assembles in water to yield polymeric micelles (PM) that efficiently solubilize anticancer drugs, such as paclitaxel (PTX), docetaxel (DCTX), teniposide (TEN) and etoposide (ETO). A PM-PTX formulation was evaluated, both, in vitro on three different cancer cell lines and in vivo for its safety, pharmacokinetics, biodistribution and antitumor activity. In vitro, cytotoxicity studies revealed that the drug-loaded PM formulation was equipotent to the commercial PTX formulation (Taxol). In the absence of drug, PVP-b-PDLLA with 37% DLLA content was less cytotoxic than CrmEL. In vivo, acute toxicity was assessed in mice after a single injection of escalating dose levels of formulated PTX. PM-PTX was well tolerated and the maximum tolerated dose (MTD) was not reached even at 100 mg/kg, whereas the MTD of Taxol was established at 20 mg/kg. At 60 mg/kg, PM-PTX demonstrated greater in vivo antitumor activity than Taxol injected at its MTD. Finally, it was shown in mice and rabbits that the areas under the plasma concentration-time curves were inversely related to PM drug loading.

Preparation and characterization of water-soluble pH-sensitive nanocarriers for drug delivery.

pH-sensitive drug delivery systems can be engineered to release their contents or change their physicochemical properties in response to variations in the acidity of the surroundings. The present work describes the preparation and characterization of novel polymeric micelles (PM) composed of amphiphilic pH-responsive poly(N-isopropylacrylamide) (PNIPAM) or poly(alkyl(meth)acrylate) derivatives. On one hand, acidification of the PNIPAM copolymers induces a coil-to-globule transition that can be exploited to destabilize the intracellular vesicle membranes. In this work, PNIPAM-based PM were loaded with either doxorubicin or aluminium chloride phthalocyanine and their cytotoxicity was assessed in murine tumoral models. On the other hand, poly(alkyl(meth)acrylate) copolymers can be designed to interact with either hydrophobic drugs or polyions and release their cargo upon an increase in pH.

Novel polymeric micelles based on the amphiphilic diblock copolymer poly(N-vinyl-2-pyrrolidone)-block-poly(D,L-lactide).

PURPOSE: The purpose of this work was to synthesize a new amphiphilic diblock copolymer of poly(N-vinyl-2-pyrrolidone and poly(D,L-lactide) (PVP-b-PDLLA) capable of self-assembling into polymeric micelles with multiple binding sites and high entrapment efficiency. METHODS: The copolymer was synthesized by ring-opening polymerization of D,L-lactide initiated by potassium PVP hydroxylate. It was characterized by gel permeation chromatography, 1H- and 13C-NMR spectroscopy. The ability of the copolymer to self-assemble was demonstrated by dynamic and static light scattering, spectrofluorimetry and 1H-NMR. The hydrophobic model drug indomethacin was incorporated into the polymeric micelles by a dialysis procedure. Results. A series of amphiphilic diblock copolymers based on PVP-b-PDLLA were successfully synthesized. The critical association concentrations in water were low, always below 15 mg/L. Micellar size was generally bimodal with a predominant population between 40 and 100 nm. PVP-b-PDLLA micelles were successfully loaded with the poorly water-soluble drug indomethacin and demonstrated an entrapment efficiency higher than that observed with control poly(ethylene glycol)-b-PDLLA micelles. It was hypothesized that specific interactions with the hydrophilic outer shell could contribute to the increase in drug loading. CONCLUSION: PVP-b-PDLLA micelles appear to exhibit multiple binding sites and thus represent a promising strategy for the delivery of a variety of drugs.

Instrumental psychosis: the Good Soldier Svejk syndrome.

The possession of severe mental illness, mainly schizophrenia and affective psychosis, may be perceived in positive terms. We have identified a group of patients, most of them with a history of previous psychotic disorder, who present with deliberately created symptoms and behaviour, and who are defined as having instrumental psychosis. Because most such patients have had a psychotic disorder in the past the symptoms are very like those of a real psychosis. A parallel is drawn with the fictional anti-hero of the Czech nation, the Good Soldier Svejk, who demonstrated both real and instrumental psychosis. A rating scale, the 'pseudopsychosis inventory', was devised to identify the main components of this disorder and was applied in 15 consecutive patients presenting with putative psychotic disorders in whom assessment could be made by two raters within five days. The inter-rater reliability of the items of the scale was good (intra-class correlation coefficient 0.68). An epidemiological study with this scale in 45 patients with a putative psychotic disorder suggested the presence of instrumental psychosis in 2.

High-rate automated deposition system for the manufacture of complex multilayer coatings.

A previously described automated thin-film deposition system based on rf-magnetron sputtering could deposit quite complex optical multilayer systems with good precision and with no one in attendance [Sullivan and Dobrowolski, Appl. Opt. 32, 2351-2360 (1993)]. However, the deposition rate was slow, and the uniform area on the substrate was limited. We describe an ac-magnetron sputtering process in which the same deposition accuracy has been combined with significantly better film uniformity and a fivefold or sevenfold increase in the deposition rate. This makes the equipment of commercial interest. Experimental results are presented for several difficult coating problems.

Can primary prevention or selective screening for melanoma be more precisely targeted through general practice? A prospective study to validate a self administered risk score.

OBJECTIVES: To establish whether a questionnaire incorporating MacKie's risk factor flow chart can identify patients at high risk for melanoma so that they can be targeted for primary and secondary prevention. To validate the risk score derived from the questionnaire and test the feasibility of self completion by comparing patients' self reported skin characteristics with a skin examination performed by an experienced general practitioner. DESIGN: Prospective questionnaire survey followed by a comparative study. SETTING: 16 randomly selected group practices in a health district in Cheshire, United Kingdom. SUBJECTS: Questionnaire survey--3105 consecutive patients aged 16 years and over attending for a primary care consultation; comparative study--a self selected subsample of 388 of the 3,105 patients. MAIN OUTCOME MEASURES: MacKie risk group for melanoma. Comparison of high risk skin characteristics reported by patients and those noted during a skin examination by a doctor (kappa statistic). RESULTS: 4.3% of patients (87% women) were in the highest risk group and 4.4% (79% men) were in the second highest risk group, as defined by the MacKie score. Agreement between patients' self appraisal of skin characteristics and clinical skin examinations was reflected in kappa values of 0.67 for freckles, 0.60 for moles, and 0.43 for atypical naevi. CONCLUSION: This questionnaire helped to identify a group at high risk for melanoma. Furthermore, good agreement was found when the patient's risk scores were compared with results of the clinical skin examination. This risk score is potentially useful in targeting primary and secondary prevention of melanoma through general practice.

The treatment of stupor associated with MRI evidence of cerebrovascular disease.

OBJECTIVE: To describe the treatment and outcome of organic stupor associated with MRI evidence of cerebrovascular disease. DESIGN: A case series of three patients. SETTING: An urban mental health of the elderly service in southeast London. PATIENTS: Aged 69 years, 72 years and 78 years. Two had organic catatonic disorder and the third organic depressive disorder. INTERVENTIONS: Diazepam, carbamazepine, antidepressants or electroconvulsive therapy (ECT). MAIN OUTCOME MEASURES: Resolution of symptoms and discharge from hospital. RESULTS: Symptoms resolved between 1 and 10 days. All patients were able to return home but relapsed over the following 12 months. One relapse occurred when a patient stopped diazepam and moclobemide. CONCLUSIONS: It is proposed that the initial treatment of organic stupor associated with cerebrovascular disease should include a benzodiazepine or carbamazepine. If patients fail to respond then ECT should be considered. The safety of ECT is not known, when treating patients with depressive disorder associated with cerebrovascular disease.

In situ reflectance measurements of soft-x-ray/extreme-ultraviolet Mo/Y multilayer mirrors.

With a new ultrahigh-vacuum deposition/ref lectometer system, Mo/Y multilayer mirrors were deposited by dc-magnetron sputtering and characterized in situ with synchrotron radiation. The Mo/Y multilayer mirrors, measured before exposure to air, had near-normal-incidence reflectances as high as 46% at wavelengths near 11.4 nm. After several days of exposure these samples typically had a relative reflectance loss of ~10% as a result of oxidation of the top Mo layer. The best Mo/Y multilayers were fabricated with base pressures below the low 10(-9) Torr range and after a bakeout to reduce water vapor in the chamber.

Mo/Y multilayer mirrors for the 8-12-nm wavelength region.

Mo/Y multilayer mirrors were deposited by dc magnetron sputtering under different deposition conditions. They were characterized by reflectance measurements at normal and grazing angles of incidence, by transmission electron microscopy, and by Auger depth profiling. Normal-incidence peak reflectances of 34% and 22% were measured at wavelengths of 11.5 and 8.1 nm, respectively. Interface roughness and contamination of the layers during deposition limit the peak reflectance of these Mo/Y mirrors.

Mo/Y multilayer mirrors for the 8-12-nm wavelength region.

Mo/Y multilayer mirrors were deposited by dc magnetron sputtering under different deposition conditions. They were characterized by reflectance measurements at normal and grazing angles of incidence, by transmission electron microscopy, and by Auger depth profiling. Normal-incidence peak reflectances of 34% and 22% were measured at wavelengths of 11.5 and 8.1 nm, respectively. Interface roughness and contamination of the layers during deposition limit the peak reflectance of these Mo/Y mirrors.

Practical magnetron sputtering system for the deposition of optical multilayer coatings.

A magnetron sputtering system is described in which, at any one time, as many as four different 15-cm x 46-cm rectangular planar magnetron targets can be mounted vertically in the deposition chamber. These can be attached to either dc or rf power supplies for direct or reactive deposition of metal, metal oxide, or nitride films. Typical target materials include Ag, Al, C, Mo, Nb, Ni, Si, W, and Zr. Good uniformity can be obtained on stationary substrates, although better results are possible with oscillating substrates. The refractive indices are given for several useful oxide materials. The materials and thicknesses of the individual layers that comprise an optical multilayer system are entered into a computer that subsequently controls the deposition parameters, the substrate motion, and the deposition time. After a relatively simple calibration process, coatings that consist of between 20 and 60 layers can be produced to within an accuracy of 1% or 2%. A wideband optical monitor is available for checking the performance of the multilayer system during its deposition. Several examples of multilayer coatings that were prepared on this equipment are given.