Cognitive function in 6- to 12-year-old offspring of women with Type 1 diabetes.

AIMS: Maternal diabetes is a recognized risk factor for congenital malformation, perinatal morbidity and obesity in later childhood. The aim of this study is to assess the impact of maternal diabetes on cognitive function in offspring. METHODS: Participants were 6- to 12-year-old offspring of women with Type 1 diabetes. All women received their antenatal care and delivered at one university hospital. HbA(1c) was monitored monthly throughout pregnancy and cognitive function was assessed using the Wechsler Intelligence Scale for Children, version 4. RESULTS: We present results in 40 offspring. There was no difference in overall full-scale IQ compared with UK normative data. However, working memory was poorer than other parts of the Wechsler Intelligence Scale for Children version 4 test and significantly lower compared with UK normative data [8.4 (2.2) vs. 10.1 (3.2), P < 0.01]. We found no correlation between measurement of digit span or HbA(1c) at any stage during pregnancy (r = -0.225 to 0.002), gestational age at delivery (r = -0.178) or infant birthweight ratio (r = -0.176). There was no relationship between working memory score and maternal hypoglycaemia episodes or maternal duration of diabetes. Comparing infants born before (n = 9) or after 37 weeks' gestation, digit span was non-significantly lower [7.9 (1.8) vs. 8.6 (2.4)]. DISCUSSION: These results suggest offspring of women with Type 1 diabetes have normal overall cognitive function but poorer working memory. We have been unable to identify specific risk factors. Further larger studies are required to increase the understanding of this memory defect and identify any modifiable risk factors.

Measurement of mismatch negativity in individuals: a study using single-trial analysis.

Mismatch negativity (MMN) is measured by subtracting the averaged response to a set of standard stimuli from the averaged response to rarer deviant stimuli, and taking the amplitude of this difference wave in a given time window. This method is problematic when used to evaluate individuals, because there is no estimate of variance. We describe a new approach, in which independent components with high trial-by-trial variance are first removed. Next, each deviant response has the preceding standard response subtracted, giving a set of single trial difference waves. We illustrate this approach in analysis of MMN to brief tones in 17 adults. The best criterion for MMN combined t-test with an index of inter-trial coherence, giving significant MMN in 14 (82%) of individuals. Single-trial methods can indicate which people show MMN. However, in some clinically normal individuals there was no MMN, despite good behavioral discrimination of stimuli.

Implementing the International Health Regulations (2005) in Europe.

The adoption of the International Health Regulations (2005) (also referred to as IHR(2005) or the revised Regulations) provides a remarkable new legal tool for the protection of international public health. Upon entry into force on 15 June 2007, Article 2 ('Purpose and scope') provides that the overall focus of the efforts of States Parties (and World Health Organization's efforts under the revised Regulations will be to prevent, protect against, control and provide a public health response to the international spread of disease in ways that are commensurate with the public health risks and which avoid unnecessary interference with international traffic. Health measures under the revised Regulations will be implemented with respect for travellers' human rights, with several specific new requirements in this area. To comply with the IHR(2005), States Parties (WHO member states that will be bound by the IHR(2005)) will have to have core public health capacities in disease surveillance and response, as well as additional capacities at designated international ports, airports and land crossings. This unique collective commitment will require close collaboration between WHO and the States Parties, but also intersectoral collaboration within the States themselves, including collaboration among different administrative or governmental levels, a particular issue for federal states, and horizontally across ministries and disciplines. Collaboration among States Parties is a key aspect of the revised Regulations, whether among neighbours, or with trading partners, members of regional economic integration organisations or other regional groups, or simply members of the international community. This collaboration is particularly relevant for the Member States of the European Union.

[Detection of meningococcal meningitis epidemics in Africa: a new recommendation]. / Mieux détecter les épidémies de méningite à méningocoque en Afrique: une nouvelle recommandation.

In sub-Saharan Africa, the control of meningococcal meningitis epidemics relies on early epidemic detection and mass vaccination. However, experience shows that interventions are often initiated too late to have a significant impact on the epidemic. A new recommendation drafted by participants of a consensus meeting proposes an alert threshold and an epidemic threshold based on the weekly number or incidence of meningitis cases, according to the population size and the epidemic risk, resulting in indicators with high sensitivity and specificity for the detection of an emerging epidemic. Meningitis outbreak investigations must include an assessment of the quality of epidemiologic surveillance. The new recommendation is published in English and French in the Weekly Epidemiologic Record [12]. The success of this consensus meeting shows the value of integrating results from surveillance, field experience and operational research for designing new health strategies.

Rapid-onset dystonia-parkinsonism: a clinical and genetic analysis of a new kindred.

BACKGROUND: Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disorder linked to chromosome 19q13 that is characterized by sudden onset of primarily bulbar and upper limb dystonia with parkinsonism. METHODS: The authors evaluated 12 individuals from three generations of an Irish family and obtained detailed medical records on a deceased member. The authors describe the clinical, psychiatric, and genetic features of the affected individuals. RESULTS: Five of eight affected members developed sudden-onset (several hours to days) dystonia with postural instability. Four of the five also had bulbar symptoms. Two have stable focal or segmental limb dystonia. One has intermittent hemidystonia with dysarthria that comes on abruptly in times of stress or anxiety. Three had a history of profound difficulty socializing, and at presentation two developed depression. Three patients had a trial of dopamine agonists without benefit. Genetic analysis suggests linkage to chromosome 19 with lod score of 2.1 at zero recombination. CONCLUSION: This is the third reported family with chromosome 19q13 rapid-onset dystonia-parkinsonism. Psychiatric morbidity appeared common in affected members of this family and may be part of the RDP phenotype.

Cortical evoked potentials due to motion contrast in the blind hemifield.

Subcortical visual inputs to motion-selective cortex in primates survive after damage to the primary visual cortex (area 17/V1). Activation of human motion cortex was examined using scalp electrodes in a V1-damaged hemianope. Blind field motion-onset visual evoked potentials (VEPs) shared many of the characteristics associated with sighted vision but were smaller in amplitude and had longer latencies. The representative negative wave (C(II) peak) showed typical dependency on stimulus contrast, its peak latency increased and amplitude decreased as contrast decreased, reflecting the difficulty with which directional information could be detected. VEPs were present at contrasts below 25% when blind field motion was imperceptible even though direction guessing was paradoxically accurate. Subcortical inputs to motion cortex contribute to visual experience but not to conscious perception.

Reversible inactivations of the cerebellum with muscimol prevent the acquisition and extinction of conditioned nictitating membrane responses in the rabbit.

Lesions of the cerebellum severely impair the classically conditioned nictitating membrane response (NMR) in rabbits. Thus, the cerebellum is essential for the production of conditioned responses (CRs), either because it is actively involved in NMR conditioning or because damage to it causes motor or other general deficits. To distinguish between these alternatives, the cerebellum may be inactivated during training. Inactivation of the cerebellum during acquisition training might result in the absence of CRs on initial trials of subsequent training without the neuronal blockade. The blockade may have prevented learning but it may have produced other deficits that require time or further training to overcome. This problem can be addressed by inactivating the cerebellum during extinction training. If inactivation during extinction training results in the immediate production of CRs when training is resumed without the blockade, then it may be concluded that extinction learning was prevented by the blockade-the presence of CRs argues against any deficits not associated with learning. We used muscimol to inactivate the cerebellum and test its involvement in acquisition and extinction of NMR conditioning in the same subjects. We injected muscimol close to the interpositus nucleus of the cerebellum 1 h before each of four daily training sessions of delay conditioning. Almost no CRs were produced in these training sessions-there was little or no acquisition of NMR conditioning during cerebellar inactivation. The subjects were then trained for four daily sessions without injections of muscimol. There were no CRs on initial trials of the first session of retraining, but all subjects produced CRs by the end of this session. The subjects then received four daily sessions of extinction training with muscimol inactivation of the nuclei-no CRs were produced. Extinction training then continued for four daily sessions without muscimol inactivation. On the first of these sessions, all subjects immediately produced high levels of CRs. These responses then extinguished within and between sessions with characteristic beginning-of-session spontaneous recovery. There was little or no extinction of NMR conditioning during cerebellar inactivation. After inactivation, the muscimol- inactivated subjects went on to acquire and extinguish NM responses at rates similar to those of appropriate controls. We conclude that cerebellar circuitry is essential for, and actively engaged in, both acquisition and extinction of this simple form of motor learning.

Cerebellar cortex and eyeblink conditioning: a reexamination.

We examined the effects of cerebellar cortical lesions upon conditioned nictitating membrane responses in rabbits. Using extended postoperative conditioning and unpaired presentations of the conditioned stimuli (CSs), we confirmed that combined lesions of lobules HVI and ansiform lobe abolished conditioned responses (CRs) established to light and white noise CSs. Extended retraining enabled some slight recovery of CR frequencies. Less extensive cortical lesions produced initial abolition of CRs but allowed more complete recoveries. Although CR frequencies and amplitudes were profoundly depressed by cortical lesions, unconditioned response (UR) amplitudes to periorbital electrical stimulation were enhanced. The dissociation of lesion effects upon conditioned and unconditioned responses is consistent with the suggestion that cerebellar cortical mechanisms are important for the learning and execution of eyeblink conditioning.

The Effect of Kainic Acid Lesions of the Cerebellar Cortex on the Conditioned Nictitating Membrane Response in the Rabbit.

In previous studies we have shown that aspiration lesions centred on lobule HVI in the cerebellar cortex of rabbits produce a profound loss of conditioned nictitating membrane (NM) responses. Because aspiration lesions of the cerebellar cortex cause retrograde degeneration in precerebellar nuclei we tested in rabbits whether excitotoxic lesions of the cerebellar cortex that spare these precerebellar nuclei also cause a loss of conditioned NM responses. Following discrete injections of kainic acid into HVI and rostral regions of the adjacent folia of crus I and crus II, we observed an immediate loss of conditioned NM responses. Following extensive retraining several subjects showed a gradual recovery of conditioned responses. But subjects with the most complete lesions never recovered more than a few conditioned responses. Kainic acid lesions did not change ipsilateral unconditioned reflex responses to a range of stimulus intensities. The kainic acid injections caused obvious degeneration of Purkinje and granule cells but not of the precerebellar nuclei. We conclude that HVI and parts of crus I and crus II are essential for normal retention of conditioned NM responses.

Visual projections to the pontine nuclei in the rabbit: orthograde and retrograde tracing studies with WGA-HRP.

Visual projections to the pontine nuclei in the rabbit were examined by means of both orthograde and retrograde tracing of WGA-HRP. The tecto-pontine projection was examined following microinjections of WGA-HRP in the right superior colliculus. The projection to the pontine nuclei is strictly ipsilateral and terminates at middle and caudal levels of the pons. The projection is absent in rostral pontine nuclei. The strongest projection is to the dorsal border of the dorsolateral pontine nuclei and is the only projection seen when the primary injection site is confined to superficial laminae. When the primary injection site also includes intermediate and deep laminae, patches of labelled terminals are also seen within dorsolateral, lateral, peduncular, paramedian, and ventral pontine nuclei as well as in the contralateral nucleus reticularis tegmenti pontis. The striate corticopontine projection was also examined with orthograde tracing of WGA-HRP. The striate corticopontine projection is ipsilateral. Most labelled terminals were seen in dorsolateral and lateral pontine nuclei throughout the rostral half of pons with some additional terminal labelling in paramedian and peduncular nuclei. Labelled terminals were also seen in ventral pontine nuclei throughout the middle and caudal levels of the pons. In a retrograde tracing study, visual projections to the pontine nuclei were examined following microinjections of WGA-HRP into the pontine nuclei. Labelled cells were seen ipsilaterally in superficial and deep laminae of the superior colliculus and in layer V of striate and surrounding occipital cortex. The pontine nuclei also receive ipsilateral projections from the ventral lateral geniculate, the nucleus of the optic tract, anterior and posterior pretectal nuclei, and the dorsal and medial terminal nuclei of the accessory optic system. These pathways are potential sources of visual input to the cerebellum.

Hippocampal lesions and trace conditioning in the rabbit.

Trace conditioning of the nictitating membrane response (NMR) was examined in rabbits with lesions of the dorsal hippocampus and fimbria-fornix. Using a white noise conditional stimulus and an electrical shock unconditional stimulus, the number and amplitude of conditional responses (CRs) was similar in hippocampus-lesioned and control subjects. At some stages of conditioning, the latencies of CRs from hippocampus-lesioned subjects were slightly shorter than those of the controls. We suggest that the hippocampus is not essential for trace conditioning but may exert a modulatory influence on the timing of the CR.

Classical conditioning of the nictitating membrane response of the rabbit. IV. Lesions of the inferior olive.

The nictitating membrane response (NMR) of 15 rabbits was conditioned to light and white noise conditional stimuli (CSs) using a periorbital shock unconditional stimulus (US). Unilateral lesions of the inferior olive were then made. Lesions restricted to the medial parts of rostral dorsal accessory olive (DAO) and principal olive (PO) abolished conditioning and prevented subsequent acquisition on either side. Unconditional responses to the US were intact. Lesions in all other parts of the olive did not impair conditioning. The effective lesions were located in that part of the olive which supplies somatosensory information from the face to cerebellar lobule HVI. Lobule HVI is also essential for NMR conditioning. We suggest that this region of the inferior olive is part of a circuit which provides US information to the cerebellar cortex during NMR conditioning.

Classical conditioning of the nictitating membrane response of the rabbit. III. Connections of cerebellar lobule HVI.

We report the connections of cerebellar cortical lobule HVI in the rabbit. We have studied the anterograde and retrograde transport of wheatgerm-agglutinated horseradish peroxidase (WGA-HRP) following its injection into HVI to reveal efferent and afferent connections. All of the cases showed strong anterograde transport to the anterior interpositus nucleus (AIP) - indicating that this is the major efferent target of HVI. Retrogradely labelled cells were found in the inferior olivary, spinal trigeminal, lateral reticular, inferior vestibular and pontine nuclei. Within the olive, the medial part of the rostral dorsal accessory olive (DAO) and the adjacent medial part of the principal olive (PO) were consistently labelled in all cases. This area is known to receive somatosensory information from the face and neck. There was no projection to the hemispheral part of lobule VI from visual parts of the olive within the dorsal cap and medial parts of the medial accessory olive. Likely sources of visual and auditory information to HVI are the dorsolateral basilar pontine nuclei and nucleus reticularis tegmenti pontis, which were densely labelled in all cases. These anatomical findings are consistent with the suggestion that, during NMR conditioning, information related to the periorbital shock unconditional stimulus (US) may be provided by climbing fibres to HVI and light and white noise conditional stimulus (CS) information may be supplied by pontine mossy fibres.