Lessons learned during the development and transfer of technology related to a new Hib conjugate vaccine to emerging vaccine manufacturers

The incidence of Haemophilus Influenzae type b (Hib) disease in developed countries has decreased since the introduction of Hib conjugate vaccines in their National Immunization Programs (NIP). In countries where Hib vaccination is not applied routinely, due to limited availability and high cost of the vaccines, invasive Hib disease is still a cause of mortality. Through the development of a production process for a Hib conjugate vaccine and related quality control tests and the transfer of this technology to emerging vaccine manufacturers in developing countries, a substantial contribution was made to the availability and affordability of Hib conjugate vaccines in these countries. Technology transfer is considered to be one of the fastest ways to get access to the technology needed for the production of vaccines. The first Hib conjugate vaccine based on the transferred technology was licensed in 2007, since then more Hib vaccines based on this technology were licensed.     

Neural activity related to self- versus externally generated painful stimuli reveals distinct differences in the lateral pain system in a parametric fMRI study

Self-generated sensory stimulation can be distinguished from externally generated stimulation that is otherwise identical. To determine how the brain differentiates external from self-generated noxious stimulation and which structures of the lateral pain system use neural signals to predict the sensory consequences of self-generated painful stimulation, we used functional magnetic resonance imaging to examine healthy human subjects who received thermal-contact stimuli with noxious and non-noxious temperatures on the resting right hand in random order. These stimuli were internally (self-generated) or externally generated. Two additional conditions served as control conditions: to account for stimulus onset uncertainty, acoustic stimuli preceding the same thermal stimuli were used with variable or fixed delays but without any stimulus-eliciting movements. Whereas graded pain-related activity in the insula and secondary somatosensory cortex (SII) was independent of how the stimulus was generated, it was attenuated in the primary somatosensory cortex (SI) during self-generated stimulation. These data agree with recent concepts of the parallel processing of nociceptive signals to the primary and secondary somatosensory cortices. They also suggest that brain areas that encode pain intensity do not distinguish between internally or externally applied noxious stimuli, i.e., this adaptive biological mechanism prevents harm to the individual. The attenuated activation of SI during self-generated painful stimulation might be a result of the predictability of the sensory consequences of the pain-related action.     

Preserved responsiveness of secondary somatosensory cortex in patients with thalamic stroke

Cortical representations may change when somatosensory input is altered. Here, we investigated the functional consequences of partial "central" deafferentation of the somatosensory cortex due to a lesion of the ventroposterior lateral nucleus (VPL) in patients at a chronic stage after solitary infarction of the thalamus. Event-related functional magnetic resonance imaging during electrical index finger stimulation of the affected and nonaffected side was performed in 6 patients exhibiting contralesional sensory deficits (mainly hypesthesia). Involvement of the VPL and additional nuclei was determined by high-resolution magnetic resonance imaging (MRI) and subsequent MRI-to-atlas coregistration. For the group, statistical parametric maps showed a reduced activation of contralateral primary somatosensory cortex (SI) in response to stimulation of the affected side. However, no significant difference in the activation of contralateral secondary somatosensory cortex (SII) compared with stimulation of the nonaffected side was detected. Correspondingly, the ratio of SII-to-SI activation for the ipsilesional hemisphere was markedly elevated as compared with the contralesional hemisphere. For preserved responsiveness of SII in thalamic stroke comparable with that of the contralesional hemisphere, possible explanations are a direct thalamocortical input to SII mediating parallel information processing, nonlinear response behavior of SII in serial processing, or reorganizational processes that evolved over time.     

The human parietal operculum. II. Stereotaxic maps and correlation with functional imaging results

In this study we describe the localization of the cytoarchitectonic subdivisions of the human parietal operculum in stereotaxic space and relate these anatomically defined cortical areas to the location of the functionally defined secondary somatosensory cortex (SII cortex) using a meta-analysis of functional imaging results. The human parietal operculum consists of four distinct cytoarchitectonic areas (OP 1-4) as shown in the preceding publication. The 10 cytoarchitectonically examined brains were 3-D-reconstructed and spatially normalized to the T1-weighted single-subject template of the Montreal Neurological Institute (MNI). A probabilistic map was calculated for each area in this standard stereotaxic space. A cytoarchitectonic summary map of the four cortical areas on the human parietal operculum which combines these probabilistic maps was subsequently computed for the comparison with a meta-analysis of functional locations of SII. The meta-analysis used the results from 57 fMRI and PET studies and allowed the comparison of the functionally defined SII region to the cytoarchitectonic map of the parietal operculum. The functional localization of SII showed a good match to the cytoarchitectonically defined region. Therefore the cytoarchitectonic maps of OP 1-4 of the human parietal operculum can be interpreted as an anatomical correlate of the (functionally defined) human SII region. Our results also suggest that the SII foci reported in functional imaging studies may actually reflect activations in either of its architectonic subregions.     

Brain response to visceral aversive conditioning: a functional magnetic resonance imaging study

BACKGROUND & AIMS: Brain-imaging studies to date have confounded visceral pain perception with anticipation. We used functional magnetic resonance imaging of the human brain to study the neuroanatomic network involved in aversive conditioning of visceral pain and, thus, anticipation. METHODS: Eight healthy volunteers (5 male) participated in the study. We used a classic conditioning paradigm in which 3 neutral stimuli (differently colored circles) that acted as conditioned stimuli were paired with painful esophageal distention, air puff to the wrist, or nothing, which acted as unconditioned stimuli. Neural activity was measured during learning, anticipation (pairing only 50% of conditioned stimuli with their unconditioned stimuli), and extinction (unpaired conditioned stimuli) phases. For magnetic resonance imaging, axial slices depicting blood oxygen level-dependent contrast were acquired with a 1.5-T system. RESULTS: Neural responses during the learning phase included areas commonly associated with visceral pain (anterior cingulate cortex, insula, and primary and secondary somatosensory cortices) and innocuous somatosensory perception (primary and secondary somatosensory cortices and insula). During the anticipation and extinction phases of aversive stimulation, brain activity resembled that seen during actual painful esophageal stimulation. In contrast, anticipation and extinction of the innocuous somatic stimulus failed to show that effect. CONCLUSIONS: We have shown that actual and anticipated visceral pain elicit similar cortical responses. These results have implications for the design and interpretation of brain-imaging studies of visceral pain. They not only contribute to our understanding of the processing of visceral pain, but also have clinical implications for the management of chronic pain states.     

Distribution of cells of origin of the corticotrigeminal projections to the nucleus caudalis of the spinal trigeminal complex in the cat. A horseradish peroxidase (HRP) study

The cortical distribution of cells of origin of the corticotrigeminal projections to the nucleus caudalis of the cat was examined using the method of retrograde axonal transport of horseradish peroxidase (HRP). After injections of HRP into the nucleus caudalis, labeled cells were distributed densely in the anterior suprasylvian gyrus, the coronal gyrus, and the ventral part of the anterior sigmoid gyrus, and moderately in the rostral part of the anterior ectosylvian gyrus on the contralateral side. In the anterior suprasylvian gyrus, the distribution extended rostrocaudally from the lateral ansate sulcal level to about 4.0 mm caudal to this level and mediolaterally throughout the convex of the anterior suprasylvian gyrus. All cortical labeled cells were pyramidal cells of various sizes in layer V.     

Effects of morphine and barbiturate on the SI and SII potentials evoked by tooth pulp stimulation of rats.

The effects of morphine and barbiturate on the evoked potentials recorded from the primary and secondary somatic sensory areas of rats were investigated. The electric stimulation of contra- and ipsilateral tooth pulp (CTP and ITP) was used. The afferent impulse from dental pulp projected to the sensory face areas I and II (SI and SII). Morphine in doses of 2.5-10 mg/kg definitely inhibited SI and SII potentials evoked by CTP stimulation. Morphine also inhibited SII potentials evoked by ITP stimulation, while it rather enhanced SI potentials evoked by ITP stimulation. Pentobarbital sodium in doses of 4-16 mg/kg tended to inhibit SI potentials, but showed no effect or rather an enhancement on SII potentials evoked by CTP stimulation. Pentobarbital sodium enhanced SI and SII potentials evoked by ITP stimulation. In a large dose of 32 mg/kg, pentobarbital sodium inhibited SI and SII potentials evoked by ITP and CTP stimulations. The results suggest that SII is more closely related to the analgesia due to morphine than is SI.     

Cortical relay neurons and interneurons in the N. ventralis posterolateralis of cats: a horseradish peroxidase, electron-microscopic, Golgi and immunocytochemical study

After injections of horseradish peroxidase involving the whole primary (SI) and secondary somatosensory (SII) areas of adult cats, 16-21% out of 2220 counted neurons in the nucleus ventralis posterolateralis were unlabelled. The mean areas of perikarya of these neurons varied between 111.8 +/- 32.3 microns2 and 180.8 +/- 48.6 microns2. The size of perikarya of retrogradely-labelled neuron ranged from 256.9 +/- 100.4 microns2 to 409 +/- 163 microns2. Retrogradely-labelled and unlabelled neurons were examined under light- and high-voltage electron-microscopy. Besides 'large', mainly multipolar or oval fusiform perikarya, retrogradely-labelled neurons may display perikarya of 'small' size. Both types of neurons correlate well with Golgi-impregnated cells with a tufted dendritic pattern usually identified as thalamocortical neurons. On the other hand, the size and morphology of perikarya and initial dendrites of neurons unlabelled by retrograde transport of horseradish peroxidase correlate well with that of Golgi-impregnated neurons which are markedly different from the thalamocortical neurons, have very characteristic and profuse dendritic appendages and have been identified by previous investigators as Golgi Type II neurons. In order to probe further whether these may correspond to the GABAergic interneurons proposed by previous evidence, an immunocytochemical approach was also applied at the light- and electron-microscope level, using an antiserum prepared in sheep against rat brain glutamate decarboxylase. By this method it is shown that 19-21% of neurons in the nucleus ventralis posterolateralis of adult cats are glutamate decarboxylase-positive and that the perikaryal size of these labelled neurons ranges between 134.6 +/- 44.5 microns2 and 164.4 +/- 47.3 microns2. Histogram distribution of the number and areas of the counted immunoreactive neurons closely matches that of unlabelled neurons in experiments with retrograde transport of horseradish peroxidase. The results give support to previous evidence suggesting that part of population of neurons in the nucleus ventralis posterolateralis is represented by a distinct class of neurons which are apparently GABAergic.     

Clinical Experience with Somatrem in Growth Hormone Deficiency

ABSTRACT. Three studies of human growth hormone (hGH) in hGH deficiency were initiated. In the first of these, adolescent patients were switched from pituitary hGH to somatrem (SI preparation) for 1 month. No significant differences were noted in any of the clinical parameters measured during treatment with either preparation. In the second study, nine patients (six of them naïve) were treated with somatrem (SII preparation) for 9–12 months. The naïve patients exhibited catch-up growth, and bone age developed in parallel to chronological age during the study period. Somatomedin activity increased and correlated positively with growth. Antibodies to hGH and Escherichia coli polypeptide (ECP) developed in some patients, but titres and binding capacities were low. In the third study, 21 patients are currently being treated with Somatonorm; the first 3–6 months are evaluable. Growth velocities increased to normal values. Antibodies to hGH and ECP were present in several patients, but again the titres and binding capacities were low, and Somatonorm was less antigenic than the SI and SII preparations.     

The corticothalamic projection from the second somatosensory cortical area in the cat an experimental study with silver impregnation methods

Summary The corticothalamic projection from the anterior ectosylvian gyrus in the cat has been studied with the silver impregnation method of Nauta. The second somatosensory cortical area (SII) projects upon the ipsilateral nucleus ventralis posterolateralis (VPL), nucleus ventralis posteromedialis (VPM), the posterior thalamic region (PO) and to a slight extent upon the reticular nucleus of the thalamus (R), the centrum medianum (CM), the parvocellular part of VPM (VPMpc) and the nucleus ventralis posterior inferior (VPI). A somatotopical arrangement in the projection upon the ventro-basal (VB) complex has been demonstrated and a topical arrangement in the corticothalamic fibers from SII to PO is also evident. The transitional area between SII and the second auditory cortex sends fibers mainly to the entire magnocellular part of the medial geniculate body (MGmc) and to a lesser degree to the principal division of this nucleus (MGp). The corticofugal fibers from SII follow various and rather complicated circuitous routes before they end in the different thalamic nuclei. The experimental findings are discussed in the light of recent anatomical and physiological observations. It is shown that zones B and C of SII which have been shown by Carreras and Andersson (1963) to possess a large number of place and modality specific neurons project upon the VB-complex. On the other hand, zone A which contains a majority of place and modality unspecific neurons sends its fibers exclusively to PO. Finally the problem of thalamocortical projections to SII is briefly discussed. Addendum: After the present paper had been submitted for publication the work of DeVito (1967) came to the author's knowledge. Several of the findings made by DeVito have been confirmed in the present study. On the other hand, DeVito has not considered Carreras and Andersson's zones A, B and C in SII and she does not describe a somatotopical arrangement in the projection from SII upon the VB complex and PO.