Responses of Neurons of the Nucleus of the Optic Tract and the Dorsal Terminal Nucleus of the Accessory Optic Tract in the Awake Monkey

The nucleus of the optic tract (NOT) and the dorsal terminal nucleus of the accessory optic tract (DTN) are essential nuclei for the generation of slow-phase eye movements during horizontal optokinetic nystagmus. We recorded from 101 neurons (all directionally selective) in four NOT/DTN of three trained and behaving rhesus monkeys. Neuronal activity increased when stimuli moved ipsiversively with respect to the recording site and decreased below spontaneous activity when stimuli moved contraversively. While the monkey fixated a small spot, some NOT/DTN neurons did not respond at all to the retinal image slip of a whole-field random dot pattern; others showed a monotonic increase of activity to increasing velocities of that stimulus. The velocity range tested was up to 100°/s. During the execution of optokinetic nystagmus, 39 of 73 cells tested showed a velocity-tuned response with an average optimum at 21°/s retinal image slip. Following saccades during optokinetic nystagmus (quick phases), the NOT/DTN neuronal activity briefly attained the level of spontaneous activity, as predicted from the velocity selectivity during optokinetic nystagmus. Immediately upon cessation of optokinetic stimulation in the preferred direction, NOT/DTN activity returned to the spontaneous level and did not reflect the ongoing optokinetic afternystagmus in darkness. Most NOT/DTN neurons displayed direction selectivity also during smooth pursuit. Twenty-one of 50 cells tested (42%) always responded to the retinal slip of the target (target velocity cells), 16 cells (32%) responded to the retinal slip of the background (background velocity cells), and 13 cells (26%) did not respond at all during smooth pursuit. We conclude from our results that the NOT/DTN is an essential structure for the processing of the direction and speed of retinal image slip. This information is then used for the generation and maintenance of slow eye movements, preferentially during horizontal optokinetic nystagmus but also during pursuit eye movements.     

Optic papilla parameters in healthy subjects--quantified with the optic nerve head analyzer

The cup-disk ratio (CDR), the size of the neuroretinal rim area as well as the other disk parameters investigated with the Optic Nerve Head Analyzer (ONHA) were measured in double examinations of 32 healthy eyes in 32 patients. Thus, "normal" values were determined for the various disk parameters. A new method is presented for calculating one average pallor value for the disk. The mean value for disk pallor in healthy eyes is determined. Examination of the CDR in the quadrants of the disk reveals significant differences. According to the results of a multi-regressional analysis of the various disk parameters, the size of the neuroretinal rim area in healthy eyes is influenced by the size of the disk, the disk volume and the elevation volume. The correlation between the size of the neuroretinal rim area and the size of the disk reveals a significant interdependence: a larger disk also has a greater neuroretinal rim area as compared to a smaller disk. This means that sizes of neuroretinal rim areas of different disk should only be compared when the disks are the same size. Relative values, such as the CDR or the ratio between the size of the neuroretinal rim area and disk size (rim area/disk area), are therefore better suited for comparison.     

Megalencephaly in sudden infant death syndrome

The fresh brain weights of 79 infants with sudden infant death syndrome (SIDS) were tabulated and compared with expected "normal" brain weights. The series included 47 males and 32 females. Their ages ranged from 8 days to 16 months with a median of 2.5 months. The weights of all these brains were above the 50th percentile for age, and 64 of 79 brains (81%) were above the 95th percentile, including 15 (19%) at or above the 99.9th percentile. The ratio of the brain stem plus cerebellum weight to the whole brain weight of 93 formalin-fixed brains from victims of SIDS showed that the cerebrum was disproportionately heavier in most cases. No gross or microscopic evidence of cerebral edema was noted to account for the heavier weight. The significance of these findings is debatable. The increase in brain weight was less obvious in infants younger than 1 month of age but accelerated after that age. The brain weights of infants with SIDS may represent the really "normal" weights, since these patients were not known to be ill prior to death. If the brain weights of SIDS infants are really heavier than "normal," the possibility must be considered that disproportionately rapid growth of the brain during early infancy may be detrimental to the neural control of the cardiorespiratory system.     

Postextrasystolic regulation patterns of blood pressure and heart rate in patients with idiopathic dilated cardiomyopathy

Assessment of fluctuations in heart rate (HR) following a premature ventricular complex (PVC) is valuable for identifying patients at high risk of sudden cardiac death. We hypothesised that postextrasystolic potentiation is the main determinant of the regulation patterns of blood pressure (BP) and HR following a PVC. Twelve patients with idiopathic dilated cardiomyopathy (IDC) and 13 control subjects with single PVCs (comparable coupling intervals) were investigated. Non-invasive finger arterial BP and ECGs were analysed. Regulation patterns following a single PVC were quantified using the indices postextrasystolic amplitude potentiation (PEAP) and maximum turbulence slope of five consecutive mean BP values (MBP-TS), and compared with the HR turbulence parameters turbulence slope (HR-TS) and turbulence onset (HR-TO). PEAP was significantly higher in IDC patients compared to controls (48.7 ± 32.6 vs. 9.8 ± 5.4 %, P < 0.01), whereas MBP-TS was lower (0.97 ± 0.60 vs. 2.07 ± 1.04 mmHg BBI⁻¹ (BBI, beat-to-beat interval), P < 0.05), as was HR-TS (8.46 ± 7.90 vs. 30.73 ± 22.90 ms BBI⁻¹, P < 0.01). HR-TO was significantly higher in IDC patients (−0.56 ± 2.19 vs. −5.52 ± 4.13 %, P < 0.01). In addition, the regulation patterns of BP and HR following a single PVC differed significantly between IDC patients and controls. Specifically, we observed pronounced PEAPs in IDC patients. The baroreflex response initiated by the low pressure amplitude of the PVC was suppressed in IDC patients due to the augmented potentiation of the first postextrasystolic blood pressure. Furthermore, IDC patients displayed impressive postextrasystolic pulsus alternans phenomena, whereas healthy subjects exhibited a typical baroreflex pattern. The pulsus alternans phenomenon seems to be triggered by a PVC.     

Effects of muscle conditioning on position sense at the human forearm during loading or fatigue of elbow flexors and the role of the sense of effort

In a forearm position-matching task in the horizontal plane, when one (reference) arm is conditioned by contraction and length changes, subjects make systematic errors in the placement of their other, indicator arm. Here we describe experiments that demonstrate the importance not just of conditioning the reference arm, but of the indicator arm as well. Total errors from muscle conditioning represented up to a quarter of the angular range available to subjects. The sizes of the observed effects have led us to repeat other, previously reported experiments. In a matching task in the vertical plane, when muscles of both arms were conditioned identically, if the subject supported their arms themselves, or when the arms were loaded by the addition of weights, the loading did not introduce new position errors. To test the effect of exercise, subjects' elbow flexors were exercised eccentrically or concentrically by asking them to lower or raise a set of weights using forearm muscles. The exercise produced 25–30% decreases in maximum voluntary contraction strength of elbow flexors and this led to significant position-matching errors. The directions and magnitudes of the errors were similar after the two forms of exercise and indicated that subjects perceived their exercised muscles to be longer than they actually were. To conclude, the new data from loading the arm are not consistent with the idea that the sense of effort accompanying support of a load, provides positional information in any simple way. Our current working hypothesis is that when muscles are active, position-sense involves operation of a forward internal model. Loading the arm produces predictable changes in motor output and afferent feedback whereas changes after exercise are unpredictable. This difference leads to exercise-dependent errors.     

Expression of keratin K2e in cutaneous and oral lesions: association with keratinocyte activation,proliferation, and keratinization

The cytoskeleton in keratinocytes is a complex of highly homologous structural proteins derived from two families of type I and type II polypeptides. Keratin K2e is a type II polypeptide that is expressed in epidermis late in differentiation. Here we report the influence of keratinocyte activation, proliferation, and keratinization on K2e expression in samples of cutaneous and oral lesions. The normal expression of K2e in the upper spinous and granular layers of interfollicular epidermis is increased in keloid scars but showed distinct down-regulation in psoriasis and hypertrophic scars where keratinocytes are known to undergo activation. Unlike normal and psoriatic skin, K2e expression in hypertrophic and keloid scars began in the deepest suprabasal layer. In cutaneous basal and squamous cell carcinomas, K2e was absent in most tumor islands but the overlying epidermis showed strong expression. No significant K2e expression in nonkeratinized or keratinized oral epithelia, including buccal mucosa, lateral border of tongue and gingiva was detected. In oral lichen planus K2e expression was undetectable, but in benign keratoses of lingual mucosa induction of K2e along with K1 and K10 was observed. In mild-to-moderate oral dysplasia with orthokeratinization, K2e was highly expressed compared with parakeratinized areas but in severe dysplasia as well as in oral squamous cell carcinoma, K2e expression was undetectable. Taken together, the data suggest that K2e expression in skin is sensitive to keratinocyte activation but its up-regulation in oral lesions is a reflection of the degree of orthokeratinization.     

Isolation of DNA from the centromere of human chromosome 7 by microdissection

Centromeres remain the least characterized regions of human chromosomes because they have a very high content of repetitive DNA. Here, we describe a micro-dissection library from the centromeric region of human chromosome 7 and its use for generating sequence tagged sites (STSs). The library contains about 1500 clones with an average insert size of 150 bp and only about 15% of the clones harbour repetitive human DNA. Seven clones hybridizing to alphoid DNA were found to correspond to a fragment of the D7Z2 alphoid array on chromosome 7, thus confirming the origin of the library. A number of clones not containing known repetitive DNA were used to generate STSs that identified yeast artificial chromosomes (YACs) and in turn allowed the STSs to be placed on the physical map. One STS is located between the two Genethon genetic markers closest to the centromere on the q side. Another STS was located 3–4 cM away in 7q11.2, while a third identified YACs containing both low-copy and alphoid sequences that are not yet mapped but are clearly centromeric. The library therefore comprises a collection of sequences from the centromeric region of chromosome 7 that can be used to generate STSs and to map the entire centromeric region.This revised version was published online in November 2005 with corrections to the Cover Date.     

Mutation of luxS of Streptococcus pneumoniae affects virulence in a mouse model

The LuxS protein is required for the biosynthesis of the type 2 autoinducer (AI-2), which is involved in quorum sensing in a wide range of bacterial species. We have determined the effects of a defined luxS mutation on the virulence of Streptococcus pneumoniae. Although the luxS mutant displayed reduced virulence relative to its wild-type parent, the type 2 strain D39, it was by no means avirulent in a mouse model. After intranasal administration, the luxS mutant was able to colonize the nasopharynx of the mouse as efficiently as the wild type. However, it was less able to spread from the nasopharynx to the lungs or the blood. Intraperitoneal coadministration studies indicated that the luxS mutant was less fit and was readily outcompeted by wild-type D39. However, when administered on its own by this route, the mutant was able to proliferate and cause fatal systemic disease, albeit at a lower rate than the wild type. Western blot analysis of whole-cell lysates of the mutant and its parent did not reveal any differences in the levels of several well-characterized virulence proteins. However, analysis of Coomassie blue-stained protein profiles after separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that mutation of luxS had pleiotropic effects on protein expression in all cellular compartments. This is consistent with the product of luxS having a regulatory role in S. pneumoniae. This is the first report of a direct role for luxS (and by inference, AI-2) in the virulence of a gram-positive pathogen. However, the fact that mutagenesis of luxS does not completely attenuate S. pneumoniae has implications for the possible use of AI-2 antagonists for treatment of pneumococcal infections.     

Trisomy 3 Is Not a Common Feature in Malignant Lymphomas of Mucosa-Associated Lymphoid Tissue Type

The genetic background of extranodal marginal zone B-cell non-Hodgkin’s lymphoma (NHL) of mucosa-associated lymphoid tissue (MALT) type is poorly understood. In contrast to most entities of primary nodal lymphomas, few cytogenetic data are available, and gene rearrangements frequently encountered in and highly characteristic of certain entities of systemic NHL are absent in this type of lymphoma. Recently, it was suggested that MALT-type NHLs are associated with certain numerical chromosome aberrations and especially with trisomy 3. We performed an extensive study using a sensitive double (bicolor) fluorescence in situ hybridization technique for the analysis of trisomies for chromosomes 3, 7, 12, and 18 in 60 samples of low-grade and 45 high-grade MALT-type tumors. In the low-grade cases, trisomy 3 was found in a frequency of only 20%. High-grade lymphomas of MALT type were associated with trisomies 3, 7, 12, and 18 in 36, 20, 18, and 13% of the cases, respectively. Whereas no difference was encountered for trisomy 3 in primary and secondary/simultaneous high-grade lymphomas, +7 and +12 were associated with primary lymphomas, and a +18 was predominantly found in secondary/simultaneous high-grade NHL. These results challenge earlier reports describing a high frequency of +3 in low-grade MALT-type NHL and indicate a possibly different genetic evolution pattern of primary and secondary/simultaneous high-grade lymphomas of primary mucosal origin.