Operational classification of cutaneous squamous cell carcinomas based on unsupervised clustering of real cases by experts.

BACKGROUND: There is currently no staging system for cutaneous squamous cell carcinoma (cSCC) that is adapted to decision-making and universally used. Experts have unconscious ability to simplify the heterogeneity of clinical situations into a few relevant groups to drive their therapeutic decisions. Therefore, we have used unsupervised clustering of real cases by experts to generate an operational classification of cSCCs, an approach that was successful for basal cell carcinomas. OBJECTIVE: To generate a consensual and operational classification of cSCCs. METHOD: Unsupervised independent clustering of 248 cases of cSCCs considered difficult-to-treat. Eighteen international experts from different specialties classified these cases into what they considered homogeneous clusters useful for management, each with freedom regarding clustering criteria. Convergences and divergences between clustering were analysed using a similarity matrix, the K-mean approach and the average silhouette method. Mathematical modelling was used to look for the best consensual clustering. The operability of the derived classification was validated on 23 new practitioners. RESULTS: Despite the high heterogeneity of the clinical cases, a mathematical consensus was observed. It was best represented by a partition into five clusters, which appeared a posteriori to describe different clinical scenarios. Applicability of this classification was shown by a good concordance (94%) in the allocation of cases between the new practitioners and the 18 experts. An additional group of easy-to-treat cSCC was included, resulting in a six-group final classification: easy-to-treat/complex to treat due to tumour and/or patient characteristics/multiple/locally advanced/regional disease/visceral metastases. CONCLUSION: Given the methodology based on the convergence of unguided intuitive clustering of cases by experts, this new classification is relevant for clinical practice. It does not compete with staging systems, but they may complement each other, whether the objective is to select the best therapeutic approach in tumour boards or to design homogeneous groups for trials.

Sclerodermiform basal cell carcinomas vs. other histotypes: analysis of specific demographic, clinical and dermatoscopic features.

BACKGROUND: Among the various types of basal cell carcinoma, the sclerodermiform variant has a high risk of recurrence and local invasiveness. A systematic description of the dermatoscopic features associated with specific body localization is lacking. OBJECTIVES: To describe the clinical and dermoscopic features of sclerodermiform basal cell carcinoma (BCC) according to localization in the body confronting with superficial and nodular types. METHODS: Clinical and dermoscopic images of sclerodermiform, nodular and superficial BCCs were retrospectively evaluated to study the location in the various body districts, maximum diameter, clinical appearance of the lesion, features of edges and presence or absence of specific dermatoscopic criteria of BCCs. RESULTS: We examined 291 histopathologically proven BCCs showing that in nodular BCCs, classical arborizing vessels were more frequently found in the body macro-area (trunk and limbs; n = 46, 97.9%) than in the head/neck area (n = 43, 82.7%); within sclerodermiform BCCs, short arborizing vessels were found more frequently in the head/neck district (n = 35, 49.3%) than in the body (n = 6, 23.1%; P-value 0.02); within nodular BCCs, multiple blue-grey dots and globules were more frequently found on the trunk (n = 23, 48.9%) than in the head/neck district (n = 12, 23.1%; P-value 0.01). In sclerodermiform BCCs, ulceration was found more frequently in the head/neck district (n = 38, 53.5%) than in the body (n = 4, 15.4%; P-value > 0.01), and in superficial BCCs, ulceration was found more frequently in the head/neck district (n = 5, 38.5%) than in the body (n = 8, 9.8%; P-value 0.02). CONCLUSION: Our study shows that superficial BCC are found frequently in the head/neck district dermoscopically characterized by ulceration and arborizing vessels; nodular BCCs are more frequently found in the body than in the head/neck district, and the dermoscopic pattern is characterized by the combination of three features: (i) classical arborizing vessels, (ii) multiple blue-grey dots and (iii) globules. Instead, sclerodermiform BCC is preferentially located in areas at high-moderate risk of recurrence; if pink-white areas and/or fine arborizing vessels are seen, clinicians should consider this diagnosis. Furthermore, location-specific dermatoscopic criteria have been described.

Clinical and dermoscopic features of genital pigmented Bowen disease.

Pigmented Bowen disease (pBD) is an uncommon variant of squamous cell carcinoma in situ. Sometimes it can show clinical and dermoscopic features that are seen in other pigmented lesions of the skin and mucosa, making the diagnosis difficult. We report six cases of pBD occurring on the anogenital area, and discuss the importance of dermoscopy for improving the diagnostic accuracy in pBD.

Evaluation of cutaneous surface parameters in psoriatic patients.

PURPOSE: The purpose of this study was to compare cutaneous surface parameters in lesional and non-lesional skin of psoriatic patients and in corresponding areas of control subjects. METHODS: Sixty-six psoriatic patients (of any grade of severity, with or without arthritis, without any therapy other than systemic biologic drugs) and 28 healthy controls were enrolled in this observational, case-control study. Exclusion criteria were current or past sebo-psoriasis and seborrheic dermatitis, pustular or erithrodermic psoriasis; treatment with immune-suppressive agents, retinoids, or ultraviolet phototherapy in the last 6 months; topical treatment in the last 2 weeks. Corneometry, sebumetry, and pHmetry were evaluated on non-lesional skin of forehead, cheek, chin and volar region of forearm, and on a psoriatic plaque (on elbow or neighboring areas); in controls, the same areas were considered. RESULTS: Corneometry values were significantly lower in psoriatic plaques vs. elbows of controls. Sebumetry showed significantly higher values in non-lesional forearm skin and plaques of psoriatic patients vs. corresponding areas of controls. pH was significantly lower in all areas in psoriasis. No differences were found between patients treated or not with biologics and with or without arthritis. CONCLUSION: Evaluating surface skin parameters in psoriasis is useful to better understand the etiopathogenic mechanism and could suggest new therapeutic approaches.

Efficacy and Safety of bimekizumab in elderly patients: real-world multicenter retrospective study - IL PSO (Italian Landscape Psoriasis).

Purpose of the article: The aim of this multicenter observational study is to report data from real world on the use of bimekizumab in patients aged ≥ 65 years with moderate-to-severe plaque psoriasis. Elderly patients are poorly represented in clinical trials on bimekizumab for plaque psoriasis, and real-world studies are important to guide clinical choices.Materials and methods: A retrospective multicenter study was conducted in 33 dermatological outpatient clinics in Italy. Patients aged ≥ 65 years, with moderate-to-severe plaque psoriasis and treated with bimekizumab were enrolled. No exclusion criteria were applied. Bimekizumab was administered following the Italian Guidelines for the management of plaque psoriasis and according to the summary of product characteristics, in adult patients who were candidates for systemic treatments. Overall, 98 subjects were included, and received bimekizumab up to week 36. Clinical and demographic data were collected before the initiation of treatment with bimekizumab. At baseline and each dermatological examination (4, 16, and 36 weeks), clinical outcomes were measured by the following parameters: (1) PASI score; (2) site-specific (scalp, palmoplantar, genital, nail) Psoriasis Global Assessment (PGA). At each visit, the occurrence of any adverse events (AEs) was recorded, including serious AEs and AEs leading to bimekizumab discontinuation.Results: The mean PASI score was 16.6 ± 9.4 at baseline and significantly decreased to 4.3 ± 5.2 after 4 weeks (p < 0.001), and 1.1 ± 1.7 after 16 week (p < 0.001). This level of improvement was maintained after 36 weeks (p < 0.001). PASI ≤2 was recorded in 36 (36.7%) at week 4, 68% and 69.4% at week 16 and 36, respectively. By week 16, 86/98 (87.8%) patients reached PASI75, 71/98 (72.4%) obtained PASI90, and 52/98 (53.1%) PASI100. Binary logistic regression tests showed a significant association of PASI100 by week 4 with lower PASI at baseline. PASI 100 at 16 or 36 weeks was not associated with baseline PASI, obesity, age, gender, previously naïve state, and presence of psoriatic arthritis. Patients naïve to biologics at baseline had similar response to bimekizumab as non-naïve subjects.Conclusions: Bimekizumab is a suitable option for elder patients as it is effective, tolerated and has a convenient schedule.

Effects of repeated ankle plantar-flexions on H-reflex and body sway during standing.

The study investigated relations between effects of repeated ankle plantar-flexion movements exercise on the soleus Hoffmann (H) reflex and on postural body sway when maintaining upright stance. Ten young volunteers performed five sets of ankle plantar-flexions of both lower limbs. Assessment of the feet centre-of-pressure (COP) displacement and H-reflex tests were carried out in quiet stance before, during and after the exercise. H-max and M-max responses were obtained in 8 subjects and reported as the peak-to-peak amplitudes of the right soleus muscle electromyographic waves. Mean dispersion of COP along the antero-posterior direction increased significantly during the exercise; whilst the overall H-reflex response indicated a reduction without a concomitant modification in the M-max response. H-reflex responses, however, varied between participants during the first sets of exercise, showing two main trends of modulation: either depression or early facilitation followed by reduction of the H-reflex amplitude. The extent of reflex modulation in standing position was correlated to the concentric work performed during the exercise (r=0.85; p<0.01), but not to the antero-posterior COP dispersion. These results suggest that during a repeated ankle plantar-flexions exercise, modulation of the H-reflex measured in upright stance differs across individuals and is not related to changes of postural sway.

Nanofat 2.0: experimental evidence for a fat grafting rich in mesenchymal stem cells.

Different strategies have been developed in the last decade to obtain fat grafts as rich as possible of mesenchymal stem cells, so exploiting their regenerative potential. Recently, a new kind of fat grafting, called "nanofat", has been obtained after several steps of fat emulsification and filtration. The final liquid suspension, virtually devoid of mature adipocytes, would improve tissue repair because of the presence of adipose mesenchymal stem cells (ASCs). However, since it is probable that many ASCs may be lost in the numerous phases of this procedure, we describe here a novel version of fat grafting, which we call "nanofat 2.0", likely richer in ASCs, obtained avoiding the final phases of the nanofat protocol. The viability, the density and proliferation rate of ASCs in nanofat 2.0 sample were compared with samples of nanofat and simple lipoaspirate. Although the density of ASCs was initially higher in lipoaspirate sample, the higher proliferation rate of cells in nanofat 2.0 virtually filled the gap within 8 days. By contrast, the density of ASCs in nanofat sample was the poorest at any time. Results show that nanofat 2.0 emulsion is considerably rich in stem cells, featuring a marked proliferation capability.

Differential expression of group I metabotropic glutamate receptors in functionally distinct hippocampal interneurons.

Metabotropic glutamate receptors (mGluRs) have been proposed to be involved in oscillatory rhythmic activity in the hippocampus. However, the subtypes of mGluRs involved and their precise distribution in different populations of interneurons is unclear. In this study, we combined functional analysis of mGluR-mediated inward currents in CA1 oriens-alveus interneurons with anatomical and immunocytochemical identification of these interneurons and expression analysis of group I mGluR using single-cell reverse transcription-PCR (RT-PCR). Four major interneuron subtypes could be distinguished based on the mGluR-mediated inward current induced by the application of 100 microm trans-(1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid (ACPD) under voltage-clamp conditions and the action potential firing pattern under current-clamp conditions. Type I interneurons responded with a large inward current of approximately 224 pA, were positive for somatostatin, and the majority expressed both mGluR1 and mGluR5. Type II interneurons responded with an inward current of approximately 80 pA, contained calbindin, and expressed mainly mGluR1. Type III interneurons responded with an inward current of approximately 60 pA. These interneurons were fast-spiking, contained parvalbumin, and expressed mainly mGluR5. Type IV interneurons did not respond with an inward current upon application of ACPD, yet they expressed group I mGluRs. Activation of group I mGluRs under current-clamp conditions increased spike frequency and resulted in rhythmic firing activity in type I and II, but not in type III and IV, interneurons. RT-PCR results suggest that activation of mGluR1 in the subsets of GABAergic interneurons, classified here as type I and II, may play an important role in mediating synchronous activity.

The electrogenic sodium bicarbonate cotransporter: developmental expression in rat brain and possible role in acid vulnerability.

The electrogenic sodium bicarbonate cotransporter (NBC) is expressed in glial cells in the brain and plays an important role in the regulation of both intracellular and extracellular pH. Differential vulnerability to acidosis between neurons and glia has been noted and may contribute to infarction after cerebral ischemia. Ionic substitution studies and inhibition of injury by 4, 4'-di-isothiocyanostilbene-2,2'-disulfonic acid suggest that NBC is involved in astrocyte vulnerability to acidic injury. Recently two NBC cDNAs differing in 5'-untranslated and N-terminal coding sequence have been cloned from kidney and pancreas. We cloned one of these cDNAs from rat brain and demonstrate here that the clone is functional by expression in Xenopus oocytes. We determined the developmental and regional expression of NBC in the brain by in situ hybridization. Expression was observed in the spinal cord at embryonic day 17, whereas expression in brain was first seen at approximately postnatal day 0 (P0), increased at P15, and persisted in the adult brain. Expression was widespread throughout the cerebellum, cortex, olfactory bulb, and subcortical structures. Cellular resolution of the in situ hybridization signal and double labeling for glial fibrillary acidic protein were consistent with a glial localization for NBC. Expression of NBC in 3T3 cells that do not normally express this transporter rendered them vulnerable to acid injury. The expression profile suggests that this transporter is critical during the later stages of brain development and could be one of the factors contributing to the different patterns of injury seen in perinatal versus adult cerebral ischemia.

Endogenous activation of group-I metabotropic glutamate receptors is required for differentiation and survival of cerebellar Purkinje cells.

We have applied subtype-selective antagonists of metabotropic glutamate (mGlu) receptors mGlu1 or mGlu5 [7-(hydroxy-imino) cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) or 2-methyl-6-(phenylethynyl)pyridine (MPEP)] to mixed rat cerebellar cultures containing both Purkinje and granule cells. The action of these two drugs on neuronal survival was cell specific. Although CPCCOEt (1, 10, 30 microm) reduced the survival of Purkinje cells, MPEP (3 or 30 microm) selectively reduced the survival of granule cells. Both effects required an early exposure of cultures to antagonists [from 3 to 6 d in vitro (DIV) for CPCCOEt, and from 3 to 6 or 6 to 9 DIV for MPEP]. Addition of MPEP from 6 to 9, 9 to 13, or 13 to 17 DIV also induced profound morphological changes in the dendritic tree and dendritic spines of Purkinje cells, suggesting that endogenous activation of mGlu5 receptors is required for the age-dependent refinement of Purkinje cell phenotype. In in vivo studies, an early blockade of mGlu1 receptors induced in rats by local injections of LY367385 (20 nmol/2 microl), local injections of mGlu1 antisense oligonucleotides (12 nmol/2 microl), or systemic administration of CPCCOEt (5 mg/kg, s.c.) from postnatal day (P) 3 to P9 reduced the number and dramatically altered the morphology of cerebellar Purkinje cells. In contrast, mGlu5 receptor blockade induced by local injections of antisense oligonucleotides reduced the number of granule cells but also produced substantial morphological changes in the dendritic tree of Purkinje cells. These results provide the first evidence that the development of cerebellar neurons is under the control of mGlu1 and mGlu5 receptors, i.e., the two mGlu receptor subtypes coupled to polyphosphoinositide hydrolysis.

[Pain in Parkinson's disease]. / Syndromes douloureux de la maladie de Parkinson.

INTRODUCTION: Pain may be a presenting symptom of Parkinson's disease or may occur during the motor fluctuation stages of the disease. The complexity and pathophysiology of pain in Parkinson's disease still remains poorly understood. OBJECTIVE: To characterize clinically the different painful presentations of Parkinson's disease, their relationship to the stage of the disease and their connections with motor fluctuations and treatment. METHODS: We reviewed painful syndromes in 388 consecutive parkinsonian patients of the Lausanne Movement Disorders Registry, based on an itemized questionnaire used prospectively to characterize the pain by its description, topography, date of appearance and possible relationship with motor fluctuations. Among these patients with clinically-diagnosed dopa-responsive Parkinson's disease, 269, i.e. 67 percent presented sensory or painful syndromes. Among them, 94 percent had muscular pain: stiffness (85 percent), cramps, pseudo-cramps, spasms (3 percent) or various myalgias (7 percent); 51 percent presented osteo-ligamentar "rheumatologic" pain, articular (23 percent), periarticular (3 percent) or spinal (31 percent), but less defined and localized neurogenic painful syndromes were less frequent (8 percent), such as paresthesia (6 percent), dysesthesia (<1 percent), burning sensation (2 percent), itching (<1 percent), ill defined discomfort (6 percent) or a feeling of heaviness (1 percent), with segmental (86 percent), axial (54 percent), radicular or pseudo-radicular (14 percent), acral distal (4 percent) or less frequently anorectal or visceral distribution. Restless legs or akathisia were occasional (10 percent). Headaches and facial pain were less frequent (1 percent), we did not encounter phantom pain. More than one quarter were present at the beginning of the disease, only (3 percent) of them resolved during the development of the disease. About one-third were clearly linked with motor fluctuations, the majority occurring in off phase (34 percent). We did not find any correlation with age, gender, duration or stage of disease, L dopa equivalent dose, depression, insomnia or autonomic dysfunction. CONCLUSION: Painful syndromes are found in two thirds of patients with Parkinson's disease, with mainly pain of muscular origin, followed by osteoarticular and neurogenic painful syndromes, a quarter of the patients experience pain in early phases of the disease and a third in relation with motor fluctuations.

Projections from the Cerebral Cortex to the Red Nucleus of the Guinea-pig. A Retrograde Tracing Study.

The origin and the topographic distribution of corticorubral (CR) projections in the guinea-pig were studied by using the retrograde axonal transport of a tracer, colloidal gold-labelled, enzymatically inactive horseradish peroxidase conjugated to wheat-germ agglutinin (WGAapoHRP - Au), which was injected in the red nucleus (RN). It was found that the bulk of the CR projections arise from layer V neurons of the agranular frontal cortex in both its medial (Agm) and lateral (Agl) subdivisions; in the Agm labelled neurons are preferentially located in the upper part of layer V, whereas in the Agl they are more concentrated in the central band of the layer. Fewer projections originate from areas of the granular parietal and the agranular cingulate and retrobulbar cortices. CR projections have a bilateral origin, with a large ipsilateral predominance. The pattern of retrograde cortical labelling observed after injection of WGAapoHRP - Au in different portions of the RN indicates that CR projections are distributed throughout the entire rostrocaudal extent of the nucleus, but are slightly more concentrated in the rostral parvocellular area. The morphological arrangement of CR projections in the guinea-pig, as demonstrated in the present study, shows several analogies with other mammals. The functional characteristics of the cortical areas in which CR neurons are located indicate that CR projections may play a significant role in the central organization of movement.

Dorsal root ganglion neurons projecting to the dorsal column nuclei of rats.

Dorsal root ganglion (DRG) neurons may give origin to ascending branches that terminate in the dorsal column nuclei (DCN); uncertainties still exist with regard to the proportion of these neurons in different DRGs and to the type of these neurons. The percentage and size of neurons that project to the DCN were determined in a large number of DRGs by means of the retrograde transport of colloidal gold-labeled wheat germ agglutinin conjugated to enzymatically inactive horseradish peroxidase (WGAapoHRP-AU). A total of 16,239 neurons was tallied in 80 DRGs from nine rats; 3,240 (20%) of these were retrogradely labeled by the tracer injected in the DCN. Percentages of DCN projecting neurons vary considerably at different segmental levels: they are higher in cervical (up to 63%) than in thoracic (up to 31% for T1, up to 12% for thoracic DRGs below T1) or lumbar DRGs (up to 15%). At cervical levels highest percentages were encountered in C6, C7, and C8 and lowest percentages in C2-C4. At lumbar levels highest percentages were encountered in L4 and lowest in L1 and L6. When considering the soma size of DRG neurons it appears that: 1) there are more large cells, labeled and unlabeled, at cervical (38%) than at lumbar levels (30%) and more at lumbar than at thoracic levels (23%); 2) at every level, most labeled, i.e., projecting, neurons are large; and 3) DRGs with the highest proportions of large vs. small cells contain the highest percentages of DCN projecting neurons. These results represent the first attempt at establishing the percentages and soma size of DCN projecting neurons from a large number of DRGs and at comparing the contribution to these nuclei from cervical, thoracic, and lumbar DRGs. Some of the differences in the ratio of projecting neurons at different levels may be explained on the basis of well-known anatomical features, e.g., the projections to the Clarke's column of many DRG neurons in lumbar ganglia. The contribution of virtually exclusively large DRG neurons to the DCN, suggested by indirect or incomplete evidence, is demonstrated by the present retrograde labeling and soma size measurements. The results relate to the functional component of peripheral receptors that relay their input via the dorsal columns and do not seem to support a recent suggestion that a sizeable fraction of unmyelinated primary afferents ascend in the dorsal columns to terminate in the DCN.

Glutamate and aspartate immunoreactivity in corticospinal neurons of rats.

A combination of retrograde tracers and immunostaining was employed to test whether corticospinal tract (CST) neurons in rats may use amino acid excitatory neurotransmitters. CST neurons were identified following injections of either Diamidino Yellow (DY) or colloidal gold-labeled enzymatically inactive horseradish peroxidase conjugated to wheat germ agglutinin (WGAapoHRP-Au) in the spinal cord. As retrograde tracers, the two substances seemed to be equally effective, but WGAapoHRP-Au was better suited than DY as a tracer to use in combination with immunocytochemistry. Sections through the primary sensorimotor cortex, which contained the bulk of identified CST neurons, and the secondary somatosensory cortex were processed with antisera raised in rabbits against glutamate (Glu) or aspartate (Asp) conjugated by glutaraldehyde to hemocyanin. In rats with DY injections, about 60-75% of the CST neurons were Glu-immunopositive, with higher ratios in SI and MI than in SII. Similar results were obtained in all areas examined from the rats with injections of WGAapoHRP-Au. Only sections from rats with injections of WGAapoHRP-Au were processed for Asp immunostaining. In this material, between 65 and 75% of the CST neurons were Asp-immunopositive, with a slightly higher ratio in SI and MI than in SII. The possibility that these results might reflect limited penetration of the antiserum and/or staining of the same population of CST neurons by either antiserum was addressed in sections processed with both the Glu and Asp antisera. In sections incubated in a mixture of the two antisera, the percentage of immunostained CST neurons was higher, about 90%, than in sections processed for only one of the two antisera. Furthermore, in rats in which Glu and Asp antibodies were visualized by two distinguishable immunostainings, four populations of CST neurons were identifiable: 1) neurons only immunopositive for Glu, 2) neurons only immunopositive for Asp, 3) neurons likely to be stained by both, and 4) neurons immunonegative for both antisera. Twenty-five to 30% of CST neurons were positive for only one antiserum, and about 50% were positive for both. No preferential distribution was evident for any one of these populations of neurons. However, perikaryal cross-sectional areas were larger for the double-stained than for the single-stained CST neurons. Glutamergic and aspartergic transmission in CST neurons has been proposed in several publications in which methods other than immunocytochemistry were employed.(ABSTRACT TRUNCATED AT 400 WORDS)

Motor cortex modulation of exteroceptive information at bulbar and thalamic lemniscal relays in the cat.

We have studied the control of the primary motor cortex on the activity of lemniscal neurons in semi-chronic implanted cats. In each experiment, two to three foci in the primary motor cortex were identified by intracortical microstimulation at low threshold (up to 20 microA) for their capacity to evoke movements of contralateral single limb joints. Neurons belonging to the dorsal column nuclei (main cuneate nucleus and gracile nucleus), or to the ventral posterolateral nucleus, were sampled for their response to stimulation of the peripheral cutaneous fields, as well as the antidromic response to stimulation of the contralateral medial lemniscus and ipsilateral somatosensory cortex, respectively. These neurons were then tested for stimulation of the cortical foci using a current intensity equal to the threshold needed to evoke motor effects, although we reduced the duration of the stimulating trains; thus, we avoided evoking movements which could elicit afferent volleys along the somatosensory paths. It was found that the primary motor cortex was able to modulate the transmission of exteroceptive signals at the level of both dorsal column nuclei and ventral posterolateral nucleus with analogous modalities. In particular: (i) a high percentage of responses, with a prevalence of excitatory effects, was observed when the receptive field of the neurons topographically corresponded to, or was very close to, the joint controlled by a given cortical focus; (ii) in these cases, higher percentages of excitations were observed in tests which concerned the distal segments of limbs than the proximal segments; (iii) the percentage of responses became lower as the neuronal receptive field was located further from the cortical motor target, the pattern being more frequently inhibitory in nature. From a functional point of view, the motor cortex control appears to be organized in a very precise manner. Its excitatory nature might subserve integrative mechanisms by which exteroceptive information arising in a given limb segment would be enhanced by a motor command inducing movements of the same body part. Moreover, a better definition of the afferent input could be obtained by a simultaneous depression of neurons, which send towards the cortex signals from adjacent or more distant cutaneous regions. It can be hypothesized that such an organization of the cortical control could improve the discriminative somatosensory aspects during the execution of explorative movements, besides supplying a sharper cutaneous feedback to the motor cortex.

Substance P-containing projections in the dorsal columns of rats and cats.

Light and electron microscopic immunocytochemical methods were used to study the distribution and the morphology of substance P-positive fibers and axon terminals in the dorsal column nuclei of rats and cats, and to determine whether they are part of an ascending input to these nuclei. In rats, substance P-positive fibers and axon terminals are present throughout the rostrocaudal extent of the dorsal column nuclei. In cats, immunostained fibers and terminals are mostly confined to the ventral region of the caudal and middle portions of these nuclei but they are more homogeneously distributed at rostral levels. In both species, substance P-positive neurons are not present in the same nuclear complex. At the electron microscope level, substance P-positive terminals are small- to medium-sized and dome-shaped; they form asymmetric contacts on dendrites and contain many round, agranular vesicles and sparse dense core vesicles. In double-labeling experiments, visualization of substance P-immunoreactivity in the dorsal root ganglia and dorsal horn of the spinal cord was combined with the retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase or of colloidal gold-labeled wheat germ agglutinin conjugated to enzymatically inactive horseradish peroxidase. These experiments show that substance P-positive axon terminals may originate from both small dorsal root ganglion neurons and from spinodorsal column nuclei neurons in lamina IV. Although quantitative evaluation of the contribution of these two pathways to the substance P innervation of the dorsal column nuclei has not been performed and other sources cannot be discarded on the basis of the present evidence, it is proposed that non-primary afferents to the dorsal column nuclei account for most of the substance P-positive fibers and terminals in the dorsal column nuclei. The experiments support previous findings suggesting that nociceptive input may access the dorsal column nuclei and that this may be mediated, though to a very limited extent, directly by way of small dorsal root ganglion neurons.

Pyramidal input to the intracerebellar nuclei of the cat.

In unanesthetized cats it has been found that pyramidal volleys elicited upon medullary pyramidal tract stimulation were capable of modifying the discharge of 41% of intracerebellar nuclear cells, via pontocerebellar systems impinging predominantly on the lateral cerebellar cortex. The incidence of responsive cells was 80% in the dentate nucleus compared with 10% in the fastigial nucleus, 11% in the anterior and 12% in the posterior division of the interpositus nucleus. The response was in 59% of the cases excitation followed by inhibition, in 30% of the cases a pure excitation and in 11% of the cases a pure inhibition. Excitation, pure or followed by inhibition, had a mean latency of 5.78 ms and a mean duration of 12.21 ms, while inhibition displayed a mean latency of 9.03 ms and a mean duration of 34.64 ms. The possible functional significance of the pyramidal input to the lateral cerebellum is briefly discussed in relation to a possible convergence of pyramidal and associative impulses in single cerebellar neurons.