Spikes alone do not behavior make: why neuroscience needs biomechanics.

Neural circuits do not function in isolation; they interact with the physical world, accepting sensory inputs and producing outputs via muscles. Since both these pathways are constrained by physics, the activity of neural circuits can only be understood by considering biomechanics of muscles, bodies, and the exterior world. We discuss how animal bodies have natural stable motions that require relatively little activation or control from the nervous system. The nervous system can substantially alter these motions, by subtly changing mechanical properties such as body or leg stiffness. Mechanics can also provide robustness to perturbations without sensory reflexes. By considering a complete neuromechanical system, neuroscientists and biomechanicians together can provide a more integrated view of neural circuitry and behavior.

Developmental changes in the ultrastructure of the lamprey lateral line nerve during metamorphosis.

The ultrastructure of the trunk lateral line nerve of larval and adult lampreys was studied with transmission electron microscopy. We confirmed that lampreys' lateral line nerve lacks myelin. Nevertheless, all axons were wrapped by Schwann cell processes. In the larval nerve, gaps between Schwann cells were observed, where the axolemma was covered only by a basal lamina, indicating an earlier developmental stage. In the adult nerve, glial (Schwann cell) ensheathment was mostly complete. Additionally, we observed variable ratios of axons to Schwann cells in larval and adult preparations. In the larval nerve, smaller axons were wrapped by one Schwann cell. Occasionally, a single Schwann cell surrounded two axons. Larger axons were associated with two to five Schwann cells. In the adult nerve, smaller axons were surrounded by one, but larger axons by three to eight Schwann cells. The larval epineurium contained large adipose cells, separated from each other by single fibroblast processes. This layer of adipose tissue was reduced in adult preparation. The larval perineurium was thin, and the fibroblasts, containing large amounts of glycogen granules, were arranged loosely. The adult perineurium was thicker, consisting of at least three layers of fibroblasts separated by collagen fibrils. The larval and adult endoneurium contained collagen fibrils oriented orthogonally to each other. Both larval and adult lateral line nerves possessed a number of putative fascicles weakly defined by a thin layer of perineurial fibroblasts. These results indicate that after a prolonged larval stage, the lamprey lateral line nerve is subjected to additional maturation processes during metamorphosis.

Enzyme replacement therapy stabilizes obstructive pulmonary Fabry disease associated with respiratory globotriaosylceramide storage.

Fabry disease is an X-linked glycosphingolipidosis caused by a deficiency of α-galactosidase A, a lysosomal enzyme. Symptoms in hemizygous males and heterozygous females are due to lysosomal storage of globotriaosylceramide in the central and peripheral nervous system, vascular endothelium, cardiac valves and myocytes, gastrointestinal tract, and renal epithelium. Pulmonary involvement is also a recognized manifestation of Fabry disease, but histopathological evidence of pulmonary lysosomal storage is scant. We report a 51-year-old woman with a G43R α-galactosidase A mutation and normal spirometry testing 2.5 years prior to presentation, who experienced a dry, nonproductive cough that persisted despite treatment with antibiotics and bronchodilators. Spirometry demonstrated a mixed restrictive/obstructive pattern as well as impaired gas exchange. Patchy ground-glass pulmonary interstitial infiltrates were found on plain radiography and computerized tomography. She underwent an open lung biopsy that demonstrated peribronchiolar fibrosis and smooth-muscle hyperplasia. Prominent inclusion bodies of the bronchiolar/arteriolar smooth muscle and endothelium were present. Electron microscopy indicated the inclusion bodies were lamellated zebra bodies consistent with globotriaosylceramide storage. Enzyme replacement therapy (ERT) with agalsidase-beta was instituted. Since initiation of therapy, she occasionally has a dry cough but markers of obstructive lung disease have remained stable in the past 4 years. This report demonstrates that pulmonary involvement in Fabry disease is due to lysosomal storage, and suggests that ERT is capable of stabilizing pulmonary Fabry disease. However, progressive worsening of her total lung capacity indicates that ERT cannot reverse the ongoing process of fibrosis also seen in Fabry disease.

Metamorphosis-related changes in the lateral line system of lampreys, Petromyzon marinus.

Lamprey metamorphosis leads to considerable changes in morphology and behavior. We have recently reported that larval lampreys possess a functional lateral line system. Here we investigated metamorphic morphological changes in the lateral line system using light and electron microscopy. Functional modifications were studied by recording the trunk lateral line nerve activity of larvae and adults while stimulating neuromasts with approximately sinusoidal water motion. We found a general re-patterning of neuromasts on the head and trunk including an increase in numbers, redistribution within the pit lines, and shifts of the pit lines relative to external features. The trunk lateral line nerve response was qualitatively similar in adults and larvae. Both showed two neuronal populations responding to opposite directions of water flow. Magnitude of the response increased monotonically with stimulus amplitude. At low frequencies, the response lag relative to the stimulus maximum was approximately 220 degrees , and the gain depended approximately linearly on frequency, confirming that superficial neuromasts are velocity detectors. Changes in phase lag with increasing stimulus frequency were steeper in larvae, suggesting slower afferent conductance. The response gain with frequency was smaller for adults, suggesting a narrower frequency discrimination range and decreased sensitivity. These changes may be adaptations for the active lifestyle of adult lampreys.

Larval lampreys possess a functional lateral line system.

Morphology of larval lampreys' neuromasts was found to be very similar to that of adults. Activity in the lateral line nerve, elicited by a vibrating ball, indicated a functional lateralis system. Analysis revealed at least two populations of afferents, responding to opposite directions of water flow, with adapting responses. The response magnitude increased monotonically with stimulus amplitude. Larval lampreys' neuromasts were less sensitive than those of teleosts. At low frequencies the response showed a phase lead of 200-220 degrees with respect to the maximum of the ball displacement and a gain that was approximately linearly proportional to frequency.

Child health care centres: an academic model for comprehensive child health care in the community.

The challenge of the discipline of paediatrics in the 21st century is to promote health and development of children in a way that will enable them to maximize their biological and social potential. The community child health centre (CHC) in Israel is a model of community health care service built to provide comprehensive health care to children and adolescents, as well as an academic setting for under- and postgraduate paediatric training. Today there are 34 CHCs in Israel, serving a population of 220 000 children from birth to 18 years of age. The CHC combines the advantages of group practice with those of an academic medical centre and enables flexibility and mutual learning. Further expansion and development are required to realize the CHC's mission of a true comprehensive academic centre for paediatric community health.

[Immunopathology of acute rejection]. / Immunopatologia del rigetto acuto.

Acute transplant rejection may be the result of two immunologic mechanisms, T-cell-mediated and antibody-mediated processes, acting alone or together. Cell-mediated rejection occurs as T cells react to donor alloantigens which are expressed in context of MHC. The major forms of cellular rejection may affect tubulo-interstitium, arteries and glomeruli. The former type is characterized by infiltration of the interstitium and tubules with activated T cells. Typically less than 50% of the cells are CD3 (T3), while the majority are usually CD8 (T8) cells. In the tubulo-interstitial form, lymphocytes migrate from peritubular capillaries into the interstitium and into the walls of tubules (tubulitis). The arterial form is characterized by the accumulation of lymphocytes and monocytes beneath endothelial cells of arteries. Endarteritis is mediated by T cells and affected arteries are devoid of antibody or complement deposits. There are two distinctive forms of acute antibody-mediated rejection, affecting different vascular beds: arterial and peritubular capillary. The arterial form is characterized by mural necrosis and inflammation. In contrast, the peritubular capillary form may have little or variable morphologic changes; it is diagnosed by identifying C4d, a stable breakdown product of complement and an indicator of immune complex deposition, in peritubular capillary walls. C4d deposition correlates with circulating antidonor antibodies.

Emphysematous pyometra in a dog.

An 8-year-old intact female West Highland White Terrier was examined for anorexia, vomiting, abdominal distension, and mild purulent vulvar discharge. The results of physical examination, laboratory testing, and radiography are presented. Emphysematous pyometra was suspected and confirmed at surgery. Clostridium perfringens was isolated from the uterine lumen. A brief discussion of emphysematous pyometra is presented.

Bronchiolitis obliterans in the 1990s in Korea and the United States.

STUDY OBJECTIVES: Our current knowledge of pediatric bronchiolitis obliterans (BO) is based largely on a few small series of patients that were reported in the older literature. In these older cases, the mortality rate was high. This study was conducted to investigate the characteristics of pediatric BO cases in two different countries. DESIGN: We extracted specific information regarding predisposing factors, symptoms and signs, diagnostic studies, treatment, and outcome from the medical records of 31 children who received diagnoses of BO at four university medical centers in Korea and the United States in the 1990s. RESULTS: The large number of Asian children reflects a clustering of cases in Korea due to adenovirus and Mycoplasma pneumoniae epidemics. The characteristic diagnostic features of BO were present in 29 of 30 high-resolution CT (HRCT) studies. Seven of nine children who underwent biopsies had histologic confirmations of BO. In two patients whose biopsy results were nondiagnostic, the diagnosis was established by HRCT together with pulmonary function testing results that were consistent with nonreversible small airways obstruction. Fifteen children (48.4%) had evidence of hypoxemia. At present, all but one are alive. Patients with elevated severity-of-illness scores were observed to have increased likelihoods of lung transplantation or death. CONCLUSIONS: We conclude that BO has a good overall prognosis and that the mortality rate has declined over the past decade. This could be related primarily to the use of HRCT for accurate diagnosis and the availability of pediatric lung transplantation. BO cases in Korea were associated with infectious epidemics, whereas those in United States had variable predisposing factors.

Isolation, characterization, and transplantation of bone marrow-derived hepatocyte stem cells.

Recently it was shown that a population of cells in the bone marrow-expressing hematopoietic stem cell antigens could differentiate into hepatocytes. However, explicitly committed hepatocyte progenitors, which exhibit highly differentiated liver functions, immediately upon isolation, have not yet been isolated from bone marrow. After studying common antigens on blast-like cells in fetal and adult regenerating cholestatic rat livers and human regenerating and malignant livers, we hypothesized that beta-2-microglobulin-negative (beta(2)m(-)) cells might represent dedifferentiated hepatocytes and/or their progenitors. Utilizing a two-step magnetic bead cell-sorting procedure, we show that in bone marrow from rat and human, beta(2)m(-)/Thy-1(+) cells consistently express liver-specific genes and functions. After intraportal infusion into rat livers, bone marrow-derived hepatocyte stem cells (BDHSC) integrated with hepatic cell plates and differentiated into mature hepatocytes. In a culture system simulating liver regeneration and containing cholestatic serum, these cells differentiated into mature hepatocytes and metabolized ammonia into urea. This differentiation was dependent on a yet nondescript humoral signal existing in the cholestatic serum. Transmission electron microscopy and three-dimensional digital reconstruction confirmed hepatocyte ultrastructure of cultured BDHSC.

Impact of movement and movement-related feedback on the lamprey central pattern generator for locomotion.

A semi-reduced, minimally restrained lamprey preparation was used to investigate the impact of movement and movement-related feedback during D-glutamate-induced locomotion. The preparation consisted of the trunk alone with the spinal cord exposed to the bathing solution. Two conditions were compared using electromyography or nerve recording: (i) muscle and spinal cord, (ii) spinal cord alone supported by the notochord. Compared with the isolated spinal cord, movement in the presence of muscle consistently and significantly increased the frequency of the motor output and reduced the phase delay among the segments. In moving preparations, coupling among the segments was reduced by two staggered hemisections to permit the strength and direction of intersegmental coupling to be estimated. The estimates revealed that movement increased the total intersegmental coupling strength and increased the proportion of the coupling that was descending over those of the isolated spinal cord. The effects on the phase and frequency of bursting can be explained in the light of the excitation evoked by bending that we have reported previously. Thus, we demonstrate that movement and movement-related feedback that arise from spinally induced motor patterns can alter the form of the movement and the functional coupling strength among the segments of the lamprey spinal cord.

Immediate post-transplant nephrosis in a patient with congenital nephrotic syndrome.

A 19-month-old girl with congenital nephrotic syndrome of the Finnish type underwent a living-related renal transplant; 24 h after transplantation she became massively nephrotic. She did not respond to steroids, plasmapheresis, and high-dose cyclosporine. A month later, a renal biopsy showed only glomerular foot process effacement. She was treated with high-dose methylprednisolone pulses and oral cyclophosphamide. She rapidly went into complete remission with no further relapses. Graft function has been stable 2 years after transplantation.

Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy.

BACKGROUND: Collapsing glomerulopathy (CG), a disorder with severe glomerular and tubular involvement, occurs either as an idiopathic lesion or in some patients with human immunodeficiency virus (HIV) infection known as HIV-associated nephropathy (HIVAN). We previously reported a renal transplant recipient with de novo CG and red cell aplasia in association with persistent parvovirus B19 (PVB19) infection. This prompted us to look for an association between PVB19 infection and CG. METHODS: DNA from archived biopsies of patients with CG was analyzed for PVB19 by polymerase chain reaction (PCR). Results were compared with HIVAN, idiopathic focal segmental glomerulosclerosis (FSGS), and controls. In situ hybridization (ISH) was done to localize PVB19 in renal biopsies. Peripheral blood specimens of patients with CG, HIV infection, healthy controls, and randomly selected hospitalized patients (sick controls) were also analyzed for PVB19. RESULTS: PVB19 DNA was detected in renal biopsies of 18 out of 23 (78.3%) patients with CG, 3 out of 19 (15.8%) with HIVAN, 6 out of 27 (22.2%) with FSGS, and 7 out of 27 (25.9%) controls (P < 0.01, CG vs. HIVAN, FSGS, and controls). PVB19 was detected in peripheral blood of 7 out of 8 (87.5%) CG patients, 3 out of 22 (13.6%) with HIV infection, 4 out of 133 (3%) healthy controls, and 2 out of 50 (4%) sick controls (P < 0.001, CG vs. HIV infected, healthy, and sick controls). PVB19 was identified in glomerular parietal and visceral epithelial and tubular cells by ISH. CONCLUSIONS: The significantly higher prevalence of PVB19 DNA in renal biopsies and peripheral blood of CG patients suggests a specific association between PVB19 infection and CG. In susceptible individuals, renal epithelial cell infection with PVB19 may induce CG.

Bending the lamprey spinal cord causes a slowly-decaying increase in the frequency of fictive swimming.

It is well known that rhythmic lateral bending of the isolated lamprey spinal cord/notochord can entrain the central pattern generator (CPG) for locomotion. During entrainment, the CPG's frequency is equal to the bending frequency. We report here that bending can also have a slowly-decaying excitatory effect on the CPG's frequency. Experiments were performed in which the caudal end of a 30-50 segment piece of spinal cord/notochord was repeatedly rhythmically bent for 0.5-12 cycles. A slowly-decaying excitation was said to be present if after the termination of bending the CPG's frequency was significantly greater than baseline and decayed back to baseline with a time constant of one or more cycles. In 14 of 16 animals, a slowly-decaying excitation could be evoked by bending. In five of the nine animals tested, this slowly-decaying excitation could be evoked with bending frequencies both faster and slower than the baseline frequency. Depending on the animal, the slowly-decaying excitation could be elicited by as little as one-half cycle of bending and by bending amplitudes as small as 6-21 degrees peak deflection. We interpret these data as evidence of a second effect of bending distinct from the phase-dependent effect that produces entrainment.

Posttransplant lymphoproliferative disease in children: correlation of histology to clinical behavior.

PURPOSE: To determine whether the morphologic features of posttransplant lymphoproliferative disease (PTLD) correlated to a response to therapy. PATIENTS AND METHODS: We reviewed our experience with PTLD in the pediatric population. We identified 32 patients with a total of 36 episodes of PTLD. The diagnosis was confirmed by tissue examination and classified according to the degree of monomorphic features of the lesion. Thirty-four of 36 episodes were managed with immunosuppression reduction, and the patients were assessed for their response to this strategy. Chemotherapy was used to treat 10 of 15 patients who had progressive disease, and their subsequent course was also analyzed. RESULTS: Sixteen of 17 (94%) patients with polymorphic morphology responded to immunosuppression reduction compared with only 5 of 17 (29%) patients with monomorphic features (P < 0.001). All of the patients with progressive disease who did not receive additional therapy died. Standard chemotherapy regimens for lymphoma were administered to 10 patients with progressive disease, with a high response rate (90%), durable remissions, and acceptable toxicity. CONCLUSIONS: We conclude that the morphologic characteristics of PTLD provide information to potentially help guide treatment strategies in the management of this disease. Standard chemotherapy regimens for malignant lymphoma appear to be a viable treatment option for patients with progressive disease, although further investigation is needed.

Modeling alternation to synchrony with inhibitory coupling: a neuromorphic VLSI approach.

We developed an analog very large-scale integrated system of two mutually inhibitory silicon neurons that display several different stable oscillations. For example, oscillations can be synchronous with weak inhibitory coupling and alternating with relatively strong inhibitory coupling. All oscillations observed experimentally were predicted by bifurcation analysis of a corresponding mathematical model. The synchronous oscillations do not require special synaptic properties and are apparently robust enough to survive the variability and constraints inherent in this physical system. In biological experiments with oscillatory neuronal networks, blockade of inhibitory synaptic coupling can sometimes lead to synchronous oscillations. An example of this phenomenon is the transition from alternating to synchronous bursting in the swimming central pattern generator of lamprey when synaptic inhibition is blocked by strychnine. Our results suggest a simple explanation for the observed oscillatory transitions in the lamprey central pattern generator network: that inhibitory connectivity alone is sufficient to produce the observed transition.

Membranous nephropathy with anti-tubular basement membrane antibody may be X-linked.

The association of membranous nephropathy with Fanconi syndrome and anti-tubular basement antibodies appears to be a distinct subset of familial membranous nephropathy. We studied two Chinese families with four affected boys to evaluate the mode of inheritance of disease. HLA haplotype analysis of the family members in these two pedigrees did not reveal any significant linkages. However, microsatellite analysis of both pedigrees using markers on the X chromosome suggested linkage to the long arm of the X chromosome between the microsatellite markers DXS1001 and DXS1227. Identification and analysis of additional pedigrees may allow more precise mapping of the disease gene for anti-tubular basement membrane antibody-associated membranous nephropathy.

Continuing medical education and primary physicians' job stress, burnout and dissatisfaction.

OBJECTIVES: The association between opportunities for continuing medical education (CME) and primary physicians' job stress, burnout and job dissatisfaction has not been investigated. It was hypothesized that participation in CME activities and perceived opportunities at work for keeping up-to-date with medical and professional developments would be correlated negatively with job stress and burnout, and positively with job satisfaction. METHOD: 309 primary care physicians (183 family physicians and 126 paediatricians) employed in health maintenance organizations in Israel responded to a mailed questionnaire. The independent variables were the extent of engagement in CME activities and perceived opportunities at work for professional updating. The dependent variables were job stress, burnout and job satisfaction. Multiple regression analyses were employed. RESULTS: After controlling for age, sex and professional status, participation in CME activities was associated negatively with job stress and positively with job satisfaction, among family physicians. Among paediatricians, CME was associated negatively with burnout. Perceived opportunities for professional updating were associated negatively with burnout and (marginally) with stress among family physicians, and negatively with stress and positively with satisfaction among paediatricians. A third of the paediatricians and a quarter of the family physicians wanted to increase their involvement in CME. DISCUSSION: In this cross-sectional study, causality cannot be established and the CME measures should be refined. However, the results are consistent with the study's hypotheses and suggest that opportunities for CME and professional updating may reduce physicians' job distress and dissatisfaction.

High incidence of posttransplant lymphoproliferative disease in pediatric patients with cystic fibrosis.

A major cause of morbidity and mortality following lung transplantation is posttransplant lymphoproliferative disease (PTLD). In a retrospective cohort analysis of pediatric patients, we evaluated the risk factors associated with PTLD in 128 first-time lung transplant recipients from 1990 to 1997. The greatest risk factor for PTLD was a diagnosis of cystic fibrosis (CF). Of the 16 patients in our analysis who had PTLD, 13 had a diagnosis of CF (odds ratio [OR]: 5.8; confidence interval 95% [CI]: 1.6 to 21.4). Because of the high frequency of PTLD in patients with CF (13 of 61; 23%), we performed a retrospective cohort analysis in which patients with CF and PTLD were designated as cases and patients with CF and without PTLD served as controls. In patients with CF, the only risk factor associated with PTLD was two or more episodes of acute rejection within 3 mo after transplantation (OR: 11.0; 95% CI: 2.7 to 55.7). Age, recipient Epstein-Barr virus or cytomegalovirus status, induction with antilymphocyte globulin or antithymocyte globulin (ATG), or use of ATG or OKT3 for acute rejection episodes were not risk factors for PTLD. The high frequency of PTLD in the subgroup of patients with two or more episodes of graft rejection within 2 mo after lung transplantation was unexpected, and warrants further investigation in prospective clinical studies and basic laboratories.

Raynaud's phenomenon as a manifestation of parvovirus B19 infection: case reports and review of parvovirus B19 rheumatic and vasculitic syndromes.

Infection with human parvovirus B19 is manifested as erythema infectiosum, transient aplastic crisis, or hydrops fetalis. Rheumatic manifestations include arthropathy and various vasculitic syndromes. Isolated Raynaud's phenomenon due to parvovirus B19 has never been described. We report on 2 previously healthy sisters with new-onset Raynaud's phenomenon accompanied by severe generalized polyarthralgia. A full workup was negative, except serology for parvovirus B19, which was positive. All symptoms gradually subsided within 3-5 months, and no recurrence has been noted during the 3 years since onset. We review all the studies in the English-language literature on parvovirus B19-induced rheumatic and vasculitic syndromes. We hypothesize that the pathogenesis of Raynaud's phenomenon in our patients involved immune-mediated endothelial damage leading to platelet activation and vasoconstriction. We recommend that in cases of unexplained Raynaud's phenomenon, serology for parvovirus B19 be included in the evaluation.