Somatotopic Mapping of the Fingers in the Somatosensory Cortex Using Functional Magnetic Resonance Imaging: A Review of Literature.

Multiple studies have demonstrated finger somatotopy in humans and other primates using a variety of brain mapping techniques including functional magnetic resonance imaging (fMRI). Here, we review the literature to better understand the reliability of fMRI for mapping the somatosensory cortex. We have chosen to focus on the hand and fingers as these areas have the largest representation and have been the subject of the largest number of somatotopic mapping experiments. Regardless of the methods used, individual finger somatosensory maps were found to be organized across Brodmann areas (BAs) 3b, 1, and 2 in lateral-to-medial and inferior-to-superior fashion moving from the thumb to the pinky. However, some consistent discrepancies are found that depend principally on the method used to stimulate the hand and fingers. Therefore, we suggest that a comparative analysis of different types of stimulation be performed to address the differences described in this review.

X-ray excited luminescence spectroscopy and imaging with NaGdF4:Eu and Tb.

X-ray excited optical luminescence from nanophosphors can be used to selectively generate light in tissue for imaging and stimulating light-responsive materials and cells. Herein, we synthesized X-ray scintillating NaGdF4:Eu and Tb nanophosphors via co-precipitate and hydrothermal methods, encapsulated with silica, functionalized with biotin, and characterized by X-ray excited optical luminescence spectroscopy and imaging. The nanophosphors synthesized by co-precipitate method were ∼90 and ∼106 nm in diameter, respectively, with hydrothermally synthesized particles showing the highest luminescence intensity. More importantly, we investigated the effect of thermal annealing/calcination on the X-ray excited luminescence spectra and intensity. At above 1000 °C, the luminescence intensity increased, but particles fused together. Coating with a 15 nm thick silica shell prevented particle fusion and enabled silane-based chemical functionalization, although luminescence decreased largely due to the increased mass of non-luminescent material. We observed an increase in luminesce intensity with temperature until at 400 °C. At above 600 °C, NaGdF4:Eu@SiO2 converts to NaGd9Si6O26:Eu, an X-ray scintillator brighter than annealed NPs at 400 °C and dimmer than NPs synthesized using the hydrothermal method. The particles generate light through tissue and can be selectively excited using a focused X-ray source for imaging and light generation applications. The particles also act as MRI contrast agents for multi-modal localization.

Focused ultrasound blood brain barrier opening mediated delivery of MRI-visible albumin nanoclusters to the rat brain for localized drug delivery with temporal control.

There is an ongoing need for noninvasive tools to manipulate brain activity with molecular, spatial and temporal specificity. Here we have investigated the use of MRI-visible, albumin-based nanoclusters for noninvasive, localized and temporally specific drug delivery to the rat brain. We demonstrated that IV injected nanoclusters could be deposited into target brain regions via focused ultrasound facilitated blood brain barrier opening. We showed that nanocluster location could be confirmed in vivo with MRI. Additionally, following confirmation of nanocluster delivery, release of the nanocluster payload into brain tissue can be triggered by a second focused ultrasound treatment performed without circulating microbubbles. Release of glutamate from nanoclusters in vivo caused enhanced c-Fos expression, indicating that the loading capacity of the nanoclusters is sufficient to induce neuronal activation. This novel technique for noninvasive stereotactic drug delivery to the brain with temporal specificity could provide a new way to study brain circuits in vivo preclinically with high relevance for clinical translation.

Somatotopic Arrangement of the Human Primary Somatosensory Cortex Derived From Functional Magnetic Resonance Imaging.

Functional magnetic resonance imaging (fMRI) was used to estimate neuronal activity in the primary somatosensory cortex of six participants undergoing cutaneous tactile stimulation on skin areas spread across the entire body. Differences between the accepted somatotopic maps derived from Penfield's work and those generated by this fMRI study were sought, including representational transpositions or replications across the cortex. MR-safe pneumatic devices mimicking the action of a Wartenberg wheel supplied touch stimuli in eight areas. Seven were on the left side of the body: foot, lower, and upper leg, trunk beneath ribcage, anterior forearm, middle fingertip, and neck above the collarbone. The eighth area was the glabella. Activation magnitude was estimated as the maximum cross-correlation coefficient at a certain phase shift between ideal time series and measured blood oxygen level dependent (BOLD) time courses on the cortical surface. Maximally correlated clusters associated with each cutaneous area were calculated, and cortical magnification factors were estimated. Activity correlated to lower limb stimulation was observed in the paracentral lobule and superomedial postcentral region. Correlations to upper extremity stimulation were observed in the postcentral area adjacent to the motor hand knob. Activity correlated to trunk, face and neck stimulation was localized in the superomedial one-third of the postcentral region, which differed from Penfield's cortical homunculus.

Normal thymic uptake of 2-deoxy-2[F-18]fluoro-D-glucose.

Whole-body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) positron emission tomography (PET) of a 54-year-old woman with a history of recurrent thyroid follicular cancer and an elevated thyroglobulin level showed significant FDG uptake in the thyroid bed and anterior mediastinum. A previous scan after high-dose I-131 therapy also showed iodine uptake in these regions. Because of a lack of response to iodine therapy, the patient had surgery. Recurrent thyroid cancer was found in the neck, but the mediastinal lesion was shown to consist of normal thymus tissue. In repeated examinations performed after surgery, there was no uptake of FDG or I-131 in the anterior mediastinum. Previous treatment with a high dose of radioiodine may have contributed to visualization of a normal adult thymus with FDG PET.

Morphologic and functional characteristics of alveolar macrophages following cryopreservation.

Cryopreservation of nucleated blood and bone marrow mononuclear cells has been used both to preserve such cells for clinical, diagnostic, or research use and to eliminate them as passengers in frozen tissue destined for transplantation. Although techniques for macrophage and monocyte cryopreservation have been described, little work has been done on the functional state of these cells following frozen storage. Using rabbit alveolar macrophages (AM), we have shown that AM can be frozen, stored, and recovered without morphologic changes. Furthermore, freshly isolated and cryopreserved AM do not differ in their adherence characteristics or the organization of their actin cytoskeleton. Cryopreserved normal AM also retained inducible functions such as superoxide anion (O2-) release and production of tumor necrosis factor (TNF) and interleukin-1 (IL-1). In order to further define the effects of cryopreservation on macrophage biology, we have also frozen macrophages which have been primed in vitro, and have demonstrated that the primed state remains at prefreezing levels after thawing and subsequent analysis. These data help define the effects of cryopreservation on cell function and establish parameters for the clinical and experimental evaluation of cryopreserved mononuclear phagocytes.

Preschool development of coloured children in Cape Town.

Developmental screening was applied during infancy to a birth cohort of 1,000 coloured infants born consecutively in Cape Town. The developmental progress of a sample of 187 children randomly selected from the cohort was followed over a period of 5 years. The value of the use of developmental screening is questioned, since 4 of the children in the cohort with major handicap had been diagnosed before the first screening was carried out and a 5th child with deafness was not detected by the screening process. Developmental milestones were similar to those studies reported in the literature. At 12 months the development correlated best with family stability. Language development at 30 months was associated with mother's education and family stability and reflected a general lag in verbal skills. By 5 years there was a good correlation between development and social indicators, particularly income and mother's education.

Growth of preschool coloured children in Cape Town.

The growth of a random sample of coloured children in Cape Town was studied from birth until 5 years. At birth they were relatively light and short for gestational age. Size at birth correlated with social class. A rapid postnatal weight gain rendered them relatively overweight between 3 and 6 months. Thereafter they became lighter and shorter than the NCHS reference values and this persisted throughout the preschool period. Genetic factors, reflected by parental growth, were found to predict growth during childhood, but they were more predictive of weight and head circumference than of length. From 12 months onwards, socio-economic factors played a significant role in determining growth even after the effects of the genetic factors had been taken into account.

Relationships between pulmonary inflammation, plasma transudation, and oxygen metabolite secretion by alveolar macrophages.

We have previously shown that alveolar macrophages from normal rabbit lungs do not synthesize reactive oxygen intermediates unless first conditioned by culture in vitro in the presence of serum for 24 to 48 hr. This conditioning process is mediated by a serum constituent that partitions on gel exclusion columns with an apparent m.w. of 30,000 to 50,000 daltons. Alveolar macrophage conditioning in vitro requires protein synthesis, is associated with the generation of membrane NADPH oxidase activity, and is reversible. We have predicted therefore that during the course of pulmonary inflammation, as observed 3 wk after i.v. injection of M. butyricum in oil, alveolar macrophages might similarly become conditioned in vivo through exposure to plasma protein transudates reaching the alveolus. In support of this hypothesis we show that after experimental production of granulomatous pulmonary inflammation in rabbits, alveolar macrophages showed an augmented capacity to secrete superoxide anion when stimulated with phorbol ester, and this enhancement increases exponentially with increased plasma transudation. This augmented enhancement was reversible, and decreased after culture in vitro in the absence of serum. Mature alveolar macrophages were responsible for this enhanced superoxide anion production rather than freshly emigrated monocytes. Moreover, superoxide anion production in this model of pulmonary inflammation appears to be an "all-or-none" phenomenon, with superoxide anion production associated with a subpopulation of optimally conditioned alveolar macrophages, whereas the remaining unconditioned alveolar macrophages produce little or none. We feel that these two classes of alveolar macrophages may be derived from inflamed and noninflamed regions of the lung, respectively, thereby reflecting the discontinuous nature of the inflammatory lesions themselves. Thus we propose that measurements of reactive oxygen intermediate production by lavaged alveolar macrophages may provide a semi-quantitative measure of chronic pulmonary inflammation.

Serum factor requirement for reactive oxygen intermediate release by rabbit alveolar macrophages.

Alveolar macrophages (AM) from pathogen-free rabbits were unable to release reactive oxygen intermediates (ROI) unless they were conditioned in serum for 24-48 h before triggering with membrane-active agents. The degree of serum conditioning of AM depended upon the concentration of serum used; optimal ROI release was obtained at or above 7.5% fetal bovine serum (FBS). FBS, autologous rabbit serum, pooled rabbit serum, and pooled human serum were each capable of conditioning AM for release of ROI. Serum conditioning of AM requires synthesis of new protein(s); and the enzyme required for ROI production, NADPH oxidase, was only detectable in serum-conditioned cells. Moreover, serum-conditioned cells lost their ability to release ROI after transfer to serum-free medium, while cells maintained in serum-free medium acquired the capacity to release ROI after their transfer to serum-containing medium, demonstrating the reversibility of the phenomenon. Initial purification data indicate that conditioning is mediated by a discrete serum constituent, which precipitates 40-80% saturated ammonium sulfate, does not bind to Cibacron Blue columns, and has a molecular weight of 30,000 to 50,000, as determined by molecular exclusion chromatography. Unlike gamma interferon, which also enhances ROI release by macrophages, our serum-conditioning factor is not acid labile, retaining 67% of its activity after 120 min incubation at pH 2.0. Moreover, it does not appear to be a contaminating endotoxin, since LPS neither conditioned AM for ROI production, nor triggered ROI production by serum-conditioned AM. We propose that such a conditioning requirement may normally protect the lung against ROI-mediated tissue injury. However, during a pulmonary inflammatory reaction initiated by other mediator systems, the resulting transudation of plasma proteins into the alveolar spaces may condition AM in situ for ROI production.

Immunologic mechanisms of parenchymal lung injury.

The lung, like most other organs, is susceptible to injury by circulating immune complexes, and also by humoral autoantibody and immune lymphocytes which specifically recognize selected lung antigens. In addition, by virtue of its direct communication with the external environment, the lung can also be injured by inhaled environmental agents which trigger inflammatory reactions mediated by immune effector systems. Although major emphasis to date has been placed on the ability of inhaled antigens to first sensitize, then provoke, immunologically specific reactions in the lung, there is increasing evidence to show that these same immune effector systems are also triggered in an immunologically nonspecific fashion by a certain environmental agents (termed "mitogens") which activate leukocytes in a polyclonal fashion. Such agents include certain viruses and other microorganisms, bacterial endotoxin, a wide variety of plant lectins, and certain chemicals, such as the phorbol esters. Although such agents act in an immunologically nonspecific fashion, they are nonetheless quite specific from a chemical viewpoint, and in many cases act by binding to specific receptors on the cell surface. By activating macrophages directly, and by activating much larger percentages of a given lymphocyte population than do specific antigens, they induce correspondingly amplified inflammatory reactions in vivo. Recent studies with animal models indicate that inhaled mitogens are strikingly effective in inducing pulmonary inflammation, whereas inhaled antigens (lacking mitogenic activity) produce little if any parenchymal injury in immunized recipients, unless administered in conjunction with a mitogen. Ongoing studies using such models promise to provide valuable new insight into the biologic properties which govern the pathogenicity of inhaled environmental agents, the mediators they release, and the biochemical basis for variations in individual susceptibility to injury by such agents.

Gas exchange alterations associated with weaning from mechanical ventilation following coronary artery bypass grafting.

This study was done to clarify the effects of positive-pressure mechanical ventilation on gas exchange in the lungs of conscious patients. Nine hemodynamically stable patients were studied following coronary artery bypass grafting at the time they were weaned from mechanical ventilation. The adequacy of gas exchange was assessed by traditional measurements as well as the multiple inert gas technique used to measure the ventilation-perfusion (VA/Q) distribution. During mechanical ventilation, gas exchange was characterized by a variable degree of VA/Q inequality as well as a substantial shunt ranging from 11.9 to 27.7 percent. Following removal from mechanical ventilation, there was a decrease in the mean VA/Q subsequent to a decrease in the minute ventilation. However, there was no significant change in the level of shunt or in the amount of VA/Q inequality.

The role of subcellular factors in pulmonary immune function: physicochemical characterization of two distinct species of lymphocyte-activating factor produced by rabbit alveolar macrophages.

T cell stimulatory factors produced by rabbit alveolar macrophages were investigated. Physicochemical characterization revealed that alveolar macrophages (harvested by bronchopulmonary lavage and stimulated in tissue culture with bacterial lipopolysaccharide) released 2 predominant species of lymphocyte-activating factor (LAF) with isoelectric points of 4.6 and 7.4, and m.w. of 14,400 and 11,600 daltons, respectively, as calculated by the Svedberg equation. Using C3H/HeJ mouse thymocytes (and in some instances nylon wool-purified nonadherent rabbit spleen or lymph node cells) as target cells, rabbit LAF was found to induce proliferative responses directly, as well as enhance proliferative responses to phytomitogens. Both LAF species were inactivated by heating, treatment with trypsin, or at low (2.3) pH. The pI 7.4 LAF was also unstable at high pH (9.0). The thymocyte stimulatory activity of both LAF species was not inhibited by the anti-proteases alpha-1-anti-trypsin, Traysylol (aprotinin), leupeptin, or pepstatin.

A study on child development in Cape Town. The cohort and sample.

A study of growth and development was initiated on a cohort of Coloured children born during May 1976 in Cape Town. Approximately 90% of the infants were born in hospital or in midwife obstetric units and about 14% weighed less than 2 500 g. Poor maternal education, low income and overcrowding are considered to be risk factors in child rearing. Sixty-five per cent of the mothers were not educated further than primary school level and over half the families were living below an effective minimum level of income. Similarly, over half the families lived in grossly overcrowded conditions.

Endogenous pyrogens made by rabbit peritoneal exudate cells are identical with lymphocyte-activating factors made by rabbit alveolar macrophages.

Purified endogenous pyrogen (EP), isolated in one laboratory from stimulated rabbit peritoneal exudate cells (PEC), was compared with purified lymphocyte activating factor (LAF), isolated in another laboratory from stimulated rabbit alveolar macrophages (AM). Both EP and LAF occurred in two forms, one with an isoelectric point (pI) of 7.3 to 7.4, the other with a pI of 4.6 to 4.7. Both forms of EP and LAF had m.w. of 13,000 to 16,000 daltons as judged by gel filtration. Both forms of EP had LAF activity, and both forms of LAF were pyrogenic. The pI 7.3 EP, which is known to have an -SH group essential for its biologic activity, bound to Thiol Sepharose columns and could be eluted with mercaptoethanol. The pI 7.3 LAF behaved in exactly the same way. Furthermore, antisera from three different goats were available that completely blocked the pyrogenicity of pI 7.3 EP in vivo; these sera also blocked the pI 7.3 LAF activity in vitro. The pI 4.6 EP and LAF did not bind to Thiol Sepharose columns, nor were they inhibited by any of the antisera that blocked the pI 7.3 EP and LAF. Moreover, isoelectric focusing of pI 4.6 EP in very shallow gradients revealed microheterogeneity with sharp peaks of EP activity observed at pH 4.6 and 4.7. Analysis for LAF activity showed an identical microheterogeneity. These results are consistent with the idea that EP and LAF are identical.

Role of polyclonal cell activation in the initiation of immune complex-mediated pulmonary injury following antigen inhalation.

The lung, by virtue of its anatomic situation, provides environmental antigens with unique access to host lymphoid tissues. In order to better understand the biologic consequences of antigen inhalation, we developed in animal model in which soluble proteins are administered in aerosol form to rabbits. By labeling these proteins with fluorochrome dyes or radioactive isotopes, the uptake, distribution, and fate of such proteins can be demonstrated both morphologically and quantitatively. Prompt host-antibody responses can be demonstrated to inhaled antigen, but not to comparable amounts of ingested antigen. Repeated administrations of antigen aerosol to immune animals produced little injury; in contrast, administration of aerosols containing phytohemagglutinin or cancanavalin A (Con A), plant lectins which activate leucocytes in a polyclonal fashion, induced a diffuse interstitial pneumonitis. When immune animals inhaled antigen plus Con A, devastating pulmonary necrosis was induced, in association with localized deposits of immune complexes containing antigen, antibody and complement. Such necrotic injury healed by scarring within 4 weeks. The necrotizing injury could be prevented by either decomplementation with cobra venom factor, or through inhibition of leucocyte responsiveness to Con A by administration of cholera toxin, a cAMP agonist. These studies indicate that antigen inhalation may serve as an important means of establishing "natural" immunity to environmental agents, but also may lead to severe pulmonary injury and fibrosis where the agents inhaled act not only as antigens but as polyclonal leucocyte activators as well.

In vivo responses to inhaled proteins. III. Inhibition of experimental immune complex pneumonitis after suppression of peripheral blood lymphocytes.

We have previously shown that inhaled Con A has a powerful enhancing effect on the formation of immune complexes between an inhaled antigen and circulating antibody. Immunohistochemical staining has demonstrated such complexes, together with host complement, in close association with foci of necrotizing destruction of the pulmonary parenchyma. We have postulated that Con A promotes immune complex formation indirectly through polyclonal activation of lymphocytes in the lung. In this paper we test this hypothesis in animals rendered unresponsive to Con A stimulation in vivo by i.v. administration of cholera toxin (CT). Such treatment raised the levels of cAMP in peripheral blood lymphocytes and inhibited their proliferative response to Con A in vitro. CT administration further blocked the local inflammatory response to intradermal injections of Con A, as well as the cell-mediated immune response to intradermal injections of BSA. Although CT failed to block the immune complex-mediated Arthus vasculitis in the skin, it did block production of immune complex pulmonary injury by antigen/mitogen aerosols, as did decomplementation with purified cobra venom factor. These findings support the hypothesis that polyclonal activation of pulmonary lymphocytes promotes immune complex-type alveolitis, possibly by facilitating interactions between humoral antibody and intra-alveolar antigen.