IgA pemphigus with paraneoplastic pemphigus-like clinical features showing IgA antibodies to desmoglein 1/3 and desmocollin 3, and IgG and IgA antibodies to the basement membrane zone.

A 79-year-old Japanese woman presented with severe recalcitrant erosions on her oral mucosa, resembling paraneoplastic pemphigus. Using indirect immunofluorescence, we detected IgA antibodies against the cell surface, and both IgG and IgA antibodies against the basement membrane zone. Immunoblotting showed that the IgG antibodies reacted weakly with bullous pemphigoid 230 and periplakin, whereas the IgA antibodies did not react with any antigen. IgA antibodies to both desmoglein (Dsg)1 and Dsg3 were detected by ELISA. IgA antibodies to desmocollin (Dsc)3 were also detected by using cDNAs for human Dsc1-3 transfected into COS-7 cells. Despite treatment with oral prednisolone, high-dose intravenous immunoglobulin and double-filtration plasmapheresis, the skin lesions remained active, and the patient died from bronchiolitis obliterans-like respiratory failure. Despite extensive investigations and postmortem examination, no underlying neoplasms were found. The complex immunopathological findings probably played an important role in the development of the patient's unusual clinical features.

Change in chemoattractant responsiveness of developing axons at an intermediate target.

Developing axons reach their final targets as a result of a series of axonal projections to successive intermediate targets. Long-range chemoattraction by intermediate targets plays a key role in this process. Growing axons, however, do not stall at the intermediate targets, where the chemoattractant concentration is expected to be maximal. Commissural axons in the metencephalon, initially attracted by a chemoattractant released from the floor plate, were shown to lose responsiveness to the chemoattractant when they crossed the floor plate in vitro. Such changes in axon responsiveness to chemoattractants may enable developing axons to continue to navigate toward their final destinations.

Floor plate chemoattracts crossed axons and chemorepels uncrossed axons in the vertebrate brain.

In the bilaterally symmetrical vertebrate CNS, all developing axons must choose between remaining on the same side of the midline or growing across it. The mechanism underlying this axonal pathfinding is, however, poorly understood. Here we demonstrate that the ventral midline floor plate (FP) chemorepels two types of ipsilaterally projecting axons, one from the alar plate and another from the basal plate in the mesencephalon. We further demonstrate that the FP chemoattracts contralaterally projecting myelencephalic as well as metencephalic axons. The FP at all axial levels displayed both chemoattractive and chemorepellent activities, suggesting that FP chemoattraction and chemorepulsion may be at work throughout the neuraxis. Chemotropic guidance by the FP may therefore play a key role in the establishment of neuronal projection laterality.

Guidance of cerebellofugal axons in the rat embryo: directed growth toward the floor plate and subsequent elongation along the longitudinal axis.

To elucidate guidance mechanisms of brain commissural axons, we examined the navigation of cerebellofugal axons. Axons were labeled by implantation of the fluorescent tracer Dil into the cerebellar plate (CP) of fixed, flat whole-mount embryonic rat brain. Axons initially grew straight toward the ventral midline floor plate (FP) in the rostral hindbrain and then, after crossing it, made a right-angled turn to grow either caudally or rostrally along the longitudinal axis. In collagen gel culture, CP axons showed directed growth toward both FP explants and heterologous cells expressing netrin-1, a FP-derived chemoattractant for spinal commissural axons. These results suggest that CP axons are guided to the midline by FP-derived chemoattractant(s) and then reoriented, possibly by another guidance cue, for longitudinal extension. Considering that the basic structures of the neural tube, including the FP, extend up to the caudal diencephalon, these results suggest that common guidance mechanisms operate for ventrally decussating commissural axons in both the brain and spinal cord.

Guidance of circumferentially growing axons by netrin-dependent and -independent floor plate chemotropism in the vertebrate brain.

Netrin-1, a diffusible signal secreted by floor plate cells at the ventral midline of the vertebrate CNS, can attract ventrally migrating axons and repel a subset of dorsally migrating axons in the spinal cord and rostral hindbrain in vitro. Whether netrin-1 can act as a global cue to guide all circumferentially migrating axons is, however, unknown. Here, we show that netrin-1 can attract alar plate axons that cross the floor plate along its entire rostrocaudal axis. Dorsally directed axons forming the posterior commissure are, however, repelled by the floor plate by a netrin-independent mechanism. These results suggest that netrin-1 functions as a global guidance cue for attraction to the midline. Moreover, floor plate-mediated chemorepulsion may also operate generally to direct dorsal migrations, but its molecular basis may involve both netrin-dependent and -independent mechanisms.

Development, validation and stability study of pediatric atenolol syrup.

Atenolol [4-(2-hydroxy-isopropylaminopropoxy)-phenylacetamide], is a cardioselective beta1-adrenergic receptor blocking agent prescribed for treatment of hypertension, angina pectoris and cardiac arrhythmias. However, most of these medicines are not formulated for easy or accurate administration to children. Atenolol is unstable in solutions and therefore the development of a liquid dosage form is a significant challenge. Studies showed that the degradation rate of atenolol is dependent on the temperature, indicating higher stability at 4 degrees C. Atenolol syrup is stable for 9 days, with acceptable apearance. A second order model adequately described atenolol decomposition when stored as syrup. A stability-indicating method was developed and validated in order to evaluate these studies.

Local directional cues control growth polarity of dopaminergic axons along the rostrocaudal axis.

The vertebrate CNS is composed of a variety of longitudinal axonal tracts extending rostrally and caudally. Although recent studies have demonstrated that chemoattraction and chemorepulsion play key roles in axon guidance along the circumferential axis in the neural tube of the vertebrate, mechanisms of axonal elongation along the longitudinal axis, and most importantly, what determines rostrocaudal polarity of axonal growth, remains unknown. Here, we examined the mechanism that guides midbrain dopaminergic axons rostrally, using flat whole-mount preparations of embryonic rat brain both in vivo and in vitro. At embryonic day 11 (E11) and early stage E12, dopaminergic neurons in the ventral midbrain extended short axons dorsally. By middle stage E12, these axons had increased in number, some deflecting rostrally and others caudally. At E13, almost all axons showed rostrally oriented growth heading toward the forebrain targets. In in vitro whole-mount preparations prepared from an E12 embryo and cultured for 24 hr, these axons showed rostrally oriented growth, but when they were forced to grow on substratum of reversed rostrocaudal polarity, they turned abruptly and grew following the polarity of the reversed midbrain substratum. These results suggest that local directional cues in the midbrain guide these axons rostrally and support the idea that substratum-associated polarized cues play an important role in axon guidance along the longitudinal axis.

Inhibitory mechanism by polysialic acid for lamina-specific branch formation of thalamocortical axons.

During development, thalamocortical axons form arbors primarily in layer 4 of the neocortex. This lamina-specific branch formation was studied in cultures of rat thalamic explants grown next to chemically fixed cortical slices. After a week in vitro, thalamic axons formed branches specifically in the target layer of fixed cortical slices, regardless of the orientation of the ingrowth. This in vitro system permits a direct assessment of contributions of membrane-associated molecules to thalamic axon branch formation. To this end, the present study uses three enzymatic perturbations: chondroitinase, phosphatidylinositol phospholipase C, or the polysialic acid (PSA)-specific endoneuraminidase (endo N). With endo N pretreatment of cortex, the number of branch points was increased significantly, whereas branch tip length was decreased. In addition, the localization of branch points to the target layer was weakened considerably. These features of branch formation were not altered by the other two enzymatic treatments, except that branch tips were shortened by chondroitinase treatment to the same extent as in endo N treatment. These results suggest that membrane-bound components are involved in lamina-specific branch formation of thalamocortical axons, and in particular that PSA moieties contribute to laminar specificity by inhibiting branch emergence in inappropriate layers.

The mode of actions of lysozyme as an immunoglobulin production stimulating factor.

As we demonstrated before, hen egg white lysozyme stimulates immunoglobulin production by a human-human hybridoma line, HB4C5 cells and human peripheral blood lymphocytes. Then, the mode of actions of lysozyme as an immunoglobulin production stimulating factor was investigated. The immunoglobulin production stimulating activity of lysozyme was inactivated by trypsin digestion, even though the enzymatic activity was completely preserved. This fact suggests that the immunoglobulin production stimulating effect of lysozyme is irrelevant to its enzymatic function. Furthermore, this means that the effect is a novel function of this enzyme. Lysozyme enhanced IgM production by transcription-suppressed HB4C5 cells treated with actinomycin D. However, the enzyme was ineffective to accelerate IgM production by translation-suppressed HB4C5 cells treated with cycloheximide or sodium fluoride. In addition, the intracellular IgM content of HB4C5 cells treated with monensin for suppression of the post-transcription activity was obviously increased by lysozyme, although the secretion of IgM was inhibited. These findings suggest that lysozyme accelerates the translation process to enhance immunoglobulin productivity.

Postnatal development of crossed and uncrossed corticorubral projections in kitten: a PHA-L study.

Morphological changes in individual corticorubral fibers and the pattern of crossed and uncrossed corticorubral projections were studied during the postnatal development of cats in order to understand cellular mechanisms for restriction of corticorubral projections with development. The anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) was injected into restricted areas of the pericruciate cortex in kittens and PHA-L-labeled axons in the red nucleus were examined at postnatal days (PND) 7-73. In accordance with our previous study (Murakami and Higashi, Brain Res. 1988; 447:98-108), a crossed corticorubral projection was observed in addition to the uncrossed one in every experimental animal. During the early period of development (PND 7-8), swellings of irregular shape were observed along the entire course of the axons and they were often interconnected with extremely fine axonal segments. These axons bifurcated only infrequently and often ended as growth cones. These features were common to both uncrossed and crossed corticorubral axons. At later stages of development (PND 28 or later), the total number of swellings decreased and axonal swellings with smooth contours became dominant. A quantitative examination of axonal branches indicated that axons on the ipsilateral side branch occurred more frequently at later stages of development. However, there was no substantial change in branching frequency for the crossed corticorubral fibers during development. In parallel with morphological changes in individual axons, the crossed projection that was initially relatively abundant was reduced during development. Since a PHA-L injection can be confined to a small region of cortex, topographic projections can easily be detected. At PND 7-8 there was no well-defined topographic order in the ipsilateral corticorubral projection. Adult-like topography was first discernible at PND 13. These observations suggest that the unilateral uncrossed corticorubral projection in the adult cat is achieved at least in part by the formation of axonal arbors in the uncrossed projection. This was accompanied by the failure of crossed fibers to form complex arbors. It is possible that a similar mechanism also operates in the formation of topographic maps.

Light and electron microscopic study of corticorubral synapses in adult cat: evidence for extensive synaptic remodeling during postnatal development.

Spine-like dendritic protrusions (SLDPs) emanating from developing dendrites have been proposed to play an important role in early synaptogenesis. We previously analyzed synaptic termination sites on soma-dendritic membrane of newborn cats and found that corticorubral (CR) axons form synapses preferentially on SLDPs (Saito et al., 1997). In the present study, we examined CR synapses in adult cats to elucidate the maturation process of CR synapses in relation to SLDPs. Electron microscopic observation of serial thin sections of Phaseolus vulgaris-leucoagglutinin-labeled axons revealed that approximately 60% of CR terminals in adult cats formed synapses on dendritic spines. We also found that CR axons terminate on dendritic spines originating from the intermediate or distal dendrites of rubrospinal cells (more than 200 microm apart from the soma), in contrast to kittens in which CR fibers terminate on SLDPs originating from the proximal dendrites (less than 100 microm apart from the soma) of rubrospinal cells (Saito et al. [1997] J. Neurosci. 17:8792-8803). These results suggest that CR synapses undergo remarkable remodeling after initial termination on SLDP during postnatal development.

Afferents of cranial sensory ganglia pathfind to their target independent of the site of entry into the hindbrain.

In vertebrates, sensory neurons interconnect a variety of peripheral tissues and central targets, conveying sensory information from different types of sensory receptors to appropriate second-order neurons in the central nervous system (CNS). To explore the possibility that the different rhombomere environments where sensory neurons enter into the hindbrain affect the pathfinding capability of growth cones, we studied the development of the VIIIth ganglion afferent both in vivo and in vitro. We focused on the vestibular nerve because it is the only cranial nerve projecting to the cerebellum, allowing for ready identification from its pattern of projection. Embryonic rat brain was cut along the dorsal midline and, with the VIIIth and Vth ganglia still attached, flat mounted and visualized with antibodies specific for sensory ganglia. Axons reached the cerebellar primordium at embryonic day (E) 13, then splayed out towards the edges of the rhombic lip of rostral hindbrain. In vitro, the VIIIth ganglion showed development similar to that in vivo and innervated the cerebellum, an appropriate target, indicating that mechanisms for axon guidance and target recognition are preserved in vitro. When the VIIIth ganglion was transplanted to the position of the Vth ganglion, axons from the transplanted ganglion entered the cerebellar primordium with a trajectory characteristic of the VIIIth nerve. These results indicate that the central projection pattern of the VIIIth nerve is not affected by the environment of nerve entry into the brainstem, suggesting that axons of sensory cranial ganglion intrinsically possess the capacity to find their target correctly.

Westernized food habits and concentrations of serum lipids in the Japanese.

To investigate the association of westernized food habits and concentrations of serum lipids in the Japanese, we studied 1200 healthy Japanese living in Hiroshima prefecture and 1483 ethnic Japanese from Hiroshima prefecture living in the Hawaii Islands and Los Angeles. The nutritional assessments were made by the same dietitians. No major difference was observed in the total energy intake between the Japanese and the Japanese-Americans in both males and females. However, the intake of animal fat and simple carbohydrates (especially fructose) were markedly greater, and that of complex carbohydrates lower, in the Japanese-Americans compared with the Japanese. The mean serum cholesterol (CH), LDL-CH and serum triglyceride (TG) levels were significantly higher in the Japanese-Americans in both sexes. The mean HDL-CH concentration was similar between the two groups in males, but it was approximately 7 mg/dl higher in Japanese-American females. Using the 75 percentile values of CH and TG in the Japanese in Hiroshima, the frequency of WHO types IIa and IIb hyperlipidemia was about twice as high in the Japanese-Americans. These results suggest that westernized food habits in the Japanese include qualitative changes in animal fat, simple carbohydrate and complex carbohydrate diet rather than an increase in the total energy intake. These changes are associated with marked increases in the concentrations of serum CH and TG and increased prevalence of types IIa and IIb hyperlipidemia.

The release of the substrate for xanthine oxidase in hypertensive patients was suppressed by angiotensin converting enzyme inhibitors and alpha1-blockers.

OBJECTIVE: Hyperuricemia is associated with the vascular injury of hypertension, and purine oxidation may play a pivotal role in this association, but the pathophysiology is not fully understood. We tested the hypothesis that in hypertensive patients, the excess amount of the purine metabolite, hypoxanthine, derived from skeletal muscles, would be oxidized by xanthine oxidase, leading to myogenic hyperuricemia as well as to impaired vascular resistance caused by oxygen radicals. METHODS: We investigated the production of hypoxanthione, the precursor of uric acid and substrate for xanthine oxidase, in hypertensive patients and found that skeletal muscles produced hypoxanthine in excess. We used the semi-ischemic forearm test to examine the release of hypoxanthine (deltaHX), ammonium (deltaAmm) and lactate (deltaLAC) from skeletal muscles in essential hypertensive patients before (UHT: n = 88) and after treatment with antihypertensive agents (THT: n = 37) in comparison to normotensive subjects (NT: n = 14). RESULTS: deltaHX, as well as deltaAmm and deltaLAC, were significantly higher in UHT and THT (P< 0.01) than in NT. This release of deltaHX from exercising skeletal muscles correlated significantly with the elevation of lactate in NT, UHT and THT (y = 0.209 + 0.031x; R2 = 0.222, n = 139: P < 0.01). Administration of doxazosin (n = 4), bevantolol (n = 5) and alacepil (n = 8) for 1 month significantly suppressed the ratio of percentage changes in deltaHX by -38.4 +/- 55.3%, -51.3 +/- 47.3% and -76.3 +/- 52.2%, respectively (P< 0.05) but losartan (n = 3), atenolol (n = 7) and manidipine (n = 10) did not reduce the ratio of changes; on the contrary, they increased it in deltaHX by +188.2 +/- 331%, +96.2 +/- 192.2% and +42.6 +/- 137.3%, respectively. The elevation of deltaHX after exercise correlated significantly with the serum concentration of uric acid at rest in untreated hypertensive patients (y = 0.194 - 0.255x; R2 = 0.185, n = 30: P < 0.05). The prevalence of reduction of both deltaHX and serum uric acid was significantly higher in the patients treated with alacepril, bevantolol and doxazosin (67%: P < 0.02) than in the patients treated with losartan, atenolol and manidipine (12%). CONCLUSIONS: It is concluded that the skeletal muscles of hypertensive patients released deltaHX in excess by activation of muscle-type adenosine monophosphate (AMP) deaminase, depending on the degree of hypoxia. The modification of deltaHX by angiotensin-converting enzyme inhibitors and alpha1-blockers influenced the level of serum uric acid, suggesting that the skeletal muscles may be an important source of uric acid as well as of the substrate of xanthine oxidase in hypertension.

Electron microscopic localization and expression on cultured cells of a novel surface-associated molecule in the rat central nervous system.

Subcellular localization and in vitro expression of a newly raised monoclonal antibody 374 antigen, which outlines a subset of neurons in various regions of the rat CNS, were studied. Electron microscopy revealed that the immunoreactivity is associated with the outer surfaces of neuronal subsets, the surfaces of glial cell processes facing such neurons and less frequently, with the Golgi apparatus and inner cell surfaces. The monoclonal antibody also stained part of the cytoplasm of a population of dendrites. In order to test whether the antigen originates from neurons, we examined the expression of the antigen in cultured cortical cells. Double immunofluorescence staining with neuron-specific enolase and glial fibrillary acidic protein revealed that the antigen is expressed on a subset of neuronal cells and to a lesser extent on glial cells. The antigen is considered to be expressed on the outer surface because the cells were stained by the monoclonal antibody irrespective of whether they were alive or fixed. The monoclonal antibody 374 antigen may be a novel neuronal surface molecule which plays a role in neuron-neuron or glial-neuron interactions in the CNS.

Dendritic and somatic appendages of identified rubrospinal neurons of the cat.

Giant neurons of the red nucleus of the cat were stained intracellularly with horseradish peroxidase and examined using light microscopy, electron microscopy of thin sections, and high voltage electron microscopy of thick sections (2-5 microns). Special attention was paid to the arrangement of dendritic spines and other appendages relative to the distribution of synaptic contacts from known sources. In the region of the neuron known to receive synaptic contacts from the nucleus interpositus of the cerebellum (soma and proximal 200-300 microns of dendrites), the dendrites were relatively unbranched, and free of long spines or complex appendages. The surface of the neurons in this region was covered with a dense layer of short thin appendages that invaginated or penetrated between the synaptic terminals that cover this part of the cells. The small spines received synapses of the types associated both with the cerebellar afferent fibers and with the local inhibitory interneurons. These same terminals made synaptic contacts directly onto the surface of the neurons and onto the lateral surfaces of the spines, suggesting that the spines may serve primarily to increase the available synaptic surface area. The more distal portion of the dendritic field, where cerebellar afferents do not make synaptic contacts, exhibited a dramatically different appearance. The dendrites were much more branched, and exhibited many and varied dendritic appendages. The appendages were of three general types. One was a large protrusion with a cup-shaped head that formed the principal postsynaptic component of a glomerular arrangement also involving an axon terminal and usually a presynaptic dendrite. A second was a long thin filiform process that usually occurred around the glomeruli. This appendage was occasionally postsynaptic. The third was a spherical appendage containing many lysosomal organelles resembling residual bodies. The glomerular dendritic protrusions were very common in the distal portion of the dendritic field, numbering at least 1000 per cell. At least some of the glomeruli are specialized for receipt of synaptic input from the corticorubral pathway, since lesions of sensorimotor cortex resulted in degeneration of the central synaptic terminal in some glomeruli on horseradish peroxidase-injected rubrospinal neurons. These specializations of dendritic structure may contribute to the differences in excitatory postsynaptic potential wave shape between cortical and cerebellar inputs, and they may play a role in the changes in the cortical excitatory postsynaptic potential that develop after lesions of cerebellar inputs.(ABSTRACT TRUNCATED AT 250 WORDS)

A monoclonal antibody identifies a novel epitope surrounding a subpopulation of the mammalian central neurons.

A monoclonal antibody was obtained by immunizing mice with an extract of monkey brain. The monoclonal antibody 473 stained a small subpopulation of neurons in various regions of monkey and rat central nervous system. The perimeters of neuronal somata and the proximal parts of dendrites bound the antibody. Electron microscopic analysis showed that the immunoreactivity was associated with the outer surface of the cell. The immunoreactivity in the rat cerebral cortex appeared gradually during the second four weeks after birth. The antibody stained fetal cartilages but otherwise was specific to the nervous system. Experiments on the stability of the immunoreactivity to enzymatic and chemical treatments of the sections suggest that the antigen molecule is of proteoglycan nature.

An alternative elastase-mediated degradation of fibrinogen and fibrin observed in a patient with herpes simplex encephalitis and pneumonia.

A 74-year-old female developed pneumonia following herpes simplex encephalitis. Her white blood cell counts reached 28,400/microliters, about 90% of which consisted of granulocytes. The polymorphonuclear (PMN) elastase/alpha 1-antitrypsin complex levels increased and reached the maximum of 5,019 ng/ml, indicating the release of a large amount of elastase derived from the granulocytes. The mechanism of PMN elastase release was most likely to be granulocyte destruction associated with phagocytosis. The cleavage of fibrinogen and fibrin by PMN elastase, independent of plasmin, was indicated by the presence of the fragments in immunoprecipitated plasma from the patient corresponding to elastase-induced FDP D and DD fragments and the absence of fragments corresponding to plasmin-induced FDP D and DD fragments on SDS-PAGE. These findings suggested that the large amount of PMN elastase released from the excessive numbers of granulocytes in this patient with herpes simplex encephalitis and pneumonia, induced the cleavage of fibrinogen and fibrin without the participation of plasmin.

Overexpression of the tumor-suppressor gene p53 in human ovarian tumor-tissues and its correlation with clinical stage.

An extensive series of histological sections from various types of benign, borderline, and malignant human ovarian tumors were examined for expression of the p53 protein by immunohistochemical staining, using a new anti-p53 mouse monoclonal antibody. Positive staining for p53 was detected in 34% of all malignant ovarian cancer tissues. A high rate of positivity was observed in serous cystadenocarcinoma (59.7%). None of the borderline or benign tumors showed any reaction. No relation was observed between clinical stage, and the frequency of p53 positivity. Mutation of the p53 gene with overexpression of the mutant protein appears to be a specific genetic change in human ovarian cancer.

Body temperature influences regional tissue blood flow during retrograde cerebral perfusion.

OBJECTIVE: This study compared the cerebral microcirculation during retrograde cerebral perfusion with that during antegrade cardiopulmonary bypass under normothermic and hypothermic conditions. METHODS: Brain tissue blood flow was measured with the hydrogen-clearance and colored microsphere (15 and 50 microns) methods during antegrade cardiopulmonary bypass and retrograde cerebral perfusion. Measurements were performed during normothermia (37 degrees C), moderate hypothermia (28 degrees C) and deep hypothermia (20 degrees C) in groups of mongrel dogs (n = 8). RESULTS: During antegrade cardiopulmonary bypass, the microsphere method showed a significant decrease in cerebral blood flow as body temperature decreased (40.1 +/- 20.8 ml/min/100 gm at 37 degrees C, 16.2 +/- 18.0 ml/min/100 gm at 20 degrees C with 50 microns microspheres) At 20 degrees C, the cerebral blood flow measured with the 15 microns microspheres was significantly lower than that assessed with the hydrogen-clearance method (11.3 +/- 7.0 vs 24.8 +/- 7.0 ml/min/100 gm). During retrograde cerebral perfusion, the microsphere method also showed a significant decrease in cerebral blood flow with cooling. At 37 degrees C, the cerebral blood flow measured with the 15 microns microspheres (0.8 +/- 0.7 ml/min/100 gm) was significantly lower than that assessed with the hydrogen-clearance method (10.1 +/- 3.5 ml/min/100 gm). At both 28 degrees and 20 degrees C, the hydrogen-clearance method showed significantly higher cerebral blood flow (10.1 +/- 5.8 and 8.2 +/- 3.7 ml/min/100 gm) than did the 50 microns microspheres (1.8 +/- 0.6 and 1.0 +/- 0.8 ml/min/100 gm) and 15 microns microspheres (0.23 +/- 0.14 and 0.18 +/- 0.15 ml/min/100 gm). CONCLUSION: (1) Cerebral blood flow that shunts to capillaries is increased during antegrade cardiopulmonary bypass under deep hypothermia. (2) During retrograde perfusion, the majority of the blood flow shunts away from brain capillaries, even under normothermic conditions, and blood flow through large venoarterial shunts increases as body temperature decreases. Although the cerebral microcirculation during retrograde perfusion is decreased, retrograde perfusion provides some degree of oxygenation to the body.