Two dynamically distinct inhibitory networks in layer 4 of the neocortex

Normal operations of the neocortex depend critically on several types of inhibitory interneurons, but the specific function of each type is unknown. One possibility is that interneurons are differentially engaged by patterns of activity that vary in frequency and timing. To explore this, we studied the strength and short-term dynamics of chemical synapses interconnecting local excitatory neurons (regular-spiking, or RS, cells) with two types of inhibitory interneurons: fast-spiking (FS) cells, and low-threshold spiking (LTS) cells of layer 4 in the rat barrel cortex. We also tested two other pathways onto the interneurons: thalamocortical connections and recurrent collaterals from corticothalamic projection neurons of layer 6. The excitatory and inhibitory synapses interconnecting RS cells and FS cells were highly reliable in response to single stimuli and displayed strong short-term depression. In contrast, excitatory and inhibitory synapses interconnecting the RS and LTS cells were less reliable when initially activated. Excitatory synapses from RS cells onto LTS cells showed dramatic short-term facilitation, whereas inhibitory synapses made by LTS cells onto RS cells facilitated modestly or slightly depressed. Thalamocortical inputs strongly excited both RS and FS cells but rarely and only weakly contacted LTS cells. Both types of interneurons were strongly excited by facilitating synapses from axon collaterals of corticothalamic neurons. We conclude that there are two parallel but dynamically distinct systems of synaptic inhibition in layer 4 of neocortex, each defined by its intrinsic spiking properties, the short-term plasticity of its chemical synapses, and (as shown previously) an exclusive set of electrical synapses. Because of their unique dynamic properties, each inhibitory network will be recruited by different temporal patterns of cortical activity.     

Diffuse malignant lymphoma with cerebriform nuclei: A B-cell lymphoma studied with monoclonal antibodies

A lymph node biopsy performed on a 55-year-old woman with asymptomatic generalized lymphadenopathy revealed a diffuse, malignant lymphoma composed of small to intermediate-sized lymphocytes with cerebriform-shaped nuclei; electron microscopy confirmed the nuclear complexity. The cerebriform nuclear configuration, coupled with an interfollicular pattern of nodal involvement with encroachment upon residual germinal centers, was presumptive of either mycosis fungoides or a peripheral T-cell lymphoma. Immunologic evaluation, however, indicated that the cerebriform lymphocytes represented a monoclonal B-cell population (IgM-IgD, lambda). Staining with monoclonal antibodies disclosed a phenotype of Ia+, B1+, BA-1+, BA-2+, Leu-1+; the neoplastic cells were unreactive with T-cell, lineage-specific antibodies (anti-Leu-2a, -3a, -4, -5) and with J5 (CALLA). In light of the immunophenotype and the distributional pattern, the cerebriform-shaped lymphocytes may represent an extreme morphologic variant of intermediate lymphocytic lymphoma.     

The Lapidus Arthrodesis: Examining the Effect of the Metatarsal Base Transfixion Screw

The modified Lapidus bunionectomy is a useful and highly powerful procedure for correcting hallux abducto valgus. Traditionally reserved for “severe” deformities, this procedure has seen a recent resurgence in the podiatric community for its unique ability to achieve tri-planar correction of this challenging deformity. Although this procedure has been extensively studied in both biomechanical labs and the clinical arenas, no clear consensus has been achieved regarding optimal fixation for this thought-provoking procedure. The current study examined the differences in strength between commercially available 5-hole locking plates with interfragmentary compression vs a crossed-screw with a third “transfixation” screw construct in a controlled setting. Ten fresh-frozen cadaveric match pair limbs (20 total limbs) were used to complete this study. Ten limbs were randomly assigned to a 3-screw construct. The other 10 contralateral limbs were assigned to a commercially available 5-hole locking plate (5 stainless steel and 5 titanium alloy) with an interfragmentary lag screw construct. The first rays were then isolated and potted into a 4-point bending device. The specimens were loaded to failure in a servohydraulic load frame at a controlled rate. Failure was defined as catastrophic or 3 mm of plantar gapping at the arthrodesis site. The mean maximal load to failure was 310.9 ± 109.4 N for the 3-screw construct. The mean maximal load to failure for the locking plate constructs was 264.1 ± 100.9 N. This difference was not statistically significant (p = .328). These results suggest that a 3-screw construct for Lapidus arthrodesis is as strong as commercially available locking plate constructs.     

Epileptiform propagation patterns mediated by NMDA and non-NMDA receptors in rat neocortex

PURPOSE: The neocortex can generate various forms of epileptiform activity, including one that depends on N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs), and another dependent on non-NMDA-type (AMPA) glutamate receptors (AMPARs). Previous work in vitro suggests that both forms of activity are initiated by neurons of layer 5, but the spatial patterns of horizontal propagation have been studied only for the AMPAR form. We have tested the hypothesis that both types of epileptiform activity spread via common pathways in one cortical layer, suggesting that lamina-specific intervention might selectively interrupt both. METHODS: Slices of rat somatosensory cortex were maintained in vitro and treated with the gamma-aminobutyric acid type A (GABA(A))-receptor antagonist picrotoxin. Single all-or-none epileptiform discharges were evoked with an electrical stimulus, and extracellular microelectrodes were used to track the vertical and lateral spread of the discharges. RESULTS: In both high and low concentrations of picrotoxin, the non-NMDAR antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) completely blocked propagation, whereas the NMDAR antagonist D-2-amino-5-phosphonovaleric acid (DAPV) only shortened the duration of discharges. When extracellular [Mg2+] was reduced in the presence of picrotoxin and CNQX, NMDAR-dependent epileptiform discharges could be initiated. NMDAR-dependent discharges spread at about one fifth the conduction velocity of AMPAR-dependent events. Analysis of spatiotemporal field-potential patterns suggested that both NMDAR- and AMPAR-mediated propagation involved early activity in layers 5 and 6, followed by larger-amplitude activity in upper cortical layers along the path of propagation. CONCLUSIONS: Our results imply that a common pathway mediates the propagation of these two forms of epileptiform activity, and suggests that lamina-specific surgical intervention might maximize anticonvulsant effect while minimally disrupting cortical function.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.

     

Effects of Extracorporeal Shock Wave Lithotripsy to One Kidney on Bilateral Glomerular Filtration Rate and PAH Clearance in Minipigs

Purpose

This study examined the acute time course of effects of extracorporeal shock wave lithotripsy (ESWL)¹ on renal hemodynamics in anesthetized minipigs with and without pretreatment with verapamil.

Materials and Methods

We applied ESWL (2000 shocks, 24 kV, unmodified Dornier HM3), to the right kidneys of isoflurane-anesthetized female pigs. Urine flow and renal hemodynamics were monitored from each kidney via ureteral balloon catheters. Arterial blood pressure and bilateral urine flow, glomerular filtration rate (GFR, inulin clearance) and renal plasma flow (RPF, para-aminohippurate clearance) were monitored for 45 minutes before ESWL, and at 1, 4 and 24 hours after ESWL.

Results

Treatment with ESWL consistently caused unilateral hematuria and subcapsular renal hematomas in the shocked kidneys and significantly reduced GFR and RPF in those kidneys at 1 and 4 hours after ESWL. Urine flow was reduced through 24 hours in the shocked kidneys. Renal plasma flow, but not GFR, was significantly reduced in the contralateral (unshocked) kidneys at 1 and 4 hours after ESWL to the other kidneys. Verapamil blunted the ESWL-induced reductions of urine flow, GFR and RPF in the shocked kidneys and eliminated the reduction of RPF in the unshocked kidneys.

Conclusions

These experiments demonstrate that ESWL to 1 kidney acutely impaired hemodynamics in both kidneys and that verapamil attenuated the response in the shocked kidneys and eliminated it in the contralateral unshocked kidneys.     

Thalamocortical responses of mouse somatosensory (barrel) cortex in vitro

We have developed a novel slice preparation of the mouse somatosensory forebrain. This preparation is unique in including both the ventrobasal nucleus of the thalamus and the sensorimotor "barrel" cortex in a 400-microns-thick slice with the functional connectivity between them preserved, and in allowing direct visualization of the various components of the barrel system in unstained living tissue. Thalamocortical connectivity was demonstrated by recording the laminar profile of cortical field potentials evoked electrically from the ventrobasal nucleus. Current-source density analysis of this profile showed that the largest and earliest sinks were coextensive with the two known sites of thalamocortical terminals, layer IV and the junction of layers V and VI. The sink in layer IV could be dissociated experimentally into a small, early sink of presynaptic origin (most probably a presynaptic spike volley in the thalamocortical terminals) and a later, larger sink generated postsynaptically. By mapping the subcortical stimulation sites that elicited a response at different layer IV recording sites we concluded that the thalamus-to-cortex projection preserves the general dorsoventral relationship of the afferents. Intracellularly recorded responses elicited by thalamic stimulation included (but were not limited to) monosynaptic excitatory and disynaptic inhibitory postsynaptic potentials. The thalamus-to-cortex connections were also mapped with the axonal fluorescent tracer dioctadecyl-tetramethylindocarbocyanine perchlorate. The thalamo-cortical slice is a very suitable system for studying the physiology and pharmacology of the thalamocortical synapse and for exploring the synaptic circuitry of the somatosensory cortex.     

Treatment of hypogonadal adolescent boys with long acting subcutaneous testosterone pellets

AIMS: Long acting subcutaneous testosterone pellets are of proved efficacy for the treatment of hypogonadal men, but have not been reported as a treatment modality in adolescent boys. Pharmacodynamic studies of subcutaneous testosterone release have shown prolonged normalisation of testosterone levels for at least four months. Administration of a long acting, safe, effective, and convenient form of treatment is desirable when life-long treatment is indicated. PATIENTS AND METHODS: Eighteen boys (aged 13.9-17.5 years at the start of treatment)-seven with primary hypogonadism, nine with secondary hypogonadism, and two boys being treated with testosterone for tall stature--were given testosterone pellets (8-10 mg/kg) every six months for 18 months. Height, weight, pubertal status, and psychosocial parameters were assessed and follicle stimulating hormone, luteinising hormone, testosterone, prolactin, and lipids were measured at 0, 1, 3, 6, 12, and 18 months. Bone age was measured at 0 and 12 months. RESULTS: In all boys growth velocity continued appropriately for bone age. Puberty continued to progress in all boys and in two boys the amount of virilisation exceeded that seen with previous treatment with intramuscular testosterone. After testosterone administration, follicle stimulating hormone and luteinising hormone suppressed incompletely in the boys with primary hypogonadism. Serum testosterone ranged from 4.3 to 26.7 nmol/l at three months to less than 10 nmol/l at six months after implantation. Prolactin and lipid levels were normal throughout the study. By report, there was an improvement in mood and emotional wellbeing. No pellet extrusions occurred in a total of 156 pellet insertions. CONCLUSIONS: All boys preferred this mode of testosterone administration to intramuscular injections. Long acting subcutaneous testosterone pellets are safe, efficacious, well tolerated, and convenient, and result in normal physical growth and improved psychological outlook in adolescent hypogonadal boys.     

Pediatric evaluation of the bispectral index (BIS) monitor and correlation of BIS with end-tidal sevoflurane concentration in infants and children

The bispectral index (BIS) has been developed in adults and correlates well with clinical hypnotic effects of anesthetics. We investigated whether BIS reflects clinical markers of hypnosis and demonstrates agent dose-responsiveness in infants and children. In an observational arm of this study, BIS values in children undergoing general anesthesia were observed and compared with similar data collected previously in a study of adults. In a second arm of the study, a range of steady-state end-tidal concentrations of sevoflurane was administered and corresponding BIS documented. Data were examined for differences between infants (0-2 yr) and children (2-12 yr). No difference was seen in BIS values in children before induction, during maintenance, and on emergence compared with adult values. There was no difference in BIS between infants and children at similar clinical levels of anesthesia. In children and infants, BIS was inversely proportional to the end-tidal concentration of sevoflurane. The sevoflurane concentration for a BIS = 50 (95% confidence interval) was significantly different: 1. 55% (1.40-1.70) for infants versus 1.25% (1.12-1.37) for children. Although validation with specific behavioral end points was not possible, BIS correlated with clinical indicators of anesthesia in children as it did in adults: as depth of anesthesia increased, BIS diminished. BIS correlated with sevoflurane concentration in infants and children. The concentration-response difference between infants and children was consistent with data showing that minimum alveolar concentration is higher in children less than 1 yr of age. IMPLICATIONS: The use of bispectral index (BIS) during general anesthesia improves the titration of anesthetics in adults. The data from this study suggest that the same equipment and method of electroencephalogram analysis may be applied to infants and children.     

Concurrent translocation of BCL2 and MYC with a single immunoglobulin locus in high-grade B-cell lymphomas.

B-cell leukaemia or lymphoma with a combination of t(8;14)(q24;q32) of Burkitt leukaemia/lymphoma and t(14;18)(q32;q21) of follicular lymphoma may present clinically as de novo acute lymphoblastic leukaemia or transformation of follicular lymphoma to aggressive histology diffuse lymphoma. A number of cell lines have been reported with a complex t(8;14;18) with fusion of MYC, IGH and BCL2 on the same derivative 8 chromosome. The objective of this study was to determine the frequency and chromosomal features of this der(8)t(8;14;18) in a series of acute leukaemias and malignant lymphomas. A database of 1350 leukaemia and lymphoma karyotypes was searched for cases with structural alterations affecting both 8q24 and 18q21. A total of 55 cases were identified, of which eight revealed a complex der(8)t(8;14;18) with an MYC-IGH-BCL2 rearrangement resulting from translocation of BCL2 and MYC with a single disrupted IGH allele. Molecular cytogenetic investigation is essential to identify cases of high-grade leukaemia/lymphoma with concurrent translocations affecting the BCL2 and MYC loci.