Kinya Nishimura

Acetylcholine–dopamine balance hypothesis in the striatum: An update

The imbalance between cholinergic activity and dopaminergic activity in the striatum causes a variety of neurological disorders, such as Parkinsons disease. During sensorimotor learning, the arrival of a conditioned stimulus reporting a reward evokes a pause response in the firing of the tonically active cholinergic interneurons in targeted areas of the striatum, whereas the same stimulus triggers an increase in the firing frequency of the dopaminergic neurons in the substantia nigra pars compacta. The pause response of the cholinergic interneurons begins with an initial depolarizing phase followed by a pause in spike firing and ensuing rebound excitation. The timing of the pause phase coincides well with the surge in dopaminergic firing, indicating that a dramatic rise in dopamine (DA) release occurs while nicotinic receptors remain unbound by acetylcholine. The pause response begins with dopamine D5 receptor‐dependent synaptic plasticity in the cholinergic neurons and an increased GABAergic IPSP, which is followed by a long pause in firing through D2 and D5 receptor‐dependent modulation of ion channels. Inactivation of muscarinic receptors on the projection neurons eventually yields endocannabinoid‐mediated, dopamine‐dependent long‐term depression in the medium spiny projection neurons. Breakdown of acetylcholine‐dopamine balance hampers proper functioning of the cortico‐basal ganglia‐thalamocortical loop circuits. In Parkinsons disease, dopamine depletion blocks autoinhibition of acetylcholine release through muscarinic autoreceptors, leading to excessive acetylcholine release which eventually prunes spines of the indirect‐pathway projection neurons of the striatum and thus interrupts information transfer from motor command centers in the cerebral cortex. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S148–S157.

Spinorphin as an Endogenous Inhibitor of Enkephalin-degrading Enzymes: Roles in Pain and Inflammation

It is possible that enkephalins are involved in the pain-modulating mechanism in the spinal cord. Enkephalins, however, are short-lived, being rapidly degraded by various endogenous enzymes. Many substances that inhibit enkephalin-degradation have been investigated and it has been reported that some inhibitors (e.g. kelatorphan and RB101) alone showed anti-nociceptive activity. We found an endogenous factor that modulated enkephalin-degrading activity and purified it from bovine spinal cord based on its inhibitory activity toward enkephalin-degrading enzymes. Structural analysis revealed the factor to be Leu-Val-Val-Tyr-Pro-Trp-Thr and it was named spinorphin. It has been found that spinorphin inhibited the activity toward various enkephalin-degrading enzymes from monkey brain, especially dipeptidyl peptidase III (DPPIII, Ki=5.1 x 10(-7) M). Recently we reported that this inhibitor significantly inhibited bradykinin (BK)-induced nociceptive flexor responses. Importantly, the mode of inhibition to BK-responses by spinorphin was different from the case with morphine. The morphine-induced blockade of BK-response was attenuated by pertussis toxin treatment, whereas that of spinorphin was not. We also have reported roles for spinorphin in inflammation. Spinorphin significantly inhibited the functions of polymorphonuclear neutrophils (PMNs) by suppressing the binding of fMLF to its receptor on PMNs. Further, this inhibitor suppressed the carrageenan-induced accumulation of PMN in mouse air pouches after intravenous administration. These results indicate that spinorphin may be an endogenous anti-inflammatory regulator. The possible role of spinorphin and its analog as regulators in pain and inflammation will be discussed.

Are the incidences of cardiac events during noncardiac surgery in Japan the same as in the United States and Europe

In Japan, an ever-present problem in the preoperative evaluation of patients with ischemic heart disease is that although such evaluations are based on Western data, these data serve as the basis for determining perioperative risk in Japanese patients. To remedy this problem, the Cardiac Ischemia and Anesthesia Research Committee was formed in 1997 and has conducted studies of perioperative complications in noncardiac surgery in Japan. In two retrospective studies in 1997, the proportions of patients with ischemic heart disease were 3.9% and 3.1%, approximately one tenth the rates reported in Europe and the United States. The incidences of perioperative cardiac complications in patients with ischemic heart disease were 16.4% and 13.2%, not widely divergent from rates reported in Europe and the United States. To investigate the baseline characteristics involved in perioperative complications, we conducted a prospective study of 237 patients classified as having intermediate risk for perioperative cardiac complications according to the American College of Cardiology/American Heart Association Guidelines for Perioperative Cardiovascular Evaluation for Noncardiac Surgery. We found that the prominent factor in intraoperative cardiac complications was the presence of hypertension (odds ratio = 2.911). Factors contributing to postoperative cardiac complications included those reflecting coronary lesion severity and cardiac dysfunction (history of heart failure; odds ratio = 6.884, coronary risk index grade; odds ratio = 2.884, and a history of intervention; odds ratio = 4.774).

Tissue hyperoxygenation promotes oxidative metabolism in motor unit

Some mutant hemoglobin (Hb) variants are found with lowered O2 affinity. Low oxygen affinity is reported to increase the O2 availability in peripheral tissues (Kunert et al. [1996] Microvasc. Res. 52:58–68). In the present study, we used a mouse model carrying two low‐affinity Hb variants, Titusville and Presbyterian, to evaluate the chronic in vivo influence of lowered oxygen affinity on the neuromuscular system. Our model mice showed an increased voluntary running ability compared with wild‐type littermates. In the tibialis anterior (TA) muscle of mutant mice, the glycolytic fibers were converted to oxidative ones in where the activity of the mitochondrial marker enzyme succinate dehydrogenase (SDH) was up‐regulated. We report that the spinal ventral horn motoneurons innervating TA skeletal fibers also showed higher mitochondrial oxidative enzyme activity. This phenomenon was evidenced by increased SDH activity and electron microscopic (EM) mitochondrial electronic density in these motoneurons. Our data suggest that, as the result of adaptation to the tissue hyperoxygenation, energy metabolism in the neuron–muscle motor unit is augmented and thus function of the motor unit is promoted.

The benefit of stay sutures during thoracoscopic esophagoesophagostomy in patients with esophageal atresia: a technical report

We report on technical modifications we developed for thoracoscopic esophagoesophagostomy in patients with esophageal atresia. They are: (1) placing stay sutures along the edges of the atretic esophagi and exteriorizing them through the thoracic wall to expose the luminal surfaces of the esophagi nicely and relieve tension on the anastomosis; (2) leaving 1/5 of the length of the distal and proximal ends of the atretic esophagi intact before placing the stay sutures, to avoid retraction of the mucosa into the lumen; (3) making the diameter of the proximal esophagus 1.5–2 times larger than the diameter of the distal esophagus to make the shape of the anastomosis more streamlined without notching.

Human substance P receptor undergoes agonist‐dependent phosphorylation by G protein‐coupled receptor kinase 5 in vitro

G protein‐coupled receptor kinases (GRKs) phosphorylate agonist‐occupied G protein‐coupled receptors, leading to receptor desensitization. Seven GRKs, designated GRK1 through 7, have been characterized. GRK5 is negatively regulated by protein kinase C. We investigated whether human substance P receptor (hSPR) is a substrate of GRK5. We report that membrane‐bound hSPR is phosphorylated by purified GRK5, and that both the rate and extent of phosphorylation increase dramatically in the presence of substance P. The phosphorylation has a high stoichiometry (20±4 mol phosphate/mol hSPR) and a low K m (1.7±0.1 nM). These data provide the first evidence that hSPR is a substrate of GRK5.

Imbalanced suppression of excitatory and inhibitory synaptic transmission onto mouse striatal projection neurons during induction of anesthesia with sevoflurane in vitro.

Suppression of movement during induction of anesthesia is mediated through subcortical structures. We studied the effects of a brief, 5‐min application of a clinically relevant concentration of sevoflurane (two minimum alveolar concentration) on the electrophysiological activities of the medium spiny neurons (MSNs) of the striatum in brain slice preparations, using a whole‐cell patch‐clamp technique. We found that sevoflurane slightly depolarized principal neurons in the cortex and the striatum without a significant alteration in spike threshold. Furthermore, it depressed the peak, as well as the net, charge transfer of intrastriatally evoked inhibitory postsynaptic currents (eIPSCs) much more strongly than those of excitatory postsynaptic currents (EPSCs), and this inhibition was accompanied by an elevated paired‐pulse ratio. The strong suppression of eIPSCs paralleled a significant suppression of the frequency, but not the amplitude, of miniature IPSCs (mIPSCs), and was associated with a transient increase in the frequency of spontaneous EPSCs. Treatment with the Ca2+ channel blocker Cd2+ restored the frequency of mIPSCs to the control level, indicating sevoflurane’s strong presynaptic suppression of γ‐aminobutyric acid release in the striatum. In contrast, in hippocampal CA1 pyramidal neurons sevoflurane produced an enhancement of the net charge transfer of IPSCs, while it suppressed EPSCs to an equivalent degree to that in striatal MSNs. These results suggest that, in contrast to its effects on other brain structures, sevoflurane shifts the balance between synaptic excitation and inhibition in the direction of excitation in the striatum, thereby causing involuntary movements during induction of anesthesia by sevoflurane.

Traction Sutures Allow Endoscopic Staples to Be Used Safely During Thoracoscopic Pulmonary Lobectomy in Children Weighing Less Than 15 Kg

PURPOSE During thoracoscopic pulmonary lobectomy (TPL) in larger children (>15 kg), an endoscopic stapler (ES) and endoscopic clipper (EC) are used during dissection and division of the pulmonary vessels (PVs) and bronchus. However, in smaller children (<15 kg), ES/EC cannot be used because of limited space. We report our technique for thoracoscopic dissection and division of the PVs and bronchus in smaller children. SUBJECTS AND METHODS Fifteen cases of sequestration/congenital cystic adenomatoid malformation weighing less than 15 kg (range, 8-15 kg; mean, 11 kg) were the subjects for this review. With the patient under single-lung ventilation in the lateral decubitus position, four ports ranging from 5 to 12 mm were placed. After the PVs and bronchus were exposed, thick silk was used to encircle them as a traction suture. By applying traction, the PVs and bronchus could be exposed, and ES/EC were used safely by applying countertraction. RESULTS All cases had uneventful TPL (upper in 3 patients, middle in 3 patients, and lower in 9 patients). ES/EC were easy to use. Mean operative time was 220 minutes. CONCLUSIONS Our technique allows the PVs and bronchus in children weighing less than 15 kg to be divided safely using ES/EC. We strongly recommend our technique, although simple, be used during TPL in smaller children.

Pulmonary lobectomy techniques in infants and children

Thoracoscopic pulmonary lobectomy (TPL) techniques in infants and children are presented practically with concise descriptions and numerous illustrations. TPL is the treatment of choice for congenital pulmonary airway malformation and intralobar pulmonary sequestration, both now commonly diagnosed prenatally. Timing of surgery is somewhat controversial in asymptomatic cases with small isolated lesions. Incomplete fissures and history of chest infections are most problematic. Thorough understanding of anatomic relations preoperatively is vital for successful outcome and thin-slice computed tomography with 3D reconstruction of vessels is valuable. Judicious placement of trocars and switching instruments between trocars improves visualization and safety. Specific techniques for all commonly performed TPL are included.

Nicotinic acetylcholine receptor-mediated GABAergic inputs to cholinergic interneurons in the striosomes and the matrix compartments of the mouse striatum.

The striatum consists of two neurochemically distinct compartments: the striosomes (or patches) and the extrastriosomal matrix. Although striatal neurons are strongly innervated by intrinsic cholinergic interneurons, acetylcholinesterase is expressed more abundantly in the matrix than in the striosomes. At present, little is known about the different cholinergic functions of the striatal compartments. In this study, we examined gamma-aminobutyric acidergic (GABAergic) inputs to cholinergic interneurons in both compartments. We found that nicotinic receptor-mediated GABAergic responses were evoked more frequently in the matrix than in the striosomes. Furthermore, a single action potential of cholinergic neurons induced nicotinic receptor-mediated GABAergic inputs to the cholinergic neurons themselves, suggesting mutual connections that shape the temporal firing pattern of cholinergic neurons. The nicotinic receptor-mediated GABAergic responses were attenuated by continuous application of acetylcholine or the acetylcholinesterase inhibitor eserine and were enhanced by desformylflustrabromine, a positive allosteric modulator of the α4β2 subunit containing a nicotinic receptor. These results suggest that the nicotinic impact on the GABAergic responses are not uniform despite the massive and continuous cholinergic innervation. It has been reported that differential activation of neurons in the striosomes and the matrix produce a repetitive behavior called stereotypy. Drugs acting on α4β2 nicotinic receptors might provide potential tools for moderating the imbalanced activities between the compartments.