Pathogenesis of idiopathic scoliosis. Experimental study in rats.

STUDY DESIGN: A radiographic examination of pinealectomized rats to observe the development of scoliosis and halt the condition by administration of melatonin. OBJECTIVES: To discover whether pinealectomy has the same effect in mammals as shown in the chicken, and to determine whether the bipedal condition is important for development of scoliosis. SUMMARY OF BACKGROUND DATA: Pinealectomizing chickens shortly after hatching consistently resulted in scoliosis closely resembling human idiopathic scoliosis. It has not been determined whether this phenomenon is restricted solely to chickens, or if this experimental model is applicable to other animals, especially those more closely related to humans. METHODS: A sham operation in five bipedal rats served as the control in this study. Pinealectomy was performed in 10 quadrupedal rats, pinealectomy in 20 bipedal rats, and pinealectomy with implantation of melatonin pellet in 10 bipedal rats. Spinal radiographs were used to measure the degree of scoliosis at 3 months after surgery. RESULTS: Scoliosis developed only in pinealectomized bipedal rats and not in quadrupedal rats. It developed in none of the sham operation group and in only 1 of 10 pinealectomized bipedal rats with melatonin treatment. CONCLUSIONS: Melatonin deficiency secondary to pinealectomy alone does not produce scoliosis if the quadrupedal condition is maintained. The bipedal condition, such as that in chickens or humans, plays an important role in the development of scoliosis. The findings suggest a critical influence of a postural mechanism for the development of scoliosis.     

Development of intrahepatic biliary stones after excision of choledochal cysts

Background: The incidence of intrahepatic cholelithiasis and cholangitis has not yet been well studied postoperatively in patients with choledochal cysts. Methods: One hundred three patients with choledochal cysts had operative cholangiography, underwent standard excision of a choledochal cyst with Roux-en-Y hepatico-jejunal anastomosis, and were at a mean follow-up of 12[frac12] years. The incidence of intrahepatic bile duct stones was analyzed according to the 3 morphologic types of intrahepatic bile duct observed at initial operative cholangiography: type 1, no dilatation of the intrahepatic bile ducts; type 2, dilatation of the intrahepatic bile ducts but without any downstream stenosis; and type 3, dilatation of the intrahepatic bile ducts associated with downstream stenosis. Initially, there was no evidence of intrahepatic bile duct stones in any of the 103 patients. Results: Among 50 type 1 patients, intrahepatic cholelithiasis developed in only 1 patient (2%). Among 43 type 2 patients, 1 patient (2%) had intrahepatic cholelithiasis, and 2 (5%) had postoperative cholangitis. Among 10 type 3 patients, 4 (40%) had intrahepatic cholelithiasis (P [lt ] .01), and 3 (30%) had postoperative cholangitis. Time intervals between the initial surgery and the first identification of intrahepatic stones ranged from 3 to 22 years. Conclusions: One of the major causes of formation of intrahepatic cholelithiasis has been clarified; patients with intrahepatic biliary dilatation with downstream stenosis can get intrahepatic bile duct stones long after excision of a choledochal cyst.     

Role of the Y1 receptor in the regulation of neuropeptide Y-mediated feeding: comparison of wild-type, Y1 receptor-deficient, and Y5 receptor-deficient mice

Neuropeptide Y (NPY) increases food intake through the action of hypothalamic NPY receptors. At least six subtypes of NPY, peptide YY (PYY), and pancreatic polypeptide (PP) receptors have been identified in mice. Although the involvement of Y1 and Y5 receptors in feeding regulation has been suggested, the relative importance of each of these NPY receptors and the participation of a novel feeding receptor are still unclear. To address this issue, we generated a Y1 receptor-deficient (Y1-/-) and a Y5 receptor-deficient (Y5-/-) mouse line in which we directly compared the orexigenic effects of NPY and its analogs after intracerebroventricular (icv) administration. The icv NPY-induced food intake was remarkably reduced in Y1-/- mice, but was not significantly altered by inactivation of the Y5 receptor. The Y1 receptor therefore plays a dominant role in NPY-induced feeding. Stimulation of feeding by moderately selective Y5 agonists [PYY-(3-36), human PP, and bovine PP] was reduced in Y5-/- mice, although food intake did not decrease to vehicle control levels. These results indicate that the Y5 receptor functions as one of the feeding receptors. In addition, the finding that Y5-preferring agonists still induce food intake in Y5-/- mice suggests a role for another NPY receptor(s), including the possibility of novel NPY receptors. Surprisingly, despite the limited efficacy of PYY-(3-36) and PPs at the Y1 receptor, food consumption induced by these agonists was significantly diminished in Y1-/- mice compared with that in wild-type controls. These observations suggest that the feeding stimulation induced by NPY and its analogs may be directly or indirectly modulated by the action of the Y1 receptor. We conclude that multiple NPY receptors, possibly including the novel feeding receptor, are involved in the feeding response evoked by NPY and its analogs. Among them, the Y1 receptor plays a key role in NPY-induced feeding in mice.     

Inhibitory neurons in the anterior piriform cortex of the mouse: Classification using molecular markers

The primary olfactory cortex (or piriform cortex, PC) is attracting increasing attention as a model system for the study of cortical sensory processing, yet little is known about inhibitory neurons in the PC. Here we provide the first systematic classification of GABA‐releasing interneurons in the anterior PC of mice, based on the expression of molecular markers. Our experiments used GAD67‐GFP transgenic mice, in which gamma‐aminobutyric acid (GABA)‐containing cells are labeled with green fluorescent protein (GFP). We first confirmed, using paired whole‐cell recordings, that GFP⁺ neurons in the anterior PC of GAD67‐GFP mice are functionally GABAergic. Next, we performed immunolabeling of GFP⁺ cells to quantify their expression of every possible pairwise combination of seven molecular markers: calbindin, calretinin, parvalbumin, cholecystokinin, neuropeptide Y, somatostatin, and vasoactive intestinal peptide. We found that six main categories of interneurons could be clearly distinguished in the anterior PC, based on the size and laminar location of their somata, intensity of GFP fluorescence, patterns of axonal projections, and expression of one or more of the seven markers. A number of rarer categories of interneurons could also be identified. These data provide a road map for further work that examines the functional properties of the six main classes of interneurons. Together, this information elucidates the cellular architecture of the PC and provides clues about the roles of GABAergic interneurons in olfactory processing. J. Comp. Neurol. 518:1670–1687, 2010. © 2009 Wiley‐Liss, Inc.     

Bortezomib induces thrombocytopenia by the inhibition of proplatelet formation of megakaryocytes

Bortezomib is a potent proteasome inhibitor that has been extensively used to treat multiple myeloma. One of the most common grade 3 adverse events is cyclic thrombocytopenia. In this study, we studied the mechanism by which bortezomib induces thrombocytopenia in a mouse model. After the intravenous administration of bortezomib (2.5 mg/kg) via tail vein, platelet counts significantly decreased on days 2–4 and recovered to the normal range on day 6. Bortezomib (2.5 mg/kg) injected into mice in vivo did not affect colony‐forming unit‐megakaryocytes (CFU‐Mk) or megakaryocytes in the bone marrow. However, proplatelet formation (PPF) significantly decreased on days 2 and 4, after bortezomib administration to mice. Meanwhile, CFU‐Mk formation and the ploidy distribution of cultured megakaryocytes in vitro were not affected by bortezomib used at concentrations of ≤1 ng/mL. The PPF of megakaryocytes in vitro significantly decreased with 0.1, 1, 10, and 100 ng/mL bortezomib. Considering the bortezomib concentration in clinical studies, these data strongly suggest that decreased PPF activity induces thrombocytopenia. To elucidate the mechanism behind decreased PPF, Western blot was performed. Activated Rho expression increased after the incubation of murine platelets with bortezomib. Decreased PPF activity was eliminated by the addition of Y27632, a Rho kinase inhibitor, in vitro. Given that the Rho/Rho kinase pathway is a negative regulator of PPF, bortezomib increases activated Rho, inducing decreased PPF, which results in decreased platelet count.     

Acute coronary syndrome associated with oral administration of ritodrine hydrochloride during pregnancy: a case report.

We report a case of acute coronary syndrome associated with the oral administration of ritodrine hydrochloride. Ten days following the administration of ritodrine hydrochloride, the patient complained of chest pain, and an electrocardiogram showed ST elevation and ST depression. Intensive care was initiated. She recovered without chest pain.     

A study on auditory disturbances after microvascular decompression for hemifacial spasm

After establishing an operation of microvascular decompression by Jannetta in 1975, an improvement rate of hemifacial spasm have increased. However, postoperative hearing deficits, equilibrium disturbances and facial paresis have been described in some publications. Fifty-seven of 119 patients with hemifacial spasm operated from 1982 to 1989, were examined by audiometry before and after operation. In patients with tinnitus at the time of facial spasm and closing eyelids, tinnitus improved almost in many cases. Of 57 patients, 8 (5 with sensorineural hearing loss, 3 with conductive hearing loss) had postoperative hearing impairments in operated ears, and 7 (7 with sensorineural hearing loss) had in the other ears, too. Of 7 patients having sensorineural hearing loss observed for several months, 4 having slight sensorineural hearing loss recovered at the same hearing level before operation. In 2 patients having profound sensorineural hearing loss, however, hearing improvement did not observed in each case.     

The Endotoxin 10,000 Reference Standard of the National Institute of Health Sciences (the Japanese Pharmacopoeia Endotoxin 10,000 Reference Standard) (Control 0001)

To establish the fourth lot (Control 0001) of the Endotoxin 10,000 Reference Standard of the National Institute of Health Sciences (the Japanese Pharmacopoeia Endotoxin 10,000 Reference Standard), a candidate standard (CS) was prepared and then evaluated. The potency of the CS was assayed against USP Endotoxin Reference Standard (Lot G-1) and defined as containing approximately 20,000 endotoxin units (EU) per vial by a collaborative study in which 5 laboratories participated. Based on the results, the CS was authorized to be the fourth lot of the Endotoxin 10,000 Reference Standard containing 20,000 EU per vial.     

Inhibition of growth of human tumor cells in nude mice by a metalloproteinase inhibitor

The effects of a new metalloproteinase inhibitor, BEI6627B [L-N-(N-hydroxy-2-isobutylsuccinynamoyl)-seryl-L-valine, MW: 375.2] isolated from microbial cultures, on human tumor cell growth in nude mice were investigated. BE16627B inhibited metalloproteinases in enzyme assays, as well as gelatinolysis and collagenolysis in cell cultures. BE16627B at 100 μg/ml showed no apparent cytotoxicity to human tumor cells in culture and its LD₅₀ in mice was more than 1,000 mg/kg (i.p.). The effects of BE16627B on the in vivo growth of 1 human tumor cell lines were examined: HT1080 fibrosarcoma, which overproduces metalloproteinases, and HCT116 colon carcinoma, which barely secretes metalloproteinases. When BE16627B was administered to mice at 2 mg/mouse/day by an osmotic pump implanted s.c. for 3 weeks from 1 week after i.v. inoculation of HT1080 cells, the number and size of nodules of HT1080 cells on the lung surface were reduced to 24.3 and 46.4%, respectively, of those of controls, and the increase in lung weight due to tumor-cell growth was inhibited 85.5% without body-weight loss. Moreover, BE16627B inhibited 71.2% of the growth of HT1080 cells inoculated s.c. into mice under the same conditions, but did not significantly inhibit the s.c. growth of HCT116 human colon-carcinoma cells. Thus, BE16627B inhibited metalloproteinase-dependent human tumor-cell growth as well as lung colonization without showing cytotoxicity in nude mice.