Mu opioid agonists potentiate amphetamine- and cocaine-induced rotational behavior in the rat

Opioids modulate brain dopaminergic function in various experimental paradigms. This study used the rotational model of behavior in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway to investigate this interaction. Doses of two presynaptically acting dopaminergic drugs, amphetamine and cocaine, were coadministered with several doses of the mu opioid agonist, morphine. Morphine, at 3.0 mg/kg, potentiated rotational behavior induced by each dose of the stimulants. To determine the receptor specificity of the actions of morphine, the mu opioid agonists buprenorphine, fentanyl, levorphanol, meperidine, and methadone, and dextrorphan, the non-opioid isomer of levorphanol, were administered alone and with 1.0 mg/kg amphetamine. Each of these drugs, as well as morphine, produced circling behavior on its own. All of the mu opioid agonists and dextrorphan increased amphetamine-induced turning; the coadministration of dextrorphan, levorphanol, meperidine, methadone and morphine with amphetamine produced turning greater than predicted by simple additivity. To determine whether an opioid receptor was involved in these interactions, the opioid antagonist, naltrexone, was administered before the amphetamine/mu opioid receptor agonist combination. Naltrexone blocked the potentiating effects of morphine, but not those of the other drugs. Moreover, naltrexone alone dose-dependently increased amphetamine-induced rotational behavior. These studies show that some mu opioid receptor agonists can potentiate stimulant-induced rotational behavior and that blockade of opioid receptors can also produce a potentiation. The role of mu opioid receptors in these effects remains unclear.     

Do mitochondria play a role in aging?

Ageing is an unavoidable and complex phenomenon which may be a price to pay to evolution. Thus genetics appear to play a predominant role besides environmental factors. Energetic metabolism slowly declines with ageing supporting a possible active role of mitochondria, the power supply of the cells, to this process. Mitochondrial DNA alterations appear during the mid-life and in degenerative diseases such as in Parkinson's and Alzheimer's; they include large scale deletions and point mutations. Since the respiratory chain plays a major role in the generation of superoxide anions which are converted into hydroxyl radicals that may impair lipids, proteins and DNA function in mitochondria, this vicious cycle may result from both an altered control of mitochondrial biogenesis dependent from the nucleus, and/or from a lack of repair and accumulation of somatic mitochondrial DNA mutations.     

Physicians play role in genetic developments

This essay defines managed care and presents three particular ways it affects the profession of dentistry. The first issue is whether managed care is needed in dentistry; the second is the effects of managed care on treatment; and finally the dentist-patient relationship is examined. It is incumbent on dental students to be highly proficient in understanding and managing managed care because of the potential this system has for vast impact on patients, the profession, and one's practice.     

Sexual differentiation of play behavior in the ferret.

Three experiments examined the endocrine mechanisms responsible for sex differences in prepubertal play behavior of ferrets. In Exp I, 6 gonadally intact adolescent males exhibited higher levels of "stand-over" behavior than 6 females did in tests between 63 and 123 days of age with gonadally intact female partners of the same age. In Exp II, with 69 Ss, those Ss exposed to androgen or to ovarian steroids over Days 5–20 of postnatal life subsequently exhibited significantly higher levels of stand-over behavior in tests with females than did control females gonadectomized on Day 5 and not given steroids. None of the Ss in Exp II exhibited levels of stand-over behavior comparable to those of the gonadally intact males in Exp I. In Exp III, with 36 Ss, males gonadectomized and implanted subcutaneously with testosterone capsules on Day 70 and tested with females at 84–96 days of age exhibited levels of stand-over behavior comparable to those observed in Exp I in gonadally intact males of the same age (Weeks 12–24). Males gonadectomized on Day 70 and given no hormone at testing exhibited significantly lower levels of this behavior. Significantly lower levels were also exhibited by males gonadectomized on Day 35 and females gonadectomized on Day 70, regardless of whether they were tested with testosterone present after Day 70. Sex differences in the expression of prepubertal play behavior of ferrets apparently result from differential exposure of males and females to androgen over an extended postnatal period. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

5 alpha-reduced androgens play a key role in murine parturition

Two steroid 5 alpha-reductase isozymes designated type 1 and 2 synthesize 5 alpha-reduced androgens and other 5 alpha-reduced steroid hormones. Naturally occurring mutations in the gene encoding 5 alpha-reductase type 2 cause male pseudohermaphroditism, indicating that this isozyme is responsible for the synthesis of dihydrotestosterone required for virilization of the embryonic male urogenital tract. To determine the physiological role of 5 alpha-reductase type 1, homologous recombination in mouse embryonic stem cells was used to produce male and female mice with a disruption (null allele) in the type 1 gene (Srd5a1). Male mice lacking 5 alpha-reductase type 1 appear normal. Females exhibit a parturition defect that is maternal in origin. The parturition defect is reversed by administration of 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-Adiol), a 5 alpha-reduced androgen previously thought to be a breakdown product. Enzymes that synthesize 3 alpha-Adiol, including 5 alpha-reductase type 1 and 3 alpha-hydroxysteroid dehydrogenase, are induced in wild type uterus during late gestation. Induction leads to peak circulating levels of 3 alpha-Adiol on days 17/18 of gestation in wild type but not mutant mice. The results document a role for 5 alpha-reduced androgens synthesized by the type 1 isozyme in normal female physiology, and they suggest that 3 alpha-Adiol is a new hormone required for parturition in mice.     

Nigrostiatally induced motor reactions in the rat. II. Cholinergic effect on rotational behavior and posture asymetry

In a period of 3 years 12 patients with meningiomas of the posterior cranial fossa were treated surgically. The group included 2 cases of meningioma situated on the cerebellar convexity, 5 on the tentorium, 2 on the posterior aspect of the pyramid bone, 1 of Blumenbach clivus, 2 of foramen magnum. The neurological findings and pneumoencephylographic changes in cases of meningiomas of cerebellar convexity, tentorium and posterior aspect of the pyramid bone made possible the diagnosis of posterior fossa tumour and the diagnosis of meningioma was made possible by carotid and vertebral angiography. In the case of Blumenbach clivus meningioma and in foramen magnum meningiomas the neurological changes were characteristic of tumours at the craniovertebral junction. One meningioma growing through the tentorium was approached from the middle cranial fossa, the remaining ones from the posterior cranial fossa. The tumour could have been removed radically in 7 cases. In 5 cases only partial removal was possible. Three patients died, two after operations for tentorial meningioma and one after operation for Blumenbach clivus tumour. The results in the remaining cases were good.     

Does pelvic irradiation play a role in the management of prostate cancer?

The optimal management of patients with lymph node-positive prostate cancer remains controversial. The role of pelvic irradiation in patients at high risk for nodal involvement continues to be debated. Studies of prostate irradiation with and without inclusion of the pelvic lymph nodes show poor outcomes for node-positive patients, supporting the concept that many of these patients have systemic disease at presentation. Although no randomized trial has examined the role of pelvic irradiation in pathologically node-positive patients, available data fail to reveal any significant benefit of this approach over prostate-alone irradiation. More promising therapeutic approaches involve the combination of local therapy and sustained hormonal therapy. Series comparing prophylactic irradiation of the pelvis and prostate to irradiation of the prostate alone have shown no clear benefit of pelvic irradiation. Pelvic irradiation may play a role in the treatment of early-stage or occult nodal disease, although this has yet to be examined. Until prospective, randomized trials demonstrate the efficacy of pelvic irradiation in the management of prostate cancer, its use cannot be routinely recommended. Data support the use of lymphadenectomy in high-risk patients to identify those with positive nodes, since these patients require androgen withdrawal therapy.     

Teaching and maintaining behavior management skills with nursing assistants in a nursing home

Since the first report of pancreatic endocrine tumors by Wilder et al. in 1927 and the development of radioimmunoassay of gut hormone by Berson and Yallow in 1961, Japanese clinicians and scientists have contributed significantly in the reporting, investigation, and management of patients with pancreatic endocrine tumors and other multiple endocrine neoplasia. This article summarizes our contribution in this field and contrasts our experiences with those reported in the English literature.     

Development of sex-typed play behavior in toddlers.

Conducted naturalistic observations of the play of 52 14–35 mo old toddlers (28 girls and 24 boys) with a set of socially stereotyped masculine, feminine, and neutral toys in a daycare setting over 14 mo. In addition, 2 potential influences on toy choice were investigated: parental expectations of play and Ss' gender knowledge. Results show that Ss played more often with toys stereotyped for their own gender than with the other toys. Girls' play with feminine toys increased with age, but boys' play with masculine toys did not vary with age, partly because even the youngest boys chose masculine toys frequently. Parents provided same-sex-typed toys for their children and made sex-typed predictions of their children's toy choices, but these measures were not clearly related to children's play. Cognitive change in understanding of gender was related to toddler boys' early sex-typed behavior. (17 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Frontal networks play a role in fatigue perception in multiple sclerosis.

Fatigue, an overwhelming lack of physical or mental energy, is a common complaint in patients affected by multiple sclerosis (MS). Although different mechanisms have been proposed to explain MS-related fatigue, injury of distinct anatomical networks seems to be relevant in fatigue etiology. Particularly, theories point to fronto-striatal network pathological changes as a possible neural basis of fatigue. To investigate the role of fronto-striatal white matter structural alterations in fatigue perception we prospectively recruited 40 relapsing remitting patients with MS and 15 healthy controls. In patients with MS, fatigue was assessed using a validated measure, the Modified Fatigue Impact Scale (MFIS; Kos et al., 2005). Brain MRI scans were acquired for each subject enrolled with diffusion tensor imaging. Diffusion tensor data were correlated with MFIS scores using voxel-wise analysis of fractional anisotropy maps and fiber tractography algorithms. A significant cluster of voxels correlating with fatigue scores located in the deep left frontal white matter was identified. Fiber tractography revealed the cluster to be included in a complex fronto-frontal, fronto-striatal, fronto-occipital, and fronto-limbic network. Structural properties of the traced white matter fiber bundles correlated with fatigue perception and patients with clinically relevant fatigue were found to present reduced white matter integrity in the aforementioned tracts compared to those with lower levels of fatigue. Our observations show a significant involvement of different frontal networks in the pathophysiology of fatigue, thus accounting for the multifaceted nature of this disabling symptom. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Periosteal attachment fibers in the rat calvarium

The anatomical relationships between the fiber tracts and bone lining cells within the rat calvarial periosteum have been studied by electron microscopy. Classical Sharpey's fibers were not observed in this location. Rather, thin unmineralized fibers originating from the periosteum traversed the cambial layer and passed to the bone surface between individual osteoblasts or groups of osteoblasts. The organizational relationship suggests that the osteogenic calvarial cell populations are compartmentalized into domains that might be particularly sensitive and responsive to the biomechanical forces of masticatory muscles.     

Effects of sympathetic efferent in diabetic hyperalgesia in rat]

Ensuring the validity and reliability of data collected in epidemiological surveys is an important consideration. The purpose of the present report is to describe a training and calibration programme for 16 examiners taking part in a national survey of oral mucosal lesions and to present an evaluation of the results. The programme included the distribution of a pictorial manual to participants and a series of lectures followed by three diagnostic sessions, two using slides and the last involving patients. At the final session, the trainees classified 88 per cent of 16 patients correctly in comparison with the definitive diagnoses of the trainer, and their sensitivity on recording oral carcinoma, leukoplakia and lichen planus was at least 0.88. However, correctly classifying submucous fibrosis on the basis of slides alone proved problematic. At the conclusion, the diagnostic accuracy of two examiners for all types of lesion remained appreciably lower than the majority. Training strategies for various types of study are discussed. The method reported is considered to represent a model approach to training and calibrating examiners for this type of survey work.     

Regional suicide rates in the Netherlands: does religion still play a role?

We investigated the influence of apolipoprotein (apo) E-containing particles on LDL receptor binding of large, buoyant LDL subfractions (LDL I) from subjects with predominantly large (phenotype A) and small (phenotype B) LDL particles. Direct binding by human fibroblast LDL receptors was tested at 4 degrees C before and after removal of apoE-containing particles by immunoaffinity chromatography. The binding affinity of total LDL I in phenotype B was greater than that in phenotype A (Kd of 1.83+/-0.3 and 3.43+/-0.9 nmol/L, respectively, P<.05). LDL I from phenotype B subjects had a higher apoE to apoB molar ratio than did that from phenotype A (0.16+/-0.04 versus 0.06+/-0.02, P<.05). Nondenaturing gradient gel electrophoresis of apoE-containing LDL I isolated by immunoaffinity chromatography revealed a substantially larger peak particle diameter than in apoE-free LDL I, and comparison of LDL I composition before and after immunoaffinity chromatography suggested an increase in triglyceride content of apoE-containing particles. After removal of these particles, there was a greater than twofold reduction in LDL receptor affinity of phenotype B LDL (Kd of 1.83+/-0.3 to 3.76+/-0.6, P<.01), whereas in phenotype A no change was observed (Kd of 3.43+/-0.9 to 3.57+/-0.4, respectively). The receptor affinity of apoE-free LDL I from phenotype A and B subjects did not differ. These findings confirm that large, buoyant LDL particles from phenotype B subjects have a higher LDL receptor affinity than does LDL I from phenotype A subjects and suggest that this difference is due to an increased content of large, triglyceride-enriched, apoE-containing lipoproteins. It is possible that the accumulation of these particles reflects abnormalities in the metabolism of remnant lipoproteins that contribute to atherosclerosis risk in phenotype B subjects.     

msh may play a conserved role in dorsoventral patterning of the neuroectoderm and mesoderm

Many of the mechanisms that govern the patterning of the Drosophila neuroectoderm and mesoderm are still unknown. Here we report the sequence, expression, and regulation of the homeobox gene msh, which is likely to play an important role in the early patterning events of these two tissue primordia. msh expression is first observed in late blastoderm embryos and occurs in longitudinal bands of cells that are fated to become lateral neuroectoderm. This expression is under the control of dorsoventral axis-determination genes and depends on dpp-mediated repression in the dorsal half of the embryo and on fib-(EGF-) mediated repression ventrally. The bands of msh expression define the cells that will form the lateral columns of proneural gene expression and give rise to the lateral row of SI neuroblasts. This suggests that msh may be one of the upstream regulators of the achaete-scute (AS-C) genes and may play a role that is analogous to that of the homeobox gene vnd/NK2 in the medial sector of the neuroectoderm. During neuroblast segregation, msh expression is maintained in a subset of neuroblasts, indicating that msh, like vnd/NK2, could function in both dorsoventral patterning of the neuroectoderm and neuroblast specification. The later phase of msh expression that occurs after the first wave of neuroblast segregation in defined ectodermal and mesodermal clusters of cells points to similar roles of msh in patterning and cell fate specification of the peripheral nervous system, dorsal musculature, and the fat body. A comparison of the expression patterns of the vertebrate homologs of msh, vnd/NK2, and AS-C genes reveals striking similarities in dorsoventral patterning of the Drosophila and vertebrate neuroectoderm and indicates that genetic circuitries in neural patterning are evolutionarily conserved.     

The lymphoid system and its role in maintaining immunocompetence

More than half of the children and adolescents with malignant brain tumors will relapse following initial therapy. Irrespective of the therapeutic modalities the prognosis of patients with recurrent or metastatic brain tumors is still poor. New strategies such as high dose chemotherapy (HDCT) with autologous blood stem cell transplantation (ABSCT) offer the possibility to improve the longterm prognosis of these patients. Following conventional chemotherapy with carboplatin/etoposide and after achieving complete or partial remission (CR or PR) 10 patients aged from 3.2 to 25.5 years (median, 10.3 years) with refractory or recurrent malignant brain tumors (anaplastic astrocytoma/glioblastoma, n = 2; medulloblastoma/PNET, n = 6; ependymoma, n = 1; plexus carcinoma, n = 1) received in a pilot study one course of HDCT with ABSCT. The consolidation regimen consisted of thiotepa (400-600mg/m2/d, i.v. 6 h, d-9), carboplatin and etoposide (500mg/m2/d, CVI 24h, d-8 to d-5, respectively) and was followed by the retransfusion of autologous blood stem cells on day 0. Before starting HDCT 6 patients showed CR and 4 patients had PR or stable disease (SD). Following the HDCT 3 of the 4 patients with residual tumor had CR or PR. 6 patients have remained in continuous CR or SD 8 to 41 months (median 17.2 months) after the HDCT. 2 patients relapsed 8.5 and 9.5 months after HDCT and died from progressive disease. Two patients died therapy-related from systemic aspergillosis and were not evaluable for response. Hematological recovery with an absolute neutrophile count of > 0.5 x 10(9)/l and a platelet count of > 30 x 10(9)/l was reached on days +11 (median; range, +9 to +14) and +16 (median; range, +6 to +47), respectively. The main nonhematological toxic effects were infections, severe mucositis, and hyperbilirubinemia. Although the long-term efficacy of HDCT with ABSCT is still not evaluable and the toxicity of this regimen is high, a multicenter phase II trial seems to be justified in view of the poor prognosis of recurrent or refractory brain tumors in children and adolescents.