Stress-induced C-fos expression in the rat locus coeruleus is dependent on neurokinin 1 receptor activation

These experiments examined the role of substance P-selective neurokinin 1 receptors in the restraint-induced activation of the rat locus coeruleus. Immunohistochemistry revealed high levels of neurokinin 1 receptor expression in the plasma membrane of tyrosine hydroxylase-positive locus coeruleus neurons. The selective neurokinin 1 receptor antagonists, RP 67580 (5 nmol) and L-760,735 (3.4 nmol), were administered intracerebroventricularly prior to restraint stress, and c-fos protein was measured as an index of locus coeruleus activation. Both antagonists attenuated the restraint-induced increase in locus coeruleus c-fos expression, whereas their inactive enantiomers were ineffective. These results suggest that neurokinin 1 receptors may mediate activation of locus coeruleus neurons during stress. Neurokinin 1 receptor antagonists may prove to be novel therapeutic compounds in the treatment of anxiety and depression.     

Internal derangements of the shoulder: decision tree and cost-effectiveness analysis of conventional arthrography, conventional MRI, and MR arthrography

Purpose. In a patient with internal derangement of the shoulder, the diagnostic method of choice is controversial. Conventional arthrography can diagnose most rotator cuff tears accurately; however, in many institutions MR arthrography is usually necessary to diagnose labral tears. We utilized decision tree methodology to compare the cost- effectiveness of conventional arthrography and conventional MRI with a hypothetical algorithm in which a patient underwent arthrography, performed with admixed gadolinium, which if negative, was followed by MRI. Design. The use of double-contrast arthrography alone, conventional MRI alone, and gadolinium-enhanced MRI used as an adjunct to conventional arthrography were modeled for the diagnosis of full-thickness rotator cuff tears (RCT), partial RCTs, labral tears, and the absence of cuff/labral tears using decision analysis methodology. English language medical publications were searched to determine the base probabilities for the accuracy of the diagnostic tests. The outcome utilities ranged from –1 to +1 to reflect the value of correct diagnostic evaluation. Charges for diagnostic tests and appropriate surgical treatments were based on 1997 Medicare reimbursement rates for professional fees and hospital charges in an outpatient setting. Sensitivity analyses were performed to evaluate the effects of uncertainty regarding the prevalence of each disease state and the accuracy of several diagnostic tests. Results. In the base-case analysis, the average effectiveness of double-contrast arthrography alone, MRI alone and arthrography selectively followed by MRI were 0.6610, 0.6715, and 0.7204, respectively. The average costs for each of these strategies were $1090, $2033, and $2339, respectively. Conclusion. Arthrography performed with admixed diluted gadolinium, which if negative is immediately followed by MRI, was somewhat more expensive than conventional MRI. However, because of much greater effectiveness, cost-effectiveness was significantly higher for our proposed algorithm. Conventional arthrography without gadolinium, although less expensive, had severely limited effectiveness. Received: 4 June 1999 Revision requested: 6 August 1999 Revision received: 30 August 1999 Accepted: 1 September 1999     

A novel sodium channel mutation in a family with hypokalemic periodic paralysis

OBJECTIVE: To identify the cause of hypokalemic periodic paralysis (HOKPP) in a family whose disease is not caused by a mutation in the dihydropyridine-sensitive (DHP) receptor alpha1-subunit gene (CACNA1S). BACKGROUND: Hypokalemic periodic paralysis is primarily caused by mutations within CACNA1S. Genetic heterogeneity for HOKPP has been reported, but no other locus has been identified. METHODS: Single-stranded conformational polymorphism (SSCP) analysis and PCR direct sequencing were used to screen the skeletal muscle alpha1-sodium channel gene (SCN4A) for a mutation in our family. RESULTS: SSCP analysis showed an abnormally migrating conformer in exon 12. Direct sequencing of the conformer showed a guanine to adenine transition at position 2006 in the cDNA sequence; this results in an amino acid substitution of a highly conserved arginine (Arg) to histidine (His) at position 669. This sequence alteration segregated only with the affected members of the kindred and was not found in a panel of 100 DNA samples from healthy controls. The amino acid substitution alters the outermost positive charge in the membrane spanning segment DII/S4, which is involved in voltage sensing. CONCLUSIONS: The first arginine in DII/S4 and in DIV/S4 within the skeletal muscle sodium channel and the L-type calcium channel genie CACNA1S appear to be critical for normal function. In all four cases, Arg to His mutations result in a disease phenotype. The identification of a mutation within the skeletal muscle sodium channel resulting in hypokalemic periodic paralysis represents a novel finding.     

Linkage analysis in alcohol dependence

Alcohol dependence often is a familial disorder and has a genetic component. Research in causative factors of alcoholism is coordinated by a multi-center program, COGA [The Collaborative Study on the Genetics of Alcoholism, Begleiter et al., 1995]. We analyzed a subset of the COGA family sample, 84 pedigrees of Caucasian ancestry comprising 745 persons, 339 of whom are affected according to DSM-III-R and Feighner criteria. Using parametric and nonparametric methods, evidence for linkage was found on chromosome 1 (near markers D1S532, D1S1588, and D1S534), as well as on chromosome 15 (near marker D15S642). Other regions of the genome showed suggestive evidence for contributing loci. Related findings are discussed in recent publications investigating linkage in humans [Reich et al., 1998] and mice [Melo et al., 1996].     

Long-term outcome of radical radiation therapy for prostatic carcinoma: 1967-1987

PURPOSE: This study was done to review long-term results of radical radiotherapy for prostate cancer. METHODS AND MATERIALS: The records of 674 patients with Stage T1a, T1b, T2a, T2b, T3, and any T,N1,M0 disease, treated with external beam radiotherapy between January 1, 1967 and December 1987, were reviewed. These patients were treated to an average total dose of 66 Gy, with an average fractional dose of 2.05 Gy, using megavoltage. The duration of follow-up for surviving patients ranged from a minimum of 7 years to more than 20 years. RESULTS: The survival for 151 Stage T1a,T1b patients was 98.5% at 5 years, 93.6% at 10 years, and 75.2% at 15 years. Survival for 346 Stage T2a,b patients was 94.4% at 5 years, 67.9% at 10 years, and 41.5% at 15 years. Survival for 92 Stage T3 patients was 87.3% at 5 years, 54% at 10 years, and 26.6% at 15 years. The survival for 85 any T,N1,M0 patients was 73.9% at 5 years, 34.4% at 10 years, and 8.5% at 15 years. At 15 years, 75.2% of Stage T1a,b patients, 41.5% of Stage T2a,b patients, 21.7% of Stage T3 patients, and 8.5% of Stage T,N1,M0 patients remained free of local recurrence and distant metastases. The elevation of prostatic acid phosphatase prior to radiotherapy was an unfavorable prognostic factor, with impact on both loco-regional recurrences and survival. CONCLUSIONS: The external beam radiotherapy for localized carcinoma of the prostate produced a good loco-regional control, NED, and overall survival. Patients with smaller tumors and low grade fared better than the ones with more aggressive and/or bulky tumors. The weakness of this study is the absence of serial prostate-specific measurements, which were not available during the period under study. The complication rate requiring surgical intervention was low, i.e. 0.4%.     

The transurethral resection syndrome

The transurethral resection syndrome ("TUR syndrome") is caused by absorption of electrolyte-free irrigating fluid, and consists of symptoms from the circulatory and nervous systems. The clinical picture is inconsistent and the syndrome is easily confused with other acute disorders. Mild forms are common and often go undiagnosed, while severe forms of the TUR syndrome are rare and potentially life-threatening. The pathophysiology is complex but includes four mechanisms: circulatory distress from the rapid absorption of electrolyte-free irrigating fluid, adverse effects of glycine, dilution of the protein and electrolyte concentrations of the body fluids, and disturbance of renal function. The treatment of the TUR syndrome consists of general life support and in specific treatment directed towards hypotension, hyponatraemia and anuria. Methods to lower the uptake of irrigating fluid are widely used and probably reduce the incidence of the TUR syndrome. However, patient safety can be guaranteed only if the absorption is monitored. An irrigating fluid containing tracer amounts of ethanol can be used for this purpose. This permits the uptake of fluid to be indicated by measuring the concentration of ethanol in the patient's exhaled breath.     

Prevention and suppression of autoimmune pancreatic Beta-cell destruction in BB rats by syngeneic lymphocytes obtained from long-term normoglycaemic donors

Summary To prove whether a cell-mediated mechanism is responsible for maintaining long-term normoglycaemia in BB/OK rats with a proved immune attack (insulitis, reduced Beta-cell volume), we transferred lymphocytes obtained from those rats into normoglycaemic diabetes-prone BB/OK rats or into diabetic BB/OK rats receiving a simultaneous syngeneic islet graft. Our results show the presence of a lymphocyte population in the long-term normoglycaemic BB/OK rats, which is able to arrest pancreatic Beta-cell destruction in diabetes-prone BB/OK rats detected by a decreased diabetes incidence following single lymphocyte transfusion. Syngeneic islets were destroyed by recurrence of the autoimmune process when transplanted into diabetic BB/OK rats. Lymphocytes obtained from long-term normoglycaemic BB/OK rats were able to protect the syngeneic BB/OK islet graft from autoimmune destruction in diabetic BB/OK rats, whereas allogeneic islet destruction was not prevented. The phenotype of the effective lymphocyte population is not yet clear, but it is negative for RT6. We conclude that the mechanism responsible for maintaining normoglycaemia in long-term normoglycaemic BB/OK rats is cell mediated, because this property can be transferred to prevent autoimmune destruction of pancreatic Beta cells.     

The effect of variability of unattended information on global and local processing: evidence for lateralization at early stages of processing

Visual objects can often be analyzed as hierarchical in structure, composed of local elements that are spatially arranged to form a global shape. The brain mechanisms involved in the analysis of hierarchical figures have been under considerable scrutiny in recent years, and one of the many interesting features that have emerged is that there is an asymmetry across the two hemispheres for global (right hemisphere) vs local (left hemisphere) processing. Event-related potentials (ERP) were used to examine selective attention to global or local levels of hierarchical figures to determine the stage of processing at which the asymmetry first emerges. Two conditions were tested, one in which unattended information was variable from trial to trial, and one in which it was not. The variability of unattended information influenced the lateralization of processing. Presentation of invariable, neutral distractors resulted in global/local processing asymmetries at early stages (P1). In contrast, presentation of variable, task-relevant distractors resulted in processing asymmetries that occurred at much later stages (N2). Our hypothesis is that lateralized enhancement of neural populations in extrastriate cortex results from both selective attention to locations in the visual field, as well as selective attention to global or local information. We suggest that unattended information that varies from trial to trial is processed in parallel with attended information, masking hemisphere biases for local vs global information at early stages of processing.     

Holoprosencephaly: recent advances and new insights

Holoprosencephaly is a relatively common brain malformation occurring in 5-12/100,000 live births. The astonishing growth in molecular genetic medicine has provided the field of developmental nervous system malformations with new perspectives and tools for unraveling its mysteries and offering better information for clinicians and families. This is particularly evident in the group of complex midline malformations known as holoprosencephaly. Although new molecular findings have shed light on some of the causes and manifestations of this malformation, there remains a need to build on the existing clinical knowledge so that we may develop more effective treatments and improve the quality of life of these patients.     

Osteoblast Gene Expression in Rat Long Bones: Effects of Ovariectomy and Dihydrotestosterone on mRNA Levels

The steroid sex hormones exert major effects on bone formation although the molecular events associated with their activity remain unclear. We have investigated the effects of ovariectomy and dihydrotestosterone (DHT) administration to both sham-operated and ovariectomized (ovx) rats on the bone mRNA levels of osteoblast genes. Rats were randomly allocated to either sham or ovariectomy operations and were administered either vehicle or 40 mg/kg body weight DHT by silastic tube implants at the time of operation for 8 weeks, at which time they were killed and total RNA was extracted from the long bones. Northern blot analysis indicated that the mRNA levels of the bone cell genes α1(I) collagen, alkaline phosphatase, osteocalcin, and osteopontin were markedly increased in ovx rats between 6- and 30-fold. DHT administration to ovary-intact, estrogen-sufficient rats increased the mRNA levels of α1(I) collagen, alkaline phosphatase, osteopontin, and osteocalcin between 3- and 9-fold. In contrast, DHT did not alter levels of these mRNA species in ovx rats. The data demonstrate that estrogen deficiency increased mRNA levels of genes expressed during osteoblast development and suggest an interplay between estrogen and androgen action in regulating the expression of a number of bone cell genes. Received: 20 May 1999 / Accepted: 21 January 2000