Cocaine impairs follicular phase pulsatile gonadotropin secretion in rhesus monkeys

BACKGROUND: Ménière's disease is a medical condition that involves hearing loss, tinnitus and attacks of vertigo. The attacks can be severely disabling with nausea, dizziness, and aural sensations. METHOD: Three scales assessing the correlates of vertigo attacks in Ménière's disease were developed and completed by 514 subjects diagnosed with the disease. The three scales measured were somatic sensations (SOM), psychological state (PSYCHOL), and situational characteristics (SIT) associated with an attack. RESULTS: Psychometric properties of the three scales were investigated showing Cronbach's alphas of 0.76, 0.80, and 0.62 for the three scales respectively. The results on the scales were related to disease progression. Principal components factor analyses showed that the SOM scale could be divided into two subscales: dizziness/vertigo/anxiety and sensations in the ear. The PSYCHOL scale showed an energy/awareness factor and a negative emotional state factor. The SIT scale, finally, showed two factors: environmental disturbances and stressful conditions. CONCLUSIONS: Knowledge of somatic, psychological and situational premonitory characteristics of attacks in Ménière's disease could lead to improved therapy and counselling.     

Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia

The etiology of the selective neuronal death that occurs in Huntington's disease (HD) is unknown. Several lines of evidence implicate the involvement of energetic defects and oxidative damage in the disease process, including a recent study that demonstrated an interaction between huntingtin protein and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using spectrophotometric assays in postmortem brain tissue, we found evidence of impaired oxidative phosphorylation enzyme activities restricted to the basal ganglia in HD brain, while enzyme activities were unaltered in three regions relatively spared by HD pathology (frontal cortex, parietal cortex, and cerebellum). Citrate synthase-corrected complex II-III activity was markedly reduced in both HD caudate (-29%) and putamen (-67%), and complex IV activity was reduced in HD putamen (-62%). Complex I and GAPDH activities were unaltered in all regions examined. We also measured levels of the oxidative damage product 8-hydroxydeoxyguanosine (OH8dG) in nuclear DNA, and superoxide dismutase (SOD) activity. OH8dG levels were significantly increased in HD caudate. Cytosolic SOD activity was slightly reduced in HD parietal cortex and cerebellum, whereas particulate SOD activity was unaltered in these regions. These results further support a role for metabolic dysfunction and oxidative damage in the pathogenesis of HD.     

Folding of the amino-terminal domain of apolipoprotein B initiates microsomal triglyceride transfer protein-dependent lipid transfer to nascent very low density lipoprotein

The initial assembly of apolipoprotein B100 (apoB) into lipoprotein particles occurs cotranslationally. To examine steps required to initiate this process, the intracellular folding and assembly of the amino-terminal 28% of apoB (apoB28) was examined using several criteria including nonreducing gel electrophoresis, sensitivity to dithiothreitol (DTT)-mediated reduction, and buoyant density gradient centrifugation. In hepatoma cells, after a 1-min pulse with radiolabeled amino acids, labeled apoB28 migrated during gel electrophoresis in the folded position and was resistant to reduction in vivo with 2 mM DTT. A similar rate and extent of folding was observed in Chinese hamster ovary cells, a microsomal triglyceride transfer protein (MTP)-negative cell line that can neither lipidate nor efficiently secrete apoB28. Amino-terminal folding of apoB28 was essential for its subsequent intracellular lipidation as apoB28 synthesized in hepatoma cells under reducing conditions remained lipid poor (d > 1.25 g/ml) and was retained intracellularly. Upon DTT removal, reduced apoB28 underwent a process of rapid (t1/2 approximately 2 min) post-translational folding followed by a slower process of MTP-dependent lipidation. As with the cotranslational assembly pathway, post-translational lipidation of apoB28 displayed a strict dependence upon amino-terminal folding. We conclude that: 1) folding of the amino-terminal disulfide bonded domain of apoB is achieved prior to the completion of translation and is independent of MTP and events associated with buoyant lipoprotein formation and 2) domain-specific folding of apoBs amino-terminal region is required to initiate MTP-dependent lipid transfer to nascent apoB in the hepatic endoplasmic reticulum.     

Transurethral enzyme injection--future management of benign prostatic hyperplasia

Although benign prostatic hyperplasia, a common condition among elderly men, has been effectively treated with transurethral resection of the prostate, this surgical procedure is associated with many well-recognized risks and complications. Because of this potential morbidity and mortality, various alternative treatment strategies for benign prostatic hyperplasia have been proposed. The use of enzyme solubilization and ablation of prostatic tissue to alleviate urinary outlet obstruction has proved effective in dogs and warrants investigation in human trials. Transurethral enzyme injection of the prostate has the potential for being a treatment modality with minimal invasiveness, limited requirements for anesthesia, and minimal associated toxicity for the management of benign prostatic hyperplasia.     

Mutations in Bartonella bacilliformis gyrB confer resistance to coumermycin A1

This study describes the first isolation and characterization of spontaneous mutants conferring natural resistance to an antibiotic for any Bartonella species. The Bartonella bacilliformis gyrB gene, which encodes the B subunit of DNA gyrase, was cloned and sequenced. The gyrB open reading frame (ORF) is 2,079 bp and encodes a deduced amino acid sequence of 692 residues, corresponding to a predicted protein of approximately 77.5 kDa. Sequence alignment indicates that B. bacilliformis GyrB is most similar to the GyrB protein from Bacillus subtilis (40.1% amino acid sequence identity) and that it contains the longest N-terminal tail (52 residues) of any GyrB characterized to date. The cloned B. bacilliformis gyrB was expressed in an Escherichia coli S30 cell extract and was able to functionally complement a temperature-sensitive E. coli Cour gyrB mutant (strain N4177). We isolated and characterized spontaneous mutants of B. bacilliformis resistant to coumermycin A1, an antibiotic that targets GyrB. Sequence analysis of gyrB from 12 Cour mutants of B. bacilliformis identified single nucleotide transitions at three separate loci in the ORF. The predicted amino acid substitutions resulting from these transitions are Gly to Ser at position 124 (Gly124-->Ser), Arg184-->Gln, and Thr214-->Ala or Thr214-->Ile, which are analogous to mutated residues found in previously characterized resistant gyrB genes from Borrelia burgdorferi, E. coli, Staphylococcus aureus, and Haloferax sp. The Cour mutants are three to five times more resistant to coumermycin A1 than the wild-type parental strain.     

Use of the appendix to replace the choledochus

Ten cases of choledochal cyst (CC) were treated by biliary-appendicoduodenostomy. The follow-up comprised a patient interview, ultrasonography (US), and single-proton ejected computerized tomography (SPECT) scanning. In all cases an anti-reflux submucosal tunnel was added to the distal appendico-duodenostomy; all showed an uneventful postoperative course. All the dilated intrahepatic bile ducts had normalized on B-US postoperatively. Four children under went SPECT examination; all of them had patent neo-bile ducts. In the authors' opinion: (1) Anastomosing the cecal end of the appendix to the common hepatic duct seemed more favorable than the other way around, because the cecal end could be easily trimmed to the size of the common hepatic duct, which was more or less dilated in the presence of a CC; (2) It is necessary to add a submucosal tunnel to the distal appendicoduodenostomy to achieve a more reliable anti-reflux effect; and (3) Transposing the vascularized appendix through the retro-transverse colon simplified the procedure and might reduce the risk of retroperitoneal complications if bile leakage should occur.     

Growth hormone-insulin-like growth factor-I axis in adult insulin-dependent diabetic patients: evidence for central hypersensitivity to growth hormone-releasing hormone and peripheral resistance to growth hormone

The aim of this study was to assess the GH-IGFI axis, GH receptor availability, as reflected by the levels of GH-BP, and the amount of GH-dependent IGFBP-3 in adult IDDM patients with different degrees of metabolic control. Thus, 10 adult well-controlled IDDMs (HbA1 7.8 +/- 0.4%), 10 adult non-ketotic poorly controlled IDDMs (HbA1 13.3 +/- 7%) and 14 sex- and age-matched healthy controls were subjected to two intravenous GH-RH stimulation tests with 0.1 and 1.0 microg/kg body weight respectively, and a plasma IGF-1 generation test induced by the administration of hGH. Poorly controlled IDDM patients exhibited an exaggerated GH response to 1.0 microg/kg of GH-RH when compared to healthy control subjects. Low fasting plasma IGF-1 levels and a blunted IGF-1 response to exogenously administered hGH were also found in poorly controlled IDDMs when compared to the healthy control group. GH-BP levels were significantly lower in IDDMs than in normal controls, and correlated positively with the IGF-1 generation capacity after hGH. Serum IGFBP-3 levels measured by RIA were similar in IDDM and control groups. Good glycemic control for 5.7 +/- 0.9 months did not correct the above mentioned abnormalities of the GH-IGF-1 axis. Our findings suggest that IDDM is associated with a diminished availability of GH receptors and synthesis of IGF-1. GH might then increase as a compensatory mechanism, further down-regulating liver GH receptors, and thus perpetuating the initial abnormality.     

Variation in photodynamic efficacy during the cellular uptake of two phthalocyanine photosensitizers

A decrease in the efficacy of photodynamic therapy (PDT) with phthalocyanine photosensitizers was observed for lymphoblastic murine and human cell lines as the time between the addition of the photosensitizer, aluminum phthalocyanine (AIPc), to the culture medium and exposure to light was increased from 4 h to 18 h. The total intracellular concentration of photosensitizer did not decrease significantly during this 18 h interval. For the murine cell lines, the maximum cytotoxic and mutagenic effects were observed when the time between addition of the photosensitizer and irradiation was between 1 and 4 h. The time course of the variations in efficacy did not vary greatly from one murine cell line to another, even though the cell lines differ markedly in the extent of their cytotoxic and mutagenic response. The time course of the variation was similar for cytotoxicity and mutagenicity, as well as for the induction of DNA fragmentation. The human lymphoblastic cell line, WTK1, showed less variation in survival and mutability with time than did the murine cell lines. With Pc 4 (HOSiPcOSi[CH3]2[CH2]3N[CH3]2) as the photosensitizer, the photocytotoxicity for murine L5178Y (LY)-S1 cells did not change significantly as the time between addition of Pc 4 and irradiation was increased from 2 to 18 h. However, the mutagenicity decreased by a factor of three during this interval. The mutagenicity of PDT with Pc 4 was much less in LY-S1 cells than that with AlPc. The results suggest that the variation in the efficacy observed for AlPc-induced photocytotoxicity is caused by changes in the intracellular distribution and/or the aggregation of the photosensitizer with time after its addition.