Reversal of dexfenfluramine-induced anorexia and c-Fos/c-Jun expression by lesion in the lateral parabrachial nucleus

The external subdivision of the lateral parabrachial nucleus (LPBE) shows strong Fos-like immunoreactivity (FLI) following anorectic doses of the indirect serotonin agonist dexfenfluramine (DFEN). In an effort to determine the contribution of the LPBE to DFEN-induced anorexia, bilateral ibotenate lesions were made in the LPBE, and the effects of the lesion on DFEN-induced anorexia and FLI as well as c-June-like immunoreactivity (JLI) were examined. It was found that LPBE lesion significantly attenuated DFEN anorexia: in a 1-h food intake test following 24-h food deprivation, DFEN (2 mg/kg) suppressed food intake by 60% in intact rats but only 34% in rats with LPBE lesions. In addition to this behavioral change, LPBE lesion completely abolished DFEN-induced FLI and JLI in the lateral subdivision of the central nucleus of the amygdala (CeL) and laterodorsal subdivision of the bed nucleus of stria terminalis (BSTLD), both of which showed strong FLI and JLI in intact rats. DFEN-induced FLI and JLI in other brain regions were not affected by LPBE lesion, including the ventromedial and lateral hypothalamus, caudate-putamen, and the nucleus of the solitary tract (NST). The parallel loss of DFEN-induced anorexia and FLI/JLI following LPBE lesion raises the novel possibility that LPBE-CeL/BSTLD pathway may be involved in DFEN anorexia.     

Association of myopathy with large-scale mitochondrial dna duplications and deletions: Which is pathogenic?

We identified large-scale heteroplasmic mitochondrial DNA (mtDNA) rearrangements in a 50–year-old woman with an adult-onset progressive myopathy. The predominant mtDNA abnormality was a 21.2–kb duplicated molecule. In addition, a small population of the corresponding partially deleted 4.6–kb molecule was detected. Skeletal muscle histology revealed fibers that were negative for cytochrome c oxidase (COX) activity and had reduced mtDNA-encoded COX subunits. By single-fiber polymerase chain reaction analysis, COX-negative fibers contained a low number of wild-type or duplicated mtDNA molecules (ie, nondeleted). In situ hybridization demonstrated that the abnormal fibers contained increased amounts of mtDNA compared with normal fibers and that most of the genomes were deleted. We concluded that deleted mtDNA molecules were primarily responsible for the phenotype in this patient.     

A randomized crossover trial of tamoxifen versus ovarian ablation for metastatic breast cancer in premenopausal women: A report of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial MA.1

Background: The outcome of breast cancer is usuallydetermined by multiple factors. Serum tumor necrosis factoralpha concentration has been found to be increasedin the circulation of patients with malignancy. Thisstudy was designed with the aim to investigateany correlation between the serum tumor necrosis factoralpha and the clinicopathological fetures and furthermore evaluatethe prognostic significance of serum tumor necrosis factoralpha concentration in breast cancer. Methods: Forty consecutivepatients with invasive breast cancer undergoing modified radicalmastectomy were prospectively included and evaluated. Venous bloodsamples were collected before the surgery. Sera wereobtained by centrifugation, and stored at – 70°C until assayed. The control group consisted 30healthy, age-matched subjects. Serum concentrations of tumor necrosisfactor alpha were measured by the quantitative sandwichenzyme immunoassay technique. The data on tumor size,age, estrogen receptor status, lymph node status andTNM staging were reviewed and recorded.Results: The mean value of serum tumor necrosis factor alphain patients with invasive breast cancer was 1.47± 0.58 pg/ml and that of the controlgroup was 0.98 ± 0.37 pg/ml, and thedifference was significant (P < 0.01). With univariableanalysis, patients with maximum tumor size of 5cm or larger (P=0.03), more advancedTNM staging (P < 0.01); and more advancedlymph node status (P < 0.01) were shownto have significantly higher serum concentrations of tumornecrosis factor alpha. However, with multivariable analysis, TNMstaging appeared as the only independent factor (P< 0.01) predicting the significant, higher serum concentrationsof tumor necrosis factor alpha. Conclusion: Preoperative evaluationof serum tumor necrosis factor alpha concentrations maybe a valuable parameter for reflecting the severityof staging for invasive breast cancer.     

Clinical pharmacokinetics of teicoplanin

Teicoplanin is a recently introduced glycopeptide antibiotic for the treatment of a variety of aerobic and anaerobic Gram-positive infections. It is a mixture of 5 closely related components, of similar polarity and biological activity, and 1 or more polar hydrolysis products. Teicoplanin is rapidly and extensively absorbed from muscle and the peritoneal cavity but very poorly absorbed from the gastrointestinal tract. Following intravenous administration, the disposition kinetics are best described by a tri-exponential equation, and the majority of drug is excreted unchanged, by glomerular filtration. In patients with normal renal function, the half-lives of the first, second and terminal phases are 35 minutes, 10 hours and 87 hours, respectively. The initial volume of distribution is 0.089 L/kg, the volume of distribution at steady-state is 0.86 L/kg, clearance is 0.0114 L/h/kg and renal clearance is 0.0083 L/h/kg. Teicoplanin is highly bound in plasma to albumin (fraction unbound = 0.1) and in tissues. The pharmacokinetics are linear over a wide dose range (2 to 26 mg/kg). The minor differences in the pharmacokinetics of the components of teicoplanin can be accounted for by differences in lipophilicity. The events following multiple dosing are predicted from single dose data; renal clearance decreases in patients with renal insufficiency in a predictable manner. Negligible drug is lost during haemodialysis. As expected, clearance per kilogram is higher in children than in adults, and lower in the elderly, associated with a decrease in glomerular filtration rate with advancing years. Tissue distribution data are limited. Concentrations, relative to those in plasma, are high in lung and bone tissue and low in fat. Animal data show high concentrations in most tissues, and particularly high in liver and kidneys. Teicoplanin penetrates slowly and poorly into cerebrospinal fluid, but relatively rapidly and effectively in synovial and pleural fluids and in soft tissue. The manufacturer's recommended intravenous or intramuscular dosage regimens rapidly achieve and maintain adequate plasma concentrations of teicoplanin; the dosing interval is usually 1 day. The maintenance dosing rate, but not the loading dose (if needed), must be reduced in patients with poor renal function and in the elderly. For those patients on continuous ambulatory peritoneal dialysis, the peritoneal cavity offers a convenient alternative route of drug administration.     

The incidence of error in young children's Wh-questions.

Many current generativist theorists suggest that young children possess the grammatical principles of inversion required for question formation but make errors because they find it difficult to learn language-specific rules about how inversion applies. The present study analyzed longitudinal spontaneous sampled data from twelve 2-3-year-old English speaking children and the intensive diary data of 1 child (age 2;7 [years;months] to 2;11) in order to test some of these theories. The results indicated significantly different rates of error use across different auxiliaries. In particular, error rates differed across 2 forms of the same auxiliary subtype (e.g., auxiliary is vs. are), and auxiliary DO and modal auxiliaries attracted significantly higher rates of errors of inversion than other auxiliaries. The authors concluded that current generativist theories might have problems explaining the patterning of errors seen in children's questions, which might be more consistent with a constructivist account of development. However, constructivists need to devise more precise predictions in order to fully explain the acquisition of questions.     

Expression of Fos in rat brain in relation to sodium appetite: furosemide and cerebroventricular renin

Two experiments were performed to investigate the relationship between the expression of sodium appetite and the appearance of Fos-like immunoreactivity (Fos-IR) in the brain of rats. In the first experiment, rats were depleted of sodium by treatment with furosemide 24 h prior to sacrifice and without access to either food or sodium solution. Some rats had access to distilled water, and others had no fluids available during the 24 h. All of the furosemide-treated rats showed Fos-IR in both the subfornical organ (SFO) and around the organum vasculosum laminae terminalis (OVLT). Rats with access to distilled water during the depletion period showed no Fos-IR in the supraoptic (SON) or paraventricular hypothalamic nuclei (PVN) and, in parallel behavioral studies, comparably-treated rats consumed only 0.3 M NaCl solution at the end of the 24 h. In rats that had no fluids during the deprivation period, only about one half showed Fos-IR in SON and PVN and, in parallel behavioral studies, comparably treated rats consumed both water and 0.3 M NaCI solution at the end of 24 h. In a second experiment, cerebroventricular administration of renin stimulated short latency intake of 0.3 M NaCI and water. The relative intakes of water and NaCl were comparable at a low dose of renin, but intake of water exceeded that of NaCl after higher doses. Renin induced Fos-IR in SFO, MnPO, peri-OVLT region, SON and PVN. Both Fos-IR and fluid intake were antagonized by administration of losartan, an angiotensin 11 type 1 receptor antagonist. Thus, only the circumventricular organs of the lamina terminalis showed Fos-IR during each natriorexigenic regimen in these studies. These data support the view that Ang 11 of both central and peripheral origin activates the SFO and/or peri-OVLT region and contributes to sodium appetite.