Grand round cases: Australian Association of Neurologists Annual Scientific Meeting, Canberra 2006.

The Annual Scientific Meeting of the Australian Association of Neurologists includes a Grand Rounds Session in which unusual cases are presented. The Chairmen of the 2006 session, Drs Richard Stark and Heather Waddy, lead the audience through a discussion of the history, physical signs, diagnostic investigations and finally the diagnosis at intervals throughout the case presentation. In introducing the cases Dr. Stark emphasized that the cases were selected because they were unusual and the final diagnosis may not be evident at the outset. The approach to the clinical problems and the process of thinking through the differential diagnoses and the method of investigation were as important to the discussion of these cases as the final diagnosis itself. These cases are reported here including an edited summary of the discussion with the same emphasis on the method of clinical analysis and the diagnostic process.     

Transperineal percutaneous iridium-192 interstitial template implant of the prostate: results and complications in 321 patients.

A total of 321 patients with localized adenocarcinoma of the prostate treated by modified pelvic lymphadenectomy, Iridium-192 implant, and external beam iridium radiation were retrospectively reviewed. Analysis covered 8 years between 1981 and 1989 with a median population age of 72 (range 42 through 82 years). Disease-free survival for the entire group is 69% at 5 years with a median follow-up of 34 months (range 1.5 months to 98.5 months). As expected, both bulkier disease and positive nodal status adversely affected 5-year disease-free survival (p = 0.0001 for both). For tumors stage T1b (A2), T2a (B1), T2b (B2), T3 (C) the disease-free survival is 89.5%, 89.9%, 64.7%, and 48.8%, respectively; for NO disease 5-year disease-free survival is 76.5% versus N1/N2 disease with 5-year disease-free survival of 33.2%. Local control was excellent except for bulkier disease (p = 0.009). Tumors T1b, T2a, T2b, and T3 have 60-month local control rates of 95%, 93%, 83.6%, and 73.1%, respectively. Histologic grade also affected disease-free survival and local control with grade 1, grade 2, grade 3 showing 81.2%, 65.7%, and 45.1% disease-free survival at 5 years; and 93.6%, 82.2%, and 72.4% local control at 5 years. Estimates obtained using Kaplan-Meier method. Radiation induced morbidity was analyzed separately for all patients, there were 41 patients (13% of total) with 54 documented complications. There were no Grade 4 or 5 complications as per RTOG categories. Only 3 cases showed grade 3 complications (1%) and 51 cases showed grade 2 complications (15.9%). Grade 1 complications were not recorded. Of the grade 2 and grade 3 complications 30 were GU and 22 were rectal. The morbidity associated with combined interstitial implantation by transperineal percutaneous template and external beam iridium radiation for the localized prostate cancer is minimal with excellent local control and disease-free survival.     

Complementary components and local variations of the pattern electroretinogram

Pattern electroretinograms have been presumed to arise from a combination of luminance and pattern detection activities. Since the responses at low spatial frequencies are linearly related to contrast and contain negligible pattern specific components, it is proposed that a retinal illuminance response for higher spatial frequencies can be computed from the optical transfer function of the eye. These computed responses are subtracted from pattern electroretinograms to reveal a pattern-specific response with a marked bandpass characteristic. The peak spatial frequency of the bandpass curve declines with increasing peripheral angle. For central vision, the peak amplitude of the pattern-specific response is larger than the retinal illuminance response, but, in the peripheral retina, the two responses are found to be almost equal. The possible origins of these signals are discussed, and it is concluded that the technique provides a method of obtaining separated illuminance and pattern responses from retinal regions having different properties of spatial selectivity.     

Metabolism of doxylamine succinate in Fischer 344 rats. Part II: Nonconjugated urinary and fecal metabolites

Elimination and metabolic profiles of doxylamine and its nonconjugated metabolites were determined after the oral administration of [14C]-doxylamine succinate (13.3 mg/kg and 133 mg/kg doses) to male and female Fischer 344 rats. Total urine and fecal recovery of the administered dose was greater than 90% regardless of sex or dose. The cumulative urinary and fecal elimination of these nonconjugated doxylamine metabolites at the 13.3 mg dose was 44.4 +/- 4.4% and 36.0 +/- 5.8% of the total recovered dose for male and female rats, respectively. The cumulative urinary and fecal elimination of the doxylamine nonconjugated metabolites at the 133 mg/kg dose was 38.7 +/- 2.7% and 41.4 +/- 1.0% of the total recovered dose for male and female rats, respectively. In order to determine the contribution of mammalian and bacterial enzymes in the overall metabolism and excretion patterns for doxylamine, two in vitro techniques were investigated. Incubation of [14C]-doxylamine succinate with human and rat intestinal microflora indicated that anaerobic bacteria were not capable of effecting the degradation of [14C]-doxylamine succinate. However, the incubation of [14C]-doxylamine succinate with isolated rat hepatocytes generated several metabolites similar to those observed in vivo. The nonconjugated doxylamine metabolites isolated and identified include: doxylamine N-oxide, desmethyldoxylamine, didesmethyldoxylamine and ring-hydroxylated products of doxylamine and desmethyldoxylamine. The studies demonstrate the role of hepatic metabolism in the elimination of doxylamine succinate in the rat.     

Diazepam-induced amnesia: a neuropharmacological model of an "organic amnestic syndrome"

Diazepam has well-known amnestic properties. These effects, however, are selective for certain psychobiologically distinct memory functions. In this study, incremental doses of diazepam administered to 10 normal volunteers selectively impaired anterograde episodic memory and attention while totally sparing access to information in long-term memory (semantic or knowledge memory). This pattern of disruption mimics that seen in patients with organic amnesias and is in sharp contrast to the pattern seen in patients with dementia. These findings provide a framework for defining specific psychobiological determinants of cognitive failure.     

Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line.

We selected two drug resistant variants of the MCF7 human breast cancer cell line by chronic in vitro exposure to doxorubicin (MCF7/D40 cell line) and mitoxantrone (MCF7/Mitox cell line), respectively. The cell lines are similar in growth characteristics including doubling time, DNA synthetic phase and cell size. Resistance to mitoxantrone conferred only partial resistance to doxorubicin; whereas resistance selected for doxorubicin appeared to confer complete resistance to mitoxantrone. Both agents selected for cross resistance to the Vinca alkaloids. MCF7/D40 cells display a classic-multi-drug resistance phenotype with expression of P-glycoprotein, decreased drug accumulation relative to the parental line and reversal of drug accumulation and drug resistance by verapamil. MCF7/Mitox cells likewise display resistance to multiple drugs, but in contrast to MCF7/D40 cells do not express P-glycoprotein by immunoblot or RNA blot analysis. Net drug accumulation in MCF7/Mitox cells was decreased relative to the parental cells but there was no selective modulation of drug accumulation or in vitro drug resistance by the addition of verapamil. Efflux of mitoxantrone was enhanced in both the MCF7/D40 and MCF7/Mitox cell lines relative to the MCF7/S cell line. We conclude that the two drug resistant cell lines have different mechanisms of decreased drug accumulation.     

Does magnesium sulfate alter the maternal cardiovascular response to vasopressor agents in gravid ewes?

Magnesium sulfate (MgSO4) attenuates the maternal compensatory response to hemorrhage in gravid ewes, perhaps by decreasing the response to endogenous vasopressors. The purpose of this study was to determine whether MgSO4 alters the cardiovascular response of gravid ewes to vasopressor agents. Sixteen gravid ewes underwent a series of experiments consisting of administration of two exogenous and two endogenous vasopressors, each with and without a concurrent MgSO4 infusion. Dose-response curves were constructed for phenylephrine (an alpha 1-adrenergic agonist), ST-91 (an alpha 2-adrenergic agonist), angiotensin II, and arginine vasopressin (AVP). MgSO4 significantly attenuated the increase in maternal mean arterial pressure and systemic vascular resistance and the decrease in cardiac output during ST-91 infusion but not during phenylephrine, angiotensin II, or AVP infusions. MgSO4 significantly attenuated the increase in uterine vascular resistance during phenylephrine, ST-91, and angiotensin II infusions and the decrease in uterine blood flow during phenylephrine and angiotensin II infusions. MgSO4 also appeared to attenuate the decrease in uterine blood flow during ST-91 infusion (P = 0.067). The present study suggests that MgSO4 antagonizes the effects of alpha 1-adrenergic agonists, alpha 2-adrenergic agonists, and angiotensin II on the uterine vasculature, thus providing a level of protection for the fetus in situations of maternal stress.