Safety and tolerability of Pau d' Arco (Tabebuia avellanedae) for primary dysmenorrhea: A single-arm, open-label trial on adults ages 18-45.

Objectives: To evaluate the safety and tolerability of encapsulated Tabebuia avellanedae in generally healthy women aged 18-45 with primary dysmenorrhea. Methods: A single arm, open-label trial was conducted in which 1050 mg/day of encapsulated Tabebuia avellanedae (Pau d'Arco) was administered to twelve healthy women aged 18-45 for eight weeks. The primary outcome was safety and tolerability as measured by standardized adverse events scales and serial collection of laboratory markers to assess general health, prothrombin times, and the presence or absence of anemia. Secondary outcomes included pain intensity, quality of life, and pain interference measured by the Visual Analog Scale (VAS), the Patient-Reported Outcomes Measurement Information System (PROMIS) 29 survey, and the PROMIS Visual Sexual Function and Satisfaction: Interfering Factors survey, respectively. Exploratory outcomes included serum concentration of high-sensitivity C-reactive protein as a marker of systemic inflammation. Results: Seventy-five percent of participants (n = 9/12) completed the study. Seventy-five percent of study participants (n = 9/12) reported an adverse event, most of which were characterized as mild, and none were determined to be a Food and Drug Administration (FDA) serious adverse event. Most laboratory markers stayed within normal limits throughout the study period with a few clinically mild abnormalities. There was a significant decrease in pain intensity compared to baseline after the first dose (p < .01), after 4 weeks of treatment (p < .01), and after 8 weeks of treatment (p < .01). Over the 8-week intervention period, pain interference, quality of life, and sexual function and satisfaction scores improved nonsignificantly and hs-CRP decreased nonsignificantly. Conclusions: Tabebuia avellanedae supplementation of 1050 mg/day dose for eight weeks in generally healthy women aged 18-45 with primary dysmenorrhea was generally safe, associated with moderate tolerability, and associated with significant improvements in pain intensity scores. Future studies examining the safety and efficacy of Tabebuia avellanedae on primary dysmenorrhea are warranted.

Fall frequency, predicting falls and participating in falls research: similarities among people with Parkinson's disease with and without cognitive impairment.

OBJECTIVE: We compared fall frequency and prediction among People with Parkinson's Disease (PwP) with and without cognitive impairment (CI); researchers sometimes overlook the former, concerned about consent, recall and adherence and differences in fall frequency and predictability. METHODS: We recruited 101 PwP from one clinic, used the Montreal Cognitive Assessment to measure CI, noted repeated falls recalled retrospectively over 12 months and evaluated 'repeated falls' and 'difficulty turning' as predictors of falls over three months. RESULTS: Participant median age was 76 years, and time since diagnosis 6 years. Of 40 participants without CI, 40% recalled falls and 55% fell during follow-up (1.9 (±3.8) falls/person), the sensitivity of fall history being 57% and of turning 36%. Of 36 participants with mild CI, 42% recalled falls and 42% fell during follow-up (1.2 (±1.8) falls/person), the sensitivity of fall history being 67% and of turning 69%. Of 25 participants with moderate CI, 60% recalled falls and 58% fell during follow-up (1.2 (±1.8) falls/person), the sensitivity of fall history being 71% and of turning 69%. CONCLUSIONS: Researchers need not exclude people with CI assuming falls are more frequent and less predictable than among those without. Fall rates (falls/person during follow-up) were similar among people with and without CI. Falls and difficulty turning were more sensitive predictors of falling in those with CI than those without: a simple mobility test may suggest an individual's risk of falling if a history is unavailable. Most PwP with moderate CI fall repeatedly: carer involvement facilitates their inclusion in research.

Sequence and onset of whole-body coordination when turning in response to a visual trigger: comparing people with Parkinson's disease and healthy adults.

Turning round is a routine everyday activity that can often lead to instability. The purpose of this study was to investigate abnormalities of turning among people with Parkinson's disease (PwPD) through the measurement of sequence of body segments and latency response. Participants were asked to turn 180° and whole-body movements were recorded using CODAmotion and Visio Fast eye tracking equipment. Thirty-one independently mobile PwPD and 15 age-matched healthy controls participated in the study. We found that contrary to common belief, the head preceded movement of all other body segments (eyes, shoulders, pelvis, first and second foot). We also found interaction between group and body segment (P=0.005), indicating that overall, PwPD took longer to move from head to second foot than age-matched healthy controls. For PwPD only, interactions were found between disease severity and body segment (P<0.0001), between age group and body segment (P<0.0001) and between gender and body segments (P<0.0001). For each interaction, longer time periods were noted between moving the first foot after the pelvis, and moving the second foot after the first, and this was noted for PwPD in Hoehn and Yahr stage III-IV (in comparison to Hoehn and Yahr stage I-II); for PwPD who were under 70 years (in comparison with 70 years or over); and for ladies (in comparison with men). Our results indicate that in PwPD and healthy elderly, turning-on-the-spot might not follow the top-to-bottom approach we know from previous research.

Identification of cholinergic and non-cholinergic neurons in the pons expressing phosphorylated cyclic adenosine monophosphate response element-binding protein as a function of rapid eye movement sleep.

Recent studies have shown that in the pedunculopontine tegmental nucleus (PPT), increased neuronal activity and kainate receptor-mediated activation of intracellular protein kinase A (PKA) are important physiological and molecular steps for the generation of rapid eye movement (REM) sleep. In the present study performed on rats, phosphorylated cyclic AMP response element-binding protein (pCREB) immunostaining was used as a marker for increased intracellular PKA activation and as a reflection of increased neuronal activity. To identify whether activated cells were either cholinergic or noncholinergic, the PPT and laterodorsal tegmental nucleus (LDT) cells were immunostained for choline acetyltransferase (ChAT) in combination with pCREB or c-Fos. The results demonstrated that during high rapid eye movement sleep (HR, approximately 27%), significantly higher numbers of cells expressed pCREB and c-Fos in the PPT, of which 95% of pCREB-expressing cells were ChAT-positive. With HR, the numbers of pCREB-positive cells were also significantly higher in the medial pontine reticular formation (mPRF), pontine reticular nucleus oral (PnO), and dorsal subcoeruleus nucleus (SubCD) but very few in the locus coeruleus (LC) and dorsal raphe nucleus (DRN). Conversely, with low rapid eye movement sleep (LR, approximately 2%), the numbers of pCREB expressing cells were very few in the PPT, mPRF, PnO, and SubCD but significantly higher in the LC and DRN. The results of regression analyses revealed significant positive relationships between the total percentages of REM sleep and numbers of ChAT+/pCREB+ (Rsqr=0.98) cells in the PPT and pCREB+ cells in the mPRF (Rsqr=0.88), PnO (Rsqr=0.87), and SubCD (Rsqr=0.84); whereas significantly negative relationships were associated with the pCREB+ cells in the LC (Rsqr=0.70) and DRN (Rsqr=0.60). These results provide evidence supporting the hypothesis that during REM sleep, the PPT cholinergic neurons are active, whereas the LC and DRN neurons are inactive. More importantly, the regression analysis indicated that pCREB activation in approximately 98% of PPT cholinergic neurons, was caused by REM sleep. Moreover the results indicate that during REM sleep, PPT intracellular PKA activation and a transcriptional cascade involving pCREB occur exclusively in the cholinergic neurons.

Dysfunctional turning in Parkinson's disease.

PURPOSE: People with Parkinson's disease (PD) frequently freeze or fall turning: They turn slowly taking numerous steps. We aimed to describe more fully the differences observed on turning between people with and without PD, in particular the extent of left-right asymmetry and the correlations between turning and age, balance and PD severity, using a simple clinical test. METHOD: Twenty-eight people with PD (median age 71; median years since diagnosis eight) and 12 controls (median age 70) performed the video-based Standing Start 180 degrees Turn Test. We counted turning steps (n), evaluated turn time (sec), type and quality (0 - 5, based on independence, ground clearance, stability, continuity and posture) and calculated the 95% limits of left-right agreement. RESULTS: The groups differed (p < 0.004) on step count (medians 4.5 vs. 3), time (2.3 sec vs. 1.7 sec) and quality (4 vs. 5). In the PD group, 75% turned 'on-the-spot' and differences turning left and right were marked (e.g., 95% upper limit for step count 6.6). Among controls, 42% turned 'on-the-spot' and turning was symmetrical (e.g., 95% upper limit for step count 1.7). Step count was most closely correlated with self-assessed disability in PD (r = 0.67; p = 0.001) and with age among controls (r = 0.87; p = 0.001). CONCLUSIONS: People having difficulty turning are likely to have trouble with many everyday activities and thus may benefit from rehabilitation. Directional asymmetry in turning is easily identifiable and future studies should explore its diagnostic value.

The circumstances of falls among people with Parkinson's disease and the use of Falls Diaries to facilitate reporting.

PURPOSE: Falls are common in Parkinson's disease (PD). Falls Diaries are one way of recording fall frequency and the surrounding circumstances; completing them encourages recall, and their content focuses intervention. We reviewed the diaries completed by people with PD during a randomized controlled trial (RCT) of fall prevention to ascertain the key circumstances surrounding falls. METHOD: We asked independently mobile, cognitively intact people with a diagnosis of PD to maintain a Falls Diary throughout a six-month RCT. We sent monthly diary sheets on which to answer questions about the 'Location', 'Fall-related activity', 'Perceived cause', 'Landing' and 'Consequences' of every fall. We coded responses and counted frequencies. RESULTS: Of the 142 RCT participants (mean age 72 years; mean years since diagnosis 8), 135 completed the trial and their diary. We excluded 11 (8%) for missing data and/or unintelligible writing. The 124 remaining diaries recorded 639 falls: 80% happened at home, commonly in bedrooms, living areas, kitchens and gardens. Fallers had been ambulant in 45% of events, standing in 32% and transferring in 21%. Six 'activity-cause combinations' accounted for 55% of falls (tripping 13%; freezing, festination and retropulsion 11%; and postural instability when bending or reaching 9%, transferring 8%, walking 7% and washing or dressing 7%). Misjudgement and distraction played a part in 12% of falls described. CONCLUSIONS: Of over 600 falls surveyed, most happened at home, provoked by postural instability, tripping and freezing. Environmental adaptation and cognitive training should be trialled in falls prevention in PD, plus or minus traditional movement rehabilitation. Most participants completed Falls Diaries successfully. We advocate diary use, with follow-up interviews, in research and clinically. People with handwriting difficulty may require a typed diary, proxy diarist or interview.

Interference between balance, gait and cognitive task performance among people with stroke living in the community.

PURPOSE: To explore differences in cognitive-motor interference between people with stroke and controls when performing functional tasks and to compare dual task performance of stroke fallers and non-fallers. METHOD: Thirty-six people with stroke (mean age 66.5, SD 11.8, mean time since onset 16 months, range 7 - 56) and 24 controls (mean age 62.3, SD 11.61) performed balance and gait tasks in isolation and in conjunction with a cognitive task (remembering a seven item-shopping list). Three-dimensional movement analysis was used to assess anterior posterior (AP) and lateral (ML) sway; 5 m walk time, stride length and velocity. RESULTS: In the single task condition, people with stroke had greater AP sway, reduced velocity and stride length and a longer 5 m walk time than controls (p < 0.01). In the dual task condition, sway reduced and gait slowed in both groups (p < 0.01 for AP sway, stride length, velocity, walk time); only the increase in walk time was greater in people with stroke than in the controls (F = 4.2, p = 0.046). Cognitive performance was maintained during the balance trials but deteriorated during the dual task gait trials in people with stroke (p = 0.017). Similar trends were noted for fallers and non-fallers with stroke: Only group effects for stride length and velocity reached significance (p < 0.05) and only the reduction in stride length was significantly greater among fallers than non-fallers (F = 12.3, p = 0.001). CONCLUSIONS: People with stroke and controls employed similar strategies during the simultaneous performance of simple functional and silent cognitive tasks and maintained postural stability. Increased walk time and decreased cognitive recall were greater for people with stroke and reduced stride length distinguished fallers from non-fallers.

Developing methods to evaluate how people with Parkinson's Disease turn 180 degrees: an activity frequently associated with falls.

PURPOSE: To develop a test that identified fallers from their turning strategies, as people with Parkinson's Disease (PD) commonly fall turning. METHOD: We compared (1) Turn Types demonstrated when turning 180 degrees during the Timed Up and Go Test (TUG Test) by 19 non-fallers and 29 fallers (median age 71) and (2) Turn Types, Turning Steps, Heelstrike, Stability and the Use of Space and Support demonstrated when turning 180 degrees during an everyday activity by 15 non-fallers and 26 fallers (median age 75). Turns were rated from video by observers blinded to group. Inter-observer agreement was tested. RESULTS: Similar proportions of fallers and non-fallers demonstrated multiple-step Turn Types during the TUG Test (69% v 58%; p=0.433) and the everyday activity (66% vs. 46%; p=0.241). When turning, similar proportions of each group lacked Heelstrike, lost Stability and used the available Space and Support (p>0.7); Turning Step counts were also similar (p=0.891). Inter-observer agreement proved acceptable except for Turn Type during everyday activity (Kappa=0.46). CONCLUSIONS: The anticipated differences between fallers and non-fallers were not identified, perhaps obscured by insufficiently or overly challenging protocols and/or the compensations deployed by fallers. Further methodological development is needed in the analysis of fall-related activities with high-risk groups.

99mTc-glucarate for detection of isoproterenol-induced myocardial infarction in rats.

Infarct-avid radiopharmaceuticals are necessary for rapid and timely diagnosis of acute myocardial infarction. The animal model used to produce infarction implies artery ligation but chemical induction can be easily obtained with isoproterenol. A new infarct-avid radiopharmaceutical based on glucaric acid was prepared in the hospital radiopharmacy of the INCMNSZ. 99mTc-glucarate was easy to prepare, stable for 96 h and was used to study its biodistribution in rats with isoproterenol-induced acute myocardial infarction. Histological studies demonstrated that the rats developed an infarct 18 h after isoproterenol administration. The rat biodistribution studies showed a rapid blood clearance via the kidneys. Thirty minutes after 99mTc-glucarate administration the standardised heart uptake value S(h)UV was 4.7 in infarcted rat heart which is six times more than in normal rats. ROIs drawn over the gamma camera images showed a ratio of 4.4. The high image quality suggests that high contrast images can be obtained in humans and the 96 h stability makes it an ideal agent to detect, in patients, early cardiac infarction.

Regulation of cyclo-oxygenase-2.

Over the past three decades studies have been conducted to determine the role of prostaglandins in normal physiology and in certain diseases. Cyclo-oxygenase (COX) or prostaglandin endoperoxide synthase (Pghs) is required for the conversion of arachidonic acid to prostaglandins. Two isoforms of this enzyme have been identified which are referred to as COX-1 and COX-2. Under most circumstances, COX-1 is produced constitutively, whereas COX-2 can be induced by several physiological stimuli and is expressed at sites of inflammation. Although these isozymes catalyze identical reactions, they are often regulated by different signalling systems. The goal of this chapter is to provide a review of the role of cyclo-oxygenase in biology and disease, and to summarize the current understanding of mechanisms for the regulation of COX-2 expression.

A pilot study of attention deficits, balance control and falls in the subacute stage following stroke.

OBJECTIVES: To (1) identify and monitor changes in deficits of attention and balance in the subacute stage following stroke, (2) investigate fall events, (3) explore relationships between deficits of attention, balance and falling post stroke. DESIGN: A prospective observational study. SETTING: Hospitalized patients with stroke were recruited from a rehabilitation ward. SUBJECTS: Fourteen subjects were recruited, 13 subjects (age 21-80 years) completed all assessments. Ten had right and three had left hemispheric lesions. Eight subjects were male. MAIN OUTCOME MEASURES: Subjects were assessed on two occasions during a six-week period. Standardized tests were used to measure unilateral visual neglect, sustained and selective attention and balance. Fall histories were collected by chart review and semi-structured interview. RESULTS: At the initial assessment six subjects had sustained auditory attention deficit, eight had deficits of auditory selective attention, 12 had visual selective attention deficits and seven subjects presented with visual inattention. Scores for visual inattention and visual selective attention improved over time (p = 0.006, p = 0.026 respectively) as did scores for balance control (p = 0.001). Auditory selective attention scores at the first assessment were found to correlate with measures of balance (p < 0.01), subjects with normal attention scores achieved better balance scores. Four subjects fell at least once during the six weeks. Scores for attention and balance of fallers were not found to be significantly different from the scores of nonfallers. CONCLUSIONS: The sample size was small but high levels of attention deficit were identified. Findings suggest a weak or no relationship between attention deficits and falls. Further studies are required to explore the extent of attention deficits post stroke and its impact on balance control and falling.

Predicting fallers in a community-based sample of people with Parkinson's disease.

BACKGROUND: The risk of people with Parkinson's disease (PD) falling is greater than that of the general population but to date, disease-specific predictors of falling have not been identified. OBJECTIVES: To identify one or more features, which would predict individuals at risk of falling during a 3-month prospective follow-up study. METHOD: A battery of standardised tests administered in the home and the laboratory with a 3-month follow-up telephone interview. RESULTS: Sixty-three people with PD were recruited from GP practices. Eleven interview variables and six gait laboratory variables were used with subsamples (55 and 44 subjects, respectively) to fit predictive models for identifying future fallers. The number of falls in the previous year was the most important variable, without exception, to be selected as a predictor in various logistic regression models. A history of two or more falls had a sensitivity of 86.4% (95% CI 67.3-96.2%) and a specificity of 85.7% (95% CI 71.2-94.2%) in predicting falling in the next 3 months. CONCLUSION: Healthcare workers should be asking their patients with PD regularly and carefully about falling, and should consider instigating programmes of fall management for patients with PD who have fallen two or more times in the previous 12 months.

A community-dwelling sample of people with Parkinson's disease: characteristics of fallers and non-fallers.

BACKGROUND: people with Parkinson's disease often fall. OBJECTIVES: to report the frequency of falls and characteristics of fallers and non-fallers in a community-based sample of people with Parkinson's disease. METHOD: we administered a battery of standardized tests in the home and the laboratory. RESULTS: we recruited 63 people with Parkinson's disease through general practices. Forty (64%, 95% confidence interval 51-74%) had fallen in the previous 12 months. Many factors associated with falling in the general population were associated with Parkinson's disease fallers (e.g. use of multiple medication and greater physical disability). Fallers were more likely to be depressed and anxious than non-fallers. Condition-specific factors associated with falling included greater disease severity (although there were exceptions) and more marked response to levodopa treatment, including more dyskinesia and on-off phenomena. Fallers took more steps to complete a test of mobility. They also had a shorter functional reach and greater postural sway whilst completing a dual task than non-fallers. CONCLUSION: this community-based study confirms the high risk of falling in Parkinson's disease. Our results suggest that disease-specific factors contribute to the increased risk and that there is scope for specific therapeutic interventions.

Uptake of (188)Re-beta-naphthyl-peptide in cervical carcinoma tumours in athymic mice.

Radiolabelled somatostatin analogues have been used in diagnostic and therapeutic nuclear medicine to treat cancerous tumours. Lanreotide, a cyclic octapeptide, beta-naphthyl-peptide, with antiproliferative action on human small cell lung carcinoma was (188)Re labelled and characterised, and its biodistribution was studied in mice. Molecular modelling indicates that the lipophilic radiopharmaceutical might be an oxo-rhenium (V) penta-coordinated complex. The implanted human cervical tumour of epidermoid origin was positive for cytokeratins and Vimentin. Uptake of (188)Re-labelled peptide in the implanted tumour in athymic mice was 6.2+/-2.9% and was rapidly cleared via the hepatobiliary system. (188)Re-beta-naphthyl-peptide might be a potential therapeutic agent.

Role of cyclooxygenase inhibitors for the prevention of colorectal cancer.

Eicosanoids play an important role in numerous physiologic and pathophysiologic processes in the gastrointestinal tract, including maintenance of mucosal integrity, stimulation of mucus and electrolyte secretion, and inflammation. A rapidly growing body of evidence implicates COX-2 in colorectal carcinogenesis. COX-2 has been shown to alter cellular adhesion, apoptosis, and angiogenesis, contributing to its neoplastic potential. NSAIDs appear to attenuate this potential by mechanisms that are COX-2 dependent and independent. Several advances have been made in understanding the details of COX-2 regulation. The downstream effect of COX-2-dependent metabolites varies with the enzymatic machinery present in a particular cell, the level of COX activity, differences in location and types of prostaglandin receptors, and differences in signal transduction pathways. Further studies are needed to understand better these complex interactions, which may provide insight into the role of COX-2 in pathologic conditions, such as intestinal inflammation and colorectal cancer.

Deltoid triceps transfer and functional independence of people with tetraplegia.

STUDY DESIGN: Matched case control study. SETTING: Two regional spinal units - Salisbury, UK (surgical centre) and London, UK (control centre). OBJECTIVE: To compare the functional independence and wheelchair mobility of spinal cord injured subjects, post deltoid triceps transfer, with matched control subjects. METHODS: Two matched groups of subjects, with tetraplegia resulting in triceps paralysis, were studied. The surgical group consisted of five of the six patients who had previously undergone deltoid triceps transfer at Salisbury. The control group (n=6) had not undergone surgical intervention but were comparable with respect to level of lesion, age, age at injury and duration of disability. All subjects completed standardised assessments of activities of daily living (Functional Independence Measure - FIM) and wheelchair mobility (10 m push and figure of 8 push). Surgical subjects completed additional questions, regarding the perceived effects of surgery on function. RESULTS: It was not possible to demonstrate absolute functional differences with the chosen outcome measures in this small series of matched case controls. All surgical subjects cited specific functional improvements since surgery and recommended the procedure. However the FIM lacked sufficient sensitivity to detect these changes. CONCLUSION: Further investigation of the functional outcome of deltoid triceps transfer in tetraplegia is warranted. Development of more sensitive outcome measures would be useful.

The temporal course of expression of c-Fos and Fos B within the medial preoptic area and other brain regions of postpartum female rats during prolonged mother--young interactions.

Maternal behavior is associated with an increase in the expression of c-Fos and Fos B within neurons of the medial preoptic area (MPOA) and ventral bed nucleus of the stria terminalis (vBST). Whether this increase wanes as the duration of mother-young interaction increases is unknown. By varying the length of mother-young interactions in postpartum rats, the authors found that within the MPOA/vBST, the levels of both c-Fos and Fos B, once elevated, remained significantly above control levels through 47 hr of pup exposure. The persistence of c-Fos and Fos B within the MPOA/vBST of females that remained with pups was almost unique in that only one other neural area, the anterior magnocellular part of the paraventricular hypothalamic nucleus, showed such a response. Because MPOA/vBST neurons are essential for maternal behavior, the results suggest that c-Fos and Fos B expression within these regions may be necessary to maintain their normal functional activity.

Fall events described by people with Parkinson's disease: implications for clinical interviewing and the research agenda.

BACKGROUND AND PURPOSE: The aim of this study was to describe the terminology used by people with Parkinson's disease (PD) when recounting falls and near-misses (fall events) and to identify the surrounding circumstances. METHOD: This cross-sectional study (part of an investigation identifying risk factors for falling in PD) utilized structured interviews about falling, conducted in participants' homes. Content analysis of participants' descriptions of events was performed. Fifty-five independently mobile, community-dwelling people with PD, identified via general practices in Southampton took part in the study. RESULTS: Mean participant age was 71.5 years (SD = 7.6 years); mean time since diagnosis was 3.6 years (SD = 2.3 years). Thirty-four participants (62%) reported having fallen and 41 (75%) reported having nearly fallen in the previous 12 months. Recounting events, participants mentioned the location, frequency, process and landing, their activity and fall-avoidance. Falls at home, tripping, events arising when turning, falling forward, frequent near-misses and unsuccessful restoration of balance were commonly described. CONCLUSIONS: Frequent recounting of processes, locations and landings suggest these details are memorable and easily recalled. Eliciting the activities during which events occurred, their frequency and avoidance-strategies, may necessitate probing by interviewers. An interview schedule is proposed. Aspects common to falls and near-misses, particularly turning, suggest a natural progression of activity-related falls.

Transport of [3H]losartan across isolated perfused rabbit proximal tubule.

The transport of the angiotensin II receptor antagonist losartan and its interaction with organic anion transport were examined in the isolated perfused rabbit proximal tubule. Losartan reversibly inhibited the secretion of para-aminohippurate (PAH) in a concentration-dependent manner (IC50 = 15 +/- 0.5 microM). Other angiotensin II receptor antagonists also inhibited PAH secretion with similar potencies: eprosartan, 11 +/- 2.3 microM; irbesartan, 17 +/- 2.2 microM; and valsartan 3 +/- 0.6 microM. [3H]Losartan was secreted by the proximal tubule by a saturable and probenecid-sensitive mechanism. The affinity of losartan for the organic anion transporter (Km = 12.3 +/-1.8 microM) was significantly greater than that of PAH (Km = 88.5 +/- 10.7 microM). [3H]Losartan secretion was stimulated in the presence of alpha-ketoglutarate, suggesting that losartan, like PAH, enters the cell in exchange for a dicarboxylate. These results demonstrate that losartan and probably other nonpeptide angiotensin II receptor antagonists are secreted by an organic anion transporter that is similar to, if not identical with, the classic PAH transporter.

Morphometric studies of the aged hippocampus: I. Volumetric analysis in behaviorally characterized rats.

The present investigation examined the structural integrity of the aged hippocampus by using computer-aided morphometry to quantify the volume of principal hippocampal circuits in young, mature adult, and aged Long-Evans rats. A key feature of the experimental design was that the status of hippocampal-dependent learning and memory was documented prior to histologic evaluation. The following regions, which were visualized by using Timm staining, were included in the analysis: 1) outer portions of the dentate gyrus molecular layer (OML) innervated by the lateral entorhinal cortex, 2) middle portions of the molecular layer (MML) that receive input from the medial entorhinal cortex, 3) the commissural/associational zone (IML) immediately adjacent to the granule cell layer, and 4) the hilus and mossy fiber projection to the CA3 pyramidal cell field (MF). To identify morphometric changes that emerge during the same segment of the life span as age-related learning impairment, analysis of the volumetric results focused on comparisons between the mature adult group and the aged group. Among the individual regions that were analyzed, age-related decreases in total volume were restricted to the MML. This effect, however, occurred against a background of other, subtle changes that, together, reflected substantial reorganization in the normal balance of hippocampal circuitry. Age-related decreases in the proportion of the molecular layer (ML) that comprises the MML were accompanied by a corresponding increase in relative IML volume. The ratio between the volumes of the MML and the MF also displayed significant age-related decline. Overall, aging affected septal levels of the hippocampus disproportionately, and, with the exception of MML/MF volume ratio, the temporal hippocampus was spared. Finally, the status of spatial learning among the aged animals correlated selectively with decreases in the MML/ML and MML/MF ratios. These results demonstrate that the effects of aging are regionally selective and circuit specific, and they suggest that connectional reorganization may contribute to age-related decline in the computational functions of the hippocampus.