The role of individuality in collective group movement.

How different levels of biological organization interact to shape each other's function is a central question in biology. One particularly important topic in this context is how individuals' variation in behaviour shapes group-level characteristics. We investigated how fish that express different locomotory behaviour in an asocial context move collectively when in groups. First, we established that individual fish have characteristic, repeatable locomotion behaviours (i.e. median speeds, variance in speeds and median turning speeds) when tested on their own. When tested in groups of two, four or eight fish, we found individuals partly maintained their asocial median speed and median turning speed preferences, while their variance in speed preference was lost. The strength of this individuality decreased as group size increased, with individuals conforming to the speed of the group, while also decreasing the variability in their own speed. Further, individuals adopted movement characteristics that were dependent on what group size they were in. This study therefore shows the influence of social context on individual behaviour. If the results found here can be generalized across species and contexts, then although individuality is not entirely lost in groups, social conformity and group-size-dependent effects drive how individuals will adjust their behaviour in groups.

Burden of illness and factors associated with duration of illness in clinical campylobacteriosis.

A population-based study investigated the burden of illness, including the duration of illness associated with laboratory-confirmed cases of campylobacteriosis in two health unit areas. Questionnaire data were collected for 250 cases. The median duration of illness was 8 days and 66% of cases reported symptoms of moderate severity or greater. A Cox proportional hazards model identified antimicrobial use factors associated with a significantly increased rate of symptom resolution (shorter duration of illness): macrolides for less than the recommended number of days, ciprofloxacin for at least 3 days, and antimicrobials not recommended for campylobacteriosis. The impact of antimicrobial use was consistent regardless of when, during the course of illness, the antimicrobial use began. The effectiveness of ciprofloxacin in these results may be due to the low prevalence of resistance to ciprofloxacin in isolates from this study. The effect of antimicrobials not recommended for campylobacteriosis should be further investigated.

Hemispheric asymmetry of electrocortical responses to speech stimuli.

In a group of normal adults, averaged cortical evoked responses to natural speech stimuli were recorded from scalp electrodes placed symmetrically over the two cerebral hemispheres at frontal, Rolandic, and temporoparietal leads. The amplitude of the most prominent component was consistently larger in left hemisphere derivations, with the major hemisphere difference observed in the temporoparietal records. These electrophysiological measures may be sensitive indicators of hemispheric specialization of function.

Conditioned inhibition: selective response of single units.

Single cell activity and local field potentials in parastriate cortex of cats and rabbits were studied during a Pavlovian discrimination procedure. Cell activity was selectively modified; conditioned changes occurred in response either to the reinforced stimulus or to the unreinforced one, but not to both. Cells exhibiting conditioned alteration in response to the unreinforced stimulus are thought to participate in specialized circuits mediating conditioned inhibition.

Baseline differences between vascular cognitive impairment no dementia reverters and non-reverters.

BACKGROUND: The underlying factors of reversion from cognitive impairment to normal cognitive functioning in stroke are not well understood. We compare demographic, cognitive and imaging factors in Vascular Cognitive Impairment, No Dementia (Vascular CIND) patients who revert to normal cognitive functioning to Vascular CIND patients who do not revert. METHODS: Thirty-one ischaemic stroke patients, who met classification criteria for Vascular CIND, were >49.5 years old, met NINDS stroke criteria, and were free from additional neurological illness, completed baseline and 1-year examinations. Forty-five per cent of the Vascular CIND participants reverted to no cognitive impairment at 1-year follow-up examination. RESULTS: There was greater cognitive impairment in non-reverters on a summary score spanning several neuropsychological domains and on psychomotor and working memory summary scores. There were no differences on demographic factors or in stroke severity between reverters and non-reverters. Structural MRI analyses revealed no baseline differences in number of strokes, stroke volume or stroke location. However, there was greater frontal white matter hyperintensity load in the non-reverter group. CONCLUSIONS: These results suggest that Vascular CIND reversion may be a function of a combination of baseline neuropsychological function and location of cerebrovascular disease.

The 'molecularly unstratified' patient: a focus for moral, psycho-social and societal research.

The biomedical paradigm of personalised precision medicine - identification of specific molecular targets for treatment of an individual patient - offers great potential for treatment of many diseases including cancer. This article provides a critical analysis of the promise, the hype and the pitfalls attending this approach. In particular, we focus on 'molecularly unstratified' patients - those who, for various reasons, are not eligible for a targeted therapy. For these patients, hope-laden therapeutic options are closed down, leaving them left out, and left behind, bobbing untidily about in the wake of technological and scientific 'advance'. This process creates a distinction between groups of patients on the basis of biomarkers and challenges our ability to provide equitable access to care for all patients. In broadening our consideration of these patients to include the research ecosystem that shapes their experience, we hypothesise that the combination of immense promise with significant complexity creates particular individual and organisational challenges for researchers. The novelty and complexity of their research consumes high levels of resource, possibly in parallel with undervaluing other 'low hanging fruit', and may be challenging current regulatory thinking. We outline future research to consider the societal, psycho-social and moral issues relating to 'molecularly unstratified' patients, and the impact of the drive towards personalisation on the research, funding, and regulatory ecosystem.

Pricing and reimbursement experiences and insights in the European Union and the United States: Lessons learned to approach adaptive payer pathways.

Earlier patient access to beneficial therapeutics that addresses unmet need is one of the main requirements of innovation in global healthcare systems already burdened by unsustainable budgets. "Adaptive pathways" encompass earlier cross-stakeholder engagement, regulatory tools, and iterative evidence generation through the life cycle of the medicinal product. A key enabler of earlier patient access is through more flexible and adaptive payer approaches to pricing and reimbursement that reflect the emerging evidence generated.

A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma.

Twenty-two patients with advanced colorectal carcinoma were enrolled in this study. Ten patients had received prior chemotherapy that included the combination of fluorouracil (5-FU) and leucovorin (LV). All patients required subcutaneous port insertion and portable external infusion pumps to allow outpatient treatment. 5-FU (2,600 mg/m2) was administered concurrently with LV (500 mg/m2) over 24 hours of continuous infusion. The mean steady-state plasma concentration of 5-FU was 10 mumol/L (range, 7 to 14 mumol/L). The 5-FU dose was based on our previous phase I study, in which maximum-tolerated dose (MTD) of 5-FU was determined to be 2,600 mg/m2 in combination with a fixed dose of LV at 500 mg/m2. The treatment was repeated weekly. Twenty-two patients received a total of 560 courses of treatment. Eleven instances of grade 2-3 toxicity were observed: diarrhea (five), stomatitis (three), hand/foot syndrome (three). The overall objective response was 45% (10 of 22) and among previously untreated patients was 58%. Three of the responders achieved complete response (CR), with lung and liver as the metastatic sites. The median duration of survival for the previously untreated patients was not reached at 22 months, and was 10 months for the previously treated patients. These results suggest that short-term infusional therapy of 5-FU and LV in patients with advanced metastatic colorectal cancer generates acceptable toxicity, with equivalent or superior survivability in previously treated and untreated patients versus alternative methods of administration of the two agents.

Spatial memory in aged rats is related to PKCgamma-dependent G-protein coupling of the M1 receptor.

In the present study, individual differences in spatial memory in aged Fischer 344 (F344) rats were associated with the extent of G-protein coupling of the M1 muscarinic receptor and the dendritic-to-somal ratio of hippocampal PKCgamma (d/sPKCgamma) immunogenicity. Following testing in the eight-arm radial maze task, 7 young and 13 aged rat brains were sectioned through the dorsal hippocampal formation (HF). G-protein coupling of the M1 receptor was assessed autoradiographically using competition binding studies in the presence and absence of a G-protein uncoupler to determine high (K(H)) and low (K(L)) affinity states for agonist in the HF, neocortex, and amygdala. In aged animals, a relationship between choice accuracy in the maze and K(H), a measure of M1 receptor-G-protein coupling was seen in the dentate gyrus, CA3, CA1, and neocortex. Furthermore, choice accuracy and d/sPKCgamma immunogenicity showed a significant relationship in CA1. Lastly, a correlation was seen in the CA1 of aged animals between K(H) and d/sPKCgamma. These relationships did not hold for the amygdala. Thus, individual differences in a naturally occurring age-dependent disruption of cholinergic-PKCgamma signal transduction is associated with spatial memory dysfunction.

Age-dependent alterations in hippocampal synaptic plasticity: relation to memory disorders.

In this paper, we review the evidence indicating that the common disturbance in recent memory associated with aging is a consequence of functional and structural impairment in the hippocampal formation. In the Fischer 344 rat, an experimental model of the human age-related memory disorder was developed. The majority of aged rats of this strain show impaired performance in the 8-arm radial maze in a manner typical of young rats with bilateral hippocampal lesions. Aged animals also exhibit rapid decay of LTP and slower kindling of the perforant path-dentate synapse. Furthermore, quantitative morphometric analysis of the hippocampal synaptic architecture revealed that aged, memory-impaired rats had a specific loss of perforated axospinous synapses in the middle third of the dentate gyrus molecular layer; the extent of loss was directly related to the degree of memory dysfunction. Most important was the fact that the electrophysiological and morphological abnormalities did not appear in equally old animals with good memory.

MRI of human entorhinal cortex: a reliable protocol for volumetric measurement.

A new protocol for measuring the volume of the entorhinal cortex (EC) from magnetic resonance images (MRI) was developed specifically to measure the EC from oblique coronal sections used in hippocampal volumetric studies. The relative positions of the anatomic landmarks demarcating EC boundaries were transposed from standard coronal sections to oblique ones. The lateral EC border, which is the most controversial among anatomists, was defined in a standard and conservative manner at the medial edge of the collateral sulcus. Two raters measured the EC twice for 78 subjects (healthy aged individuals, very mild AD patients, and elderly patients who did not meet criteria for dementia) to study intra- and inter-rater reproducibility and reliability of measurements. The level of accuracy achieved (coefficients of reproducibility of 1.40-3.86%) and reliability of measurements (intraclass correlation coefficients of 0.959-0.997) indicated that this method provides a feasible tool for measuring the volume of the EC in vivo.

Alzheimer's disease: in vivo detection of differential vulnerability of brain regions.

The severe cognitive impairment during the later stages of Alzheimer's disease is usually preceded by a selective disturbance in the ability to remember new experiences. With quantitative, high-resolution magnetic resonance imaging techniques, it is now possible to determine, in vivo, differences in the pattern of anatomical changes that might reflect behavioral symptomatology during different stages of the disease. In the present investigation, magnetic resonance imaging examinations were carried out in aged controls and in clinically diagnosed Alzheimer's disease patients who were divided into three groups based upon dementia severity. Atrophy of the hippocampal formation, a region important for memory function, was observed even in Alzheimer's disease patients with the mildest dementia. With more prominent dementia, atrophy extended to the parahippocampal gyrus and the temporal neocortex.

MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer's disease.

With high resolution, quantitative magnetic resonance imaging (MRI) techniques, it is now possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In this study, we compared MRI-derived entorhinal and hippocampal volume in healthy elderly controls, patients who presented at the clinic with cognitive complaints, but did not meet criteria for dementia (non-demented), and patients with very mild AD. The two patient groups differed significantly from controls in entorhinal volume, but not from each other; in contrast, they differed from each other, as well as from controls, in hippocampal volume, with the mild AD cases showing the greatest atrophy. Follow-up clinical evaluations available on 23/28 non-demented patients indicated that 12/23 had converted to AD within 12-77 months from the baseline MRI examination. Converters could be best differentiated from non-converters on the basis of entorhinal, but not hippocampal volume. These data suggest that although both the EC and hippocampal formation degenerate before the onset of overt dementia, EC volume is a better predictor of conversion.

Synapse restructuring associated with the maintenance phase of hippocampal long-term potentiation.

Synapses in the middle molecular layer of the rat dentate gyrus were analyzed by electron microscopy during the maintenance phase of long-term potentiation (LTP). LTP was induced by high-frequency stimulation of the medial perforant path carried out on each of 4 consecutive days. The dentate gyrus was examined electron microscopically 13 days following the fourth stimulation. At this time point, synaptic responses were still significantly enhanced relative to baseline, although the extent of their potentiation was lower than 1 hour after the last high-frequency stimulation. Stimulated, but not potentiated, rats served as controls. Using the stereological double disector method, estimates of the number of different morphological types of synapses per postsynaptic neuron were obtained. The number of asymmetrical axodendritic synapses increased (by 28%) during LTP maintenance, whereas the number of other synaptic types was not significantly altered. Our previous work demonstrated that the induction of LTP is followed by a selective increase in the number of axospinous perforated synapses with multiple, completely partitioned, transmission zones. Thus, the induction and maintenance phases of LTP are characterized by different structural synaptic alterations. These alterations may be related to each other as indicated by another finding of the present study regarding the existence of perforated synapses that appear to be transitional between axospinous and axodendritic junctions. This suggests a model of structural synaptic plasticity associated with LTP in which some axospinous perforated synapses increase in numbers shortly after the induction of LTP and are then converted into axodendritic ones during LTP maintenance.

A 'stress' test for memory dysfunction. Electrophysiologic manifestations of early Alzheimer's disease.

Long-latency event-related potentials (P300) were assessed in patients with early probable Alzheimer's disease (AD), age-matched controls, and young adults during a task that imposed various degrees of demand on memory. Although patients with AD did not differ from age-matched controls when one item had to be remembered, their P300 potential was dramatically reduced in amplitude or absent with increasing memory load. Aged controls did not differ from young adults on this measure. P300 latency, however, did not differentiate patients with AD. Thus, electrophysiological abnormalities detected in the context of mnemonic demand may provide a sensitive marker of the early stages of probable AD.

Tailored anterior temporal lobectomy. Relation between extent of resection of mesial structures and postsurgical seizure outcome.

OBJECTIVE: The purpose of this study was to assess the relationship between the extent of resection of mesial temporal structures and postsurgical seizure outcome in a group of patients who had undergone a tailored anterior temporal lobectomy. METHODS: Twenty-four patients with unilateral interictal and ictal foci restricted to anterior/mesial temporal regions underwent resection of mesial and temporal lateral structures, the extent of which was tailored by intraoperative electrocorticographic findings and functional mapping of eloquent cortex. The extent of resection was determined with postoperative magnetic resonance imaging scans, using a semiquantitative method, based on a 20-compartment model of the temporal lobe. The magnetic resonance imaging scans were rated by three investigators blinded to seizure outcome. Follow-up period ranged between 18 months and 5 years. RESULTS: Amygdala and hippocampus were spared in six patients; nine patients had a partial to total resection of amygdala, eight patients had a resection of amygdala and the anterior third of the hippocampus, and one patient underwent resection of amygdala and anterior two thirds of hippocampus. Twenty-one of the 24 patients were seizure free (Engel's class I) and three had rare seizures (Engel's class II). Among these three patients, one had a resection of amygdala; one had resection of amygdala and anterior third of hippocampus; while in the third patient, mesial structures were spared. CONCLUSION: These data suggest that in patients with an anterotemporal seizure focus, the sparing or limited resection of amygdala and/or hippocampus is not necessarily associated with a poor seizure outcome, as had been previously suggested, provided that the decision not to resect is based on the absence of epileptiform activity during intraoperative electrocorticography or during recordings with depth electrodes.

The importance of postoperative radiation therapy in multimodality management of locally advanced breast cancer: a phase II trial of neoadjuvant MVAC, surgery, and radiation.

PURPOSE: To determine the impact of postoperative radiation on locoregional relapse and overall survival rate in a multimodality protocol for locally advanced breast cancer (LABC). MATERIAL AND METHODS: Of the patients entered in the protocol, 55 were evaluable. Treatment consisted of: neoadjuvant MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) until a maximum response had been achieved; modified radical mastectomy; 6 courses of postoperative adjuvant MVAC chemotherapy, and chest wall irradiation (CWXRT). Multivariate analysis of locoregional response and overall survival was done. RESULTS: Of the total, 42 patients received chest wall radiation; 28 of these also received radiation to regional lymph nodes. Chest wall doses ranged from 45 Gy to 50.4 Gy to the whole chest wall, with 31 patients receiving an additional chest-wall boost. The incidence of locoregional relapse with and without radiation was 7% vs. 31%, respectively (p = 0.026). An overall survival benefit was seen in those receiving radiation, with a mean overall survival of 50 months vs. 20 months, and a 3-year overall survival of 88% vs. 46% with and without radiation, respectively (p = 0.003). Multivariate analysis showed that overall survival was affected by the presence of pathological CR (p = .047), the number of pre-operative chemotherapy cycles (p = .036) and whether or not they received radiation (p = 0.003). Neither the interval between surgery and radiation, technique of radiation, nor radiation modality significantly affected local control. CONCLUSION: The significant improvement in local regional control and overall survival with the addition of radiation suggests that radiation should be an integral part of multimodality management of locally advanced breast cancer.

Phase I study of high dose 5-fluorouracil and high dose Leucovorin with low dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies.

Twenty-eight patients with refractory advanced malignancies were treated with a 24 hr infusion of 5-fluorouracil (5-FU), Leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable for the assessment of toxicity and anti-tumor activity. PALA was administered as intravenous bolus over 15 min at a fixed dose, 250 mg/m2 24 hr before the start of 5-FU and LV infusions. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 2600 mg/m2. LV was administered in a fixed dose of 500 mg/m2 concurrently with 5-FU over a 24-hr period. The course was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among dose-limiting toxic effects. Other toxicities observed were hand-foot syndrome, hair loss of scalp/eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. Maximum tolerated dose (MTD) of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated at 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose de-escalation, a majority of whom contained 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients had been previously treated. Eight patients achieved a partial response, all of whom were previously treated, except three patients. A complete response was observed in a patient with pancreatic carcinoma, previously untreated. Overall response rate for the patients who were treated at the 5-FU dose of 2100 mg/m2 or 2600 mg/m2 is 9 of 18 patients (50%).

Age-dependent deficits in spatial memory are related to impaired hippocampal kindling.

Fischer 344 rats, 3 and 26 months of age, were first tested in an eight-arm spatial maze to assess memory function behaviorally. The same animals were then subjected to hippocampal kindling to examine alterations in neuronal plasticity as a function of aging. The results indicated that spatial memory was poorer and hippocampal kindling slower in aged rats than in young ones. Furthermore, there was a striking positive relation between performance in the eight-arm spatial maze and speed of kindling. This finding suggests that age-related deficits in spatial memory and hippocampal kindling reflect decreased efficacy of synaptic transmission in a common neuroanatomical substrate.

From healthy aging to early Alzheimer's disease: in vivo detection of entorhinal cortex atrophy.

Using quantitative structural MRI protocols, we examined the effects of age on alterations in entorhinal cortex (EC) volume. The left EC was found to be smaller than the right in both young and healthy aged subjects. More importantly, the right EC, but not the left, was significantly smaller in elderly participants compared to young controls. In an attempt to determine the earliest sites of involvement in mild and incipient Alzheimer's disease (AD), we compared entorhinal and hippocampal volume in (1) healthy elderly controls, (2) patients with very mild AD, and (3) elderly patients who were evaluated for cognitive complaints, but did not meet criteria for dementia. Both patient groups differed from controls in EC volume, but not from each other. In contrast, the two patient groups differed in hippocampal volume from controls, as well as from each other, with the mild AD cases showing the greatest atrophy. These results suggest that degeneration of the EC and hippocampal formation occurs before the onset of overt dementia. In fact, follow-up clinical evaluations available on 23 of 28 nondemented patients indicated that 12 of 23 had converted to AD. Converters could be best differentiated from nonconverters on the basis of entorhinal volume.