SEM-microphotogrammetry, a new take on an old method for generating high-resolution 3D models from SEM images.

The method we present here uses a scanning electron microscope programmed via macros to automatically capture dozens of images at suitable angles to generate accurate, detailed three-dimensional (3D) surface models with micron-scale resolution. We demonstrate that it is possible to use these Scanning Electron Microscope (SEM) images in conjunction with commercially available software originally developed for photogrammetry reconstructions from Digital Single Lens Reflex (DSLR) cameras and to reconstruct 3D models of the specimen. These 3D models can then be exported as polygon meshes and eventually 3D printed. This technique offers the potential to obtain data suitable to reconstruct very tiny features (e.g. diatoms, butterfly scales and mineral fabrics) at nanometre resolution. Ultimately, we foresee this as being a useful tool for better understanding spatial relationships at very high resolution. However, our motivation is also to use it to produce 3D models to be used in public outreach events and exhibitions, especially for the blind or partially sighted.

Ca2+ transients are not required as signals for long-term neurite outgrowth from cultured sympathetic neurons.

A method for clamping cytosolic free Ca2+ ([Ca2+]i) in cultures of rat sympathetic neurons at or below resting levels for several days was devised to determine whether Ca2+ signals are required for neurite outgrowth from neurons that depend on Nerve Growth Factor (NGF) for their growth and survival. To control [Ca2+]i, normal Ca2+ influx was eliminated by titration of extracellular Ca2+ with EGTA and reinstated through voltage-sensitive Ca2+ channels. The rate of neurite outgrowth and the number of neurites thus became dependent on the extent of depolarization by KCl, and withdrawal of KCl caused an immediate cessation of growth. Neurite outgrowth was completely blocked by the L type Ca2+ channel antagonists nifedipine, nitrendipine, D600, or diltiazem at sub- or micromolar concentrations. Measurement of [Ca2+]i in cell bodies using the fluorescent Ca2+ indicator fura-2 established that optimal growth, similar to that seen in normal medium, was obtained when [Ca2+]i was clamped at resting levels. These levels of [Ca2+]i were set by serum, which elevated [Ca2+]i by integral of 30 nM, whereas the addition of NGF had no effect on [Ca2+]i. The reduction of [Ca2+]o prevented neurite fasciculation but this had no effect on the rate of neurite elongation or on the number of extending neurites. These results show that neurite outgrowth from NGF-dependent neurons occurs over long periods in the complete absence of Ca2+ signals, suggesting that Ca2+ signals are not necessary for operating the basic machinery of neurite outgrowth.

Antipsychotics and cognitive decline in Alzheimer's disease: the LASER-Alzheimer's disease longitudinal study.

OBJECTIVE: To investigate in a longitudinal cohort of people with Alzheimer's disease whether taking antipsychotics is associated with more rapid cognitive deterioration. METHOD: From a sample of 224 people with Alzheimer's disease recruited as epidemiologically representative, those taking antipsychotic drugs for more than 6 months were compared with those who were not, in terms of change in three measures of cognition. The effects of potential mediators and confounders (demographic factors, neuropsychiatric symptoms, cognitive severity and cholinesterase inhibitors) were also examined. RESULTS: No significant difference was observed in cognitive decline between those taking antipsychotics (atypical or any) and others on any measure of cognition. The only predictor of more cognitive decline was greater baseline cognitive severity (B = 3.3, 95% confidence interval 0.6 to 6.1, t = 2.4, p<0.05). Although mortality was higher in those treated with antipsychotics, this reflected their greater age and severity of dementia. The results were the same when the whole cohort was included rather than the select group with potential to change who had been taking antipsychotics continuously. CONCLUSIONS: In this, the first cohort study investigating the effects of atypical antipsychotics on cognitive outcome in Alzheimer's disease, those taking antipsychotics were no more likely to decline cognitively over 6 months. Although clinicians should remain cautious when prescribing antipsychotic drugs to people with Alzheimer's disease, any increase in cognitive deterioration is not of the magnitude previously reported. There is a need for cohort studies that follow up patients from first prescription in clinical practice for a period of months rather than weeks to determine "real-life" risks and benefits.

Issues in data monitoring and interim analysis of trials.

OBJECTIVES: To address issues about data monitoring committees (DMCs) for randomised controlled trials (RCTs). DATA SOURCES: Electronic databases. Handsearching of selected books. Personal contacts with experts in the field. REVIEW METHODS: Systematic literature reviews of DMCs and small group processes in decision-making; sample surveys of: reports of RCTs, recently completed and ongoing RCTs and policies of major organisations involved in RCTs; case studies of four DMCs; and interviews with experienced DMC members. All focused on 23 prestated questions. RESULTS: Although still a minority, RCTs increasingly have DMCs. There is wide agreement that nearly all trials need some form of data monitoring. Central to the role of the DMC is monitoring accumulating evidence related to benefit and toxicity; variation in emphasis has been reflected in the plethora of names. DMCs for trials performed for regulatory purposes should be aware of any special requirements and regulatory consequences. Advantages were identified for both larger and smaller DMCs. There is general agreement that a DMC should be independent and multidisciplinary. Consumer and ethicist membership is controversial. The chair is recognised as being particularly influential, and likely to be most effective if he or she is experienced, understands both statistical and clinical issues, and is facilitating in style and impartial. There is no evidence available to judge suggested approaches to training. The review suggested that costs should be covered, but other rewards must be so minimal as to not affect decision-making. It is usual to have a minimum frequency of DMC meetings, with evidence that face-to-face meetings are preferable. It is common to have open sessions and a closed session. A report to a DMC should cover benefits and risks in a balanced way, summarised in an accessible style, avoiding excessive detail, and be as current as possible. Disadvantages of blinded analyses seem to outweigh advantages. Information about comparable studies should be included, although interaction with the DMCs of similar ongoing trials is controversial. A range of formal statistical approaches can be used, although this is only one of a number of considerations. DMCs usually reach decisions by consensus, but other approaches are sometimes used. The general, but not unanimous, view is that DMCs should be advisory rather than executive on the basis that it is the trial organisers who are ultimately responsible for the conduct of the trial. CONCLUSIONS: Some form of data monitoring should be considered for all RCTs, with reasons given where there is no DMC or when any member is not independent. An early DMC meeting is helpful, determining roles and responsibilities; planned operations can be agreed with investigators and sponsors/funders. A template for a DMC charter is suggested. Competing interests should be declared. DMC size (commonly three to eight people) is chosen to optimise performance. Members are usually independent and drawn from appropriate backgrounds, and some, particularly the chair, are experienced. A minimum frequency of meetings is usually agreed, with flexibility for more if needed. The DMC should understand and agree the statistical approach (and guidelines) chosen, with both the DMC statistician and analysis statistician competent to apply the method. A DMC's primary purpose is to ensure that continuing a trial according to its protocol is ethical, taking account of both individual and collective ethics. A broader remit in respect of wider ethical issues is controversial; arguably, these are primarily the responsibility of research ethics committees, trial steering committees and investigators. The DMC should know the range of recommendations or decisions open to it, in advance. A record should be kept describing the key issues discussed and the rationale for decisions taken. Errors are likely to be reduced if a DMC makes a thorough review of the evidence and has a clear understanding of how it should function, there is active participation by all members, differences are resolved through discussion and there is systematic consideration of the various decision options. DMCs should be encouraged to comment on draft final trial reports. These should include information about the data monitoring process and detail the DMC membership. It is recommended that groups responsible for data monitoring be given the standard name 'Data Monitoring Committee' (DMC). Areas for further research include: widening DMC membership beyond clinicians, trialists and statisticians; initiatives to train DMC members; methods of DMC decision-making; 'open' data monitoring; DMCs covering a portfolio of trials rather than single trials; DMC size and membership, incorporating issues of group dynamics; empirical study of the workings of DMCs and their decision-making, and which trials should or should not have a DMC.

The neuropathological findings in irreversible coma. A critque of the "respirator".

1. Postmortem examinations were made on 240 of the 459 cases succumbing (52 percent of the deaths) in the Collaborative Study on Cerebral Survival; the central nervous system was examined in 226 cases. 2. The autopsy was performed on an average of 15.3 hours after death. 3. The mean weight of the brains was 1450 plus or minus 196 grams; the mean weight of the brains of patients on whom resuscitation was stopped, presumably on the basis of "cerebral death," was greater than that of the patients succumbing to cardiac failure. There was a tendency for the brain to increase in weight about 24 hours after the initiation of resuscitative measures. At that time, swelling, discoloration, softening, congestion, and brain herniations also became more prominent. 4. On the basis of a survey of American neuropathologists and the data from this study, the entity commonly termed "respirator brain" may be confirmed. This is a dynamic process that is complicated by concurrent postmortem changes. The respirator brain requires time (approximately 24 hours) for maturation; many patients die a cardiac death during the metamorphosis. If the patient survives for 3 to 4 days, the percentage dying with typical respirator brains is less, and more patients have electroencephalograms with biological activity. 5. The following clinical factors tend to be associated with an increased number of respirator brains: A. Cerebral trauma B. Subnormal body timperature C. Low systolic blood pressure D. Dilated pupils E. Pupils unresponsive to light F. Absence of cephalic reflexes G. Electrocerebral Silence (ECS) 6. The following factors have no apparent effect on the number of respirator brains or tend to be associated with fewer respirator brains: A. Severe drug intoxications B. Small reacting pupils C. Medications D. Presence of spinal reflexes E. Presence of biological activity (BA) in the electroencephalogram 7. A set of common criteria for a respirator brain was used to test the following: A. The local and consultant neuropathologist's diagnosis of respirator brain B. The significance of critical perfusion pressure and critical oxygen tension in respirator brain C. The role of cardiac output in the production of a respirator brain 8. Since a respirator brain is an imperfectly defined entity, an exact correlation with any combination of clinical and EEG findings could not be expected. The use of a standardized measurement of CBF seems a logical and promising confirmatory test for respirator brain.

The prediction of posttraumatic epilepsy. A mathematical approach.

Simple mathematical equations can be used to estimate the probability of posttraumatic seizures. Risk factors and time since the injury are taken into consideration in the calculations. The equations are based on a constant probability model derived from published data. When these formulae are applied to data from a variety of published studies, the predicted incidence of posttraumatic epilepsy based on the mathematical model agrees well with the incidence observed in the study groups.

The fate of World War II veterans with posttraumatic seizures.

Of 244 men who, as the result of a brain wound sustained in World War II, had had one or more convulsive seizures, 101 have died. Except for men who succumbed in the first decade of complications of the wounding--infection, systemic or mental disease, status epilepticus, etc--the cause of death was similar to that of men of similar age in the general population. Of the men whose status is known, 74% have had no unconscious attacks in the past ten years or in the ten years before their death. The absence of seizures is not related to the continued ingestion of anticonvulsant medication. Approximately 25% of the men have had varying degrees of mental deterioration. The death rate of men with posttraumatic epilepsy is higher than that of normal men. Wounds of the right cerebral hemisphere seem to shorten the life span more than similar injuries of the left hemisphere.

Epidemiology of brain tumors: the national survey of intracranial neoplasms.

A national survey, based on a probability sample of patients admitted to short-term hospitals in the United States during 1973 to 1974 with a discharge diagnosis of an intracranial neoplasm, was conducted in 157 hospitals. The annual incidence was estimated at 17,000 for primary intracranial neoplasms and 17,400 for secondary intracranial neoplasms--8.2 and 8.3 per 100,000 US population, respectively. Rates of primary intracranial neoplasms increased steadily with advancing age. The age-adjusted rates were higher among men than among women (8.5 versus 7.9 per 100,000). However, although men were more susceptible to gliomas and neuronomas, incidence rates for meningiomas and pituitary adenomas were higher among women.

Assessment of nutritional status in hospital in-patients.

BACKGROUND: The King's Fund and British Association of Parenteral and Enteral Nutrition recommend that all hospital patients should have height and weight recorded, to detect the need for nutritional support. Systematic review evidence also suggests that protein and energy supplementation of adults in hospital with a wide range of conditions improves outcome. AIM: To assess the recording of weight and height in hospitals. DESIGN: Survey (random sample). METHODS: As part of a survey on the provision of deep venous thrombosis prophylaxis, we collected information on height and weight recording from medical and nursing notes. We randomly selected five medical, five surgical, five orthopaedic, and five obstetrics and gynaecology directorates from across Scotland. Six hundred case notes were requested, and 88% were available for data extraction. Some 67% of hospital episodes provided information about weight, and 41% on both height and weight. General medicine directorates had the lowest recording of weight, and in medical and surgical directorates, both weight and height were rarely recorded in comparison with the other two directorates (p<0.001). DISCUSSION: Our survey suggests that recommendations to assess nutritional risk are not being followed, and that many patients at risk of malnutrition are not being detected or treated.

DC potentials of temporal lobe seizures in the monkey.

In 8 monkeys, made epileptic by alum or penicillin injection into temporal lobe structures, 40 seizures were studied by both DC cortical potential and subcortical EEG recordings. Eighteen seizures of lateral temporal origin had an abrupt negative DC potential shift of 0.5 to 2.0 mV in and around the focus. The frontal, parietal and occipital cortices did not develop DC potential changes, perhaps due to the limited propagation of the neocortical seizures. Twenty-two seizures of medial temporal origin showed a negative shift of the anterior, inferior or lateral temporal cortex in 85% of seizures. The other 15% had a positive or no shift. In hippocampal seizures, a positive displacement was sometimes seen prior to the main negative shift in the lateral temporal cortex. The remote cortex developed only a minimal positive shift in 30% of the mediotemporal seizures. A marked negative shift in the frontocentral cortex was the first sign of impending generalization, which may result from a series of chain reactions with seizure propagation, involving more and more structures of the brain. Registration of DC potentials in temporal lobe seizures may give insight into the nature of abnormal EEG activities and to some extent into the origin of seizures.

Bullous transient acantholytic dermatosis.

We have been three cases of a bullous variant of transient acantholytic dermatosis. Skin biopsy specimens showed histopathologic changes identical to pemphigus foliaceus, but immunofluorescent studies showed no tissue-fixed or circulating antibodies to intercellular antigens. The bullous eruption lasted a few weeks to several months and healed without scarring or recurrence. The lesions healed with topical and/or systemic corticosteroid therapy.

Long-term effects of severe penetrating head injury on psychosocial adjustment.

The long-term effects of severe penetrating head injury on adjustment levels were studied. Forty-one World War II veterans who suffered penetrating injury to the brain were interviewed 40 years after their initial injury using the Washington Psycho-Social Seizure Inventory (WPSI). The results support a comparable behavioral impact of right and left hemispheric lesions. Similarly, no significant relations were found between anterior and posterior locus of damage and psychosocial difficulties, although the results pertaining to the right-anterior group could be interpreted as suggestive of much greater maladjustment in all life dimensions assessed by the WPSI. Findings are discussed in terms of theoretical positions on hemispheric specialization and long-term expectancies that hold implications for planning rehabilitation programs for such patients.

The physiological basis of concussion: 50 years later.

In this brief narrative, the author compares what is known today about the physiological basis of concussion with the results of studies described 50 years ago in the Journal of Neurosurgery. The author was a member of the team that originally reported these findings in the first volume of the Journal of Neurosurgery.

Pulsatile cerebral echo in diagnosis of brain death.

Conclusive diagnosis of brain death can be made by the demonstration of prolonged cessation of cerebral blood flow. This report describes a simple method to determine the presence or absence of the blood flow in the brain by recording the pulsatile midline echo on one channel of the electroencephalogram (EEG) or on any four-channel monitoring system in the intensive care unit. A firm transducer holder has been developed to eliminate artifacts caused by transducer motion, The pulsations of the midline echo are assumed to be the result of displacement of the midline structures by the arterial injection of each cardiac systole. Thus, the absence of these midline pulsatile echoes correlates with the absence of cerebral blood flow and, if the absence persists over 30 minutes in the presence of normal blood pressure, then the result is brain death. Twenty-eight cases of clinical brain death with electrocerebral silence of EEG and 18 obtained patients with various types of cerebral pathology were examined by the echo-pulsation technique. Twenty-six of the 28 cases showed no pulsation of the midline echo. The validity of the technique was documented in four cases by four-vessel cerebral angiogram.

Respirator brain. Report of a survey and review of current concepts.

Because of renewed public and scientific interest in the concept of brain death and its diagnostic criteria, an opinion survey was undertaken, polling the membership of the American Association of Neuropathologists, regarding the definition, gross and microscopical features, and pathogenesis of the syndrome popularly designated the "respirator brain." Of the 191 respondents who completed the questionnaire, 174 (91%) indicated that the term respirator brain is properly used to describe a specific pathological entity, and 160 (84%) considered the characteristics of respirator brain to be distinct from those of late fixation. Of the 174 respondents who accepted the designation, 148 (85%) regarded a history of respiratory dependency as essential, and a vast majority (95%) agreed that extensive tissue necrosis occurs with little inflammatory cell reaction; other criteria were more controversial. Microscopical changes that suggest a pathogenetic mechanism attracted a number of informative, limiting, or qualifying remarks. Nonetheless, 54% thought that impaired cerebral blood flow contributed to pathogenesis.

Continuous intracranial pressure recording in adult hydrocephalus.

An implantable intracranial pressure sensor was used to diagnose and monitor the treatment of 17 adults with hydrocephalus. The intracranial pressure sensor was implanted before shunting in most cases and patients were studied in a sleep laboratory for two nights during which the intracranial pressure was measured throughout the night. Cases included five examples of acute hydrocephalus secondary to tumor, subarachnoid hemorrhage or meningitis, and 12 cases of long standing hydrocephalus diagnosed as normal pressure hydrocephalus, aque-ductal stenosis, or hydrocephalus ex vacuo. Continuous intracranial pressure monitoring was a valuable adjunct in the diagnosis and management of these patients. Continuous overnight recordings of intracranial pressure were helpful in determining compromised cerebral compliance by observing the shape and the amplitude of the intracranial pressure waves during desynchronized sleep. A second method for checking cerebral compliance is also described.

Clinical evaluation of long-term epidural monitoring of intracranial pressure.

Forty-two epidural sensors for measuring intracranial pressure were implanted in 38 patients over the last four years. The sensor is a passive device consisting of an inductance and a pressure sensitive capacitance resonant at about 50 megahertz. The study involved 17 cases of hydrocephalus, nine of pseudotumor cerebri, and the remainder included cases of cranial trauma, brain tumors, and aneurysms. Four of the sensors failed in patients and were removed. Two of these had to be replaced to continue the pressure monitoring. The intracranial pressure is still being monitored in 22 patients, while 15 have been lost to follow-up for various reasons. Fourteen patients have been followed for about a year, and four for two years. The baseline drift rate in most sensors is between 1 and 2 mm H2O per day, with a few having greater rates of drift. Calibration errors were found in some of the sensors after implantation. These errors were corrected by direct measurement of the cerebral spinal fluid pressure via lumbar puncture. The sensors have proven to be a valuable adjunct in the management and diagnosis of neurosurgical patients by simplifying the intermittent and continuous recording of intracranial pressure. This was so despite the presence of calibration errors and a drift which necessitated an occasional lumbar puncture for making corrections.

A recruitment strategy for cluster randomized trials in secondary care settings.

Trials of educational or organizational interventions to change clinical practice require cluster randomization, that is, randomization of units such as hospitals or clinical teams rather than individual patients. Cluster randomization is relatively novel in health care settings and raises new methodological challenges, in particular: are units willing to be randomized at an organizational level; and, what procedures should be followed to successfully enrol all of the clinicians in a unit rather than individual clinicians as in conventional multicentre trials. This is particularly problematic for trials of large units such as hospitals. The aim of this study was to develop and partially evaluate a strategy to recruit acute, secondary care NHS hospitals in the UK into cluster randomized trials. Literature search and interviews with senior staff in acute hospitals and relevant national organizations were used to develop a recruitment strategy. The strategy was evaluated by inviting 32 randomly selected clinical directorates to participate in a trial feasibility study. A seven step recruitment strategy was developed: (1) Identify stakeholders and gatekeepers; (2) Inform stakeholders and gatekeepers; (3) Approach gatekeepers; (4) Local negotiation; (5) Conduct the research; (6) Feedback to gatekeepers; (7) Feedback to stakeholders. Key problems were the possibility of multiple gatekeepers and identification of all possible stakeholders in varying organizational structures. The strategy was effective in two respects. First, 32 (100%) of the directorates approached agreed to participate. Second, baseline data collection was successfully achieved in all of the directorates. However, the strategy is costly in terms of time and resources. We conclude that NHS trusts are willing to participate in cluster randomized trials. This recruitment strategy is successful and could be widely adopted, but realistic time and financial cost estimates are required at the planning stage.

Sedative drug surveys in coma: how reliable are they?

Routine blood tests of comatose patients for drugs that depress the CNS are highly desirable, but techniques of analysis are not well standardized and the results do not correlate well with clinical condition. Determining the role of sedative drugs in coma requires a high degree of suspicion and sound clinical judgment.

Transient bone marrow oedema syndrome in an HIV-infected patient on highly active antiretroviral therapy.

Bone marrow oedema syndrome (BMES, also known as transient osteoporosis) is an uncommon, self-limiting condition characterized by disabling pain, reversible osteopaenia on X-rays and by bone marrow oedema pattern on magnetic resonance imaging (MRI). Here we describe the first reported case of BMES in an HIV-positive patient on highly active antiretroviral therapy.