Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes.

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

Transgenerational disruption of functional 5-HT1AR-induced connectivity in the adult mouse brain by traumatic stress in early life.

Traumatic stress in early life is a strong risk factor for psychiatric disorders that can affect individuals across several generations. Although the underlying mechanisms have been proposed to implicate serotonergic transmission in the brain, the neural circuits involved remain poorly delineated. Using pharmacological functional magnetic resonance imaging in mice, we demonstrate that traumatic stress in postnatal life alters 5-HT1A receptor-evoked local and global functions in both, the exposed animals and their progeny when adult. Disrupted functional connectivity is consistent across generations and match limbic circuits implicated in mood disorders, but also networks not previously linked to traumatic stress. These findings underscore the neurobiology and functional mapping of transgenerational effects of early life experiences.

Multispectral Near-Infrared Optical Tomography for Cancer Hypoxia Study in Mice.

Oxygenation of a tumor is one of the most important predictive factors: hypoxia is associated with aggressive tumors and substantially lower survival rate. Despite this high relevance of tumor oxygenation, there is currently no bedside technique available to measure it in clinical routine care. The aim of this work is to determine the oxygenation of tissue in mice by a continuous wave multispectral near-infrared optical tomograph (mNIROT). Tomographic reconstructions were processed by a massively modified NIRFAST software. We quantitatively measured the tissue oxygen saturation of the tumors in 4 BALB/c nude, female mice with human colon carcinoma cancer cells DLD-1 KRASwt injected subcutaneously. The study revealed changes of oxygenation in tumors on the long-term.

Multimodal imaging of pancreatic beta cells in vivo by targeting transmembrane protein 27 (TMEM27).

AIMS/HYPOTHESIS: Non-invasive diagnostic tools specific for pancreatic beta cells will have a profound impact on our understanding of the pathophysiology of metabolic diseases such as diabetes. The objective of this study was to use molecular imaging probes specifically targeting beta cells on human samples and animal models using state-of-the-art imaging modalities (fluorescence and PET) with preclinical and clinical perspective. METHODS: We generated a monoclonal antibody, 8/9-mAb, targeting transmembrane protein 27 (TMEM27; a surface N-glycoprotein that is highly expressed on beta cells), compared its expression in human and mouse pancreas, and demonstrated beta cell-specific binding in both. In vivo imaging was performed in mice with subcutaneous insulinomas overexpressing the human TMEM27 gene, or transgenic mice with beta cell-specific hTMEM27 expression under the control of rat insulin promoter (RIP-hTMEM27-tg), using fluorescence and radioactively labelled antibody, followed by tissue ex vivo analysis and fluorescence microscopy. RESULTS: Fluorescently labelled 8/9-mAb showed beta cell-specific staining on human and mouse pancreatic sections. Real-time PCR on islet cDNA indicated about tenfold higher expression of hTMEM27 in RIP-hTMEM27-tg mice than in humans. In vivo fluorescence and PET imaging in nude mice with insulinoma xenografts expressing hTMEM27 showed high 8/9-mAb uptake in tumours after 72 h. Antibody homing was also observed in beta cells of RIP-hTMEM27-tg mice by in vivo fluorescence imaging. Ex vivo analysis of intact pancreas and fluorescence microscopy in beta cells confirmed these findings. CONCLUSIONS/INTERPRETATION: hTMEM27 constitutes an attractive target for in vivo visualisation of pancreatic beta cells. Studies in mouse insulinoma models and mice expressing hTMEM27 demonstrate the feasibility of beta cell-targeted in vivo imaging, which is attractive for preclinical investigations and holds potential in clinical diagnostics.

Continuous apple consumption induces oral tolerance in birch-pollen-associated apple allergy.

BACKGROUND: Patients with birch pollen allergy (major allergen: Bet v 1) have often an associated oral allergy syndrome (OAS) to apple, which contains the cross-reactive allergen Mal d 1. As successful birch pollen immunotherapy does not consistently improve apple related OAS symptoms, we evaluated whether regular apple consumption has an effect on OAS and immune parameters of Mal d 1 or Bet v 1 allergy. METHODS: A total of 40 patients with a clear history of birch pollen rhinoconjunctivitis and associated OAS to apple were included in an open, randomized, controlled clinical trial: 27 patients consumed daily defined amount of apple (1-128 g), doubling the amount every two to three weeks, while 13 patients remained untreated. Primary endpoint was the proportion of patients that achieved tolerance to at least 128 g of apple at the end of the study after 8 months. Exploratory endpoints were questionnaire about cross-reactive food and pollen allergy symptoms, conjunctival provocation test with birch pollen and Bet v 1, and in vitro tests (tIgE, sIgE, and IgG4 to Mal d 1 and Bet v 1; basophil activation test with both allergens). RESULTS: Seventeen of 27 patients in active group and none of 13 patients in control group (P = 0.0001) could tolerate a whole apple after the intervention. However, differences in endpoints reflecting systemic immune reactivity did not reach statistical significance. CONCLUSION: In patients with OAS to apple, tolerance can be safely induced with slowly, gradually increasing consumption of apple. However, the observation of a relapse after discounting of apple consumption and absence of immunologic changes suggest that induced tolerance is only transient.

Video-assisted open supraclavicular sympathectomy following air embolism.

BACKGROUND: Air embolism is a relatively rare complication of thoracoscopic surgery. METHODS: Open supraclavicular sympathectomy was indicated to overcome the risk of re-embolization. A novel video-assisted technique was performed. conclusions: The previously prevalent open supraclavicular sympathectomy is a good choice for avoiding air embolism. Laparoscopic instrumentation and technology can be used to improve open procedures, especially when exposure and visibility are limited. Sometimes we should remember to use the experience of our teachers.

Establishment of Wolbachia Strain wAlbB in Malaysian Populations of Aedes aegypti for Dengue Control.

Dengue has enormous health impacts globally. A novel approach to decrease dengue incidence involves the introduction of Wolbachia endosymbionts that block dengue virus transmission into populations of the primary vector mosquito, Aedes aegypti. The wMel Wolbachia strain has previously been trialed in open releases of Ae. aegypti; however, the wAlbB strain has been shown to maintain higher density than wMel at high larval rearing temperatures. Releases of Ae. aegypti mosquitoes carrying wAlbB were carried out in 6 diverse sites in greater Kuala Lumpur, Malaysia, with high endemic dengue transmission. The strain was successfully established and maintained at very high population frequency at some sites or persisted with additional releases following fluctuations at other sites. Based on passive case monitoring, reduced human dengue incidence was observed in the release sites when compared to control sites. The wAlbB strain of Wolbachia provides a promising option as a tool for dengue control, particularly in very hot climates.

Increasing isoflurane dose reduces homotopic correlation and functional segregation of brain networks in mice as revealed by resting-state fMRI.

Effects of anesthetics on brain functional networks are not fully understood. In this work, we investigated functional brain networks derived from resting-state fMRI data obtained under different doses of isoflurane in mice using stationary and dynamic functional connectivity (dFC) analysis. Stationary network analysis using FSL Nets revealed a modular structure of functional networks, which could be segregated into a lateral cortical, an associative cortical network, elements of the prefrontal network, a subcortical network, and a thalamic network. Increasing isoflurane dose led to a loss of functional connectivity between the bilateral cortical regions. In addition, dFC analysis revealed a dominance of dynamic functional states (dFS) exhibiting modular structure in mice anesthetized with a low dose of isoflurane, while at high isoflurane levels dFS showing widespread unstructured correlation displayed highest weights. This indicates that spatial segregation across brain functional networks is lost with increasing dose of the anesthetic drug used. To what extent this indicates a state of deep anesthesia remains to be shown. Combining the results of stationary and dynamic FC analysis indicates that increasing isoflurane levels leads to loss of modular network organization, which includes loss of the strong bilateral interactions between homotopic brain areas.

Editorial peer review for improving the quality of reports of biomedical studies.

BACKGROUND: Scientific findings must withstand critical review if they are to be accepted as valid, and editorial peer review (critique, effort to disprove) is an essential element of the scientific process. We review the evidence of the editorial peer-review process of original research studies submitted for paper or electronic publication in biomedical journals. OBJECTIVES: To estimate the effect of processes in editorial peer review. SEARCH STRATEGY: The following databases were searched to June 2004: CINAHL, Ovid, Cochrane Methodology Register, Dissertation abstracts, EMBASE, Evidence Based Medicine Reviews: ACP Journal Club, MEDLINE, PsycINFO, PubMed. SELECTION CRITERIA: We included prospective or retrospective comparative studies with two or more comparison groups, generated by random or other appropriate methods, and reporting original research, regardless of publication status. We hoped to find studies identifying good submissions on the basis of: importance of the topic dealt with, relevance of the topic to the journal, usefulness of the topic, soundness of methods, soundness of ethics, completeness and accuracy of reporting. DATA COLLECTION AND ANALYSIS: Because of the diversity of study questions, viewpoints, methods, and outcomes, we carried out a descriptive review of included studies grouping them by broad study question. MAIN RESULTS: We included 28 studies. We found no clear-cut evidence of effect of the well-researched practice of reviewer and/or author concealment on the outcome of the quality assessment process (9 studies). Checklists and other standardisation media have some evidence to support their use (2 studies). There is no evidence that referees' training has any effect on the quality of the outcome (1 study). Different methods of communicating with reviewers and means of dissemination do not appear to have an effect on quality (3 studies). On the basis of one study, little can be said about the ability of the peer-review process to detect bias against unconventional drugs. Validity of peer review was tested by only one small study in a specialist area. Editorial peer review appears to make papers more readable and improve the general quality of reporting (2 studies), but the evidence for this has very limited generalisability. AUTHORS' CONCLUSIONS: At present, little empirical evidence is available to support the use of editorial peer review as a mechanism to ensure quality of biomedical research. However, the methodological problems in studying peer review are many and complex. At present, the absence of evidence on efficacy and effectiveness cannot be interpreted as evidence of their absence. A large, well-funded programme of research on the effects of editorial peer review should be urgently launched.

Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review.

BACKGROUND: Influenza vaccination of elderly individuals is recommended worldwide. Our aim was to review the evidence of efficacy and effectiveness of influenza vaccines in individuals aged 65 years or older. METHODS: We searched five electronic databases to December, 2004, in any language, for randomised (n=5), cohort (n=49), and case-control (n=10) studies, assessing efficacy against influenza (reduction in laboratory-confirmed cases) or effectiveness against influenza-like illness (reduction in symptomatic cases). We expressed vaccine efficacy or effectiveness as a proportion, using the formula VE=1-relative risk (RR) or VE*=1-odds ratio (OR). We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications, and deaths. FINDINGS: In homes for elderly individuals (with good vaccine match and high viral circulation) the effectiveness of vaccines against influenza-like illness was 23% (95% CI 6-36) and non-significant against influenza (RR 1.04, 0.43-2.51). Well matched vaccines prevented pneumonia (VE 46%, 30-58) and hospital admission (VE 45%, 16-64) for and deaths from influenza or pneumonia (VE 42%, 17-59), and reduced all-cause mortality (VE 60%, 23-79). In elderly individuals living in the community, vaccines were not significantly effective against influenza (RR 0.19, 0.02-2.01), influenza-like illness (RR 1.05, 0.58-1.89), or pneumonia (RR 0.88, 0.64-1.20). Well matched vaccines prevented hospital admission for influenza and pneumonia (VE 26%, 12-38) and all-cause mortality (VE 42%, 24-55). After adjustment for confounders, vaccine performance was improved for admissions to hospital for influenza or pneumonia (VE* 27%, 21-33), respiratory diseases (VE* 22%, 15-28), and cardiac disease (VE* 24%, 18-30), and for all-cause mortality (VE* 47%, 39-54). INTERPRETATION: In long-term care facilities, where vaccination is most effective against complications, the aims of the vaccination campaign are fulfilled, at least in part. However, according to reliable evidence the usefulness of vaccines in the community is modest.

Vaccines for preventing influenza in the elderly.

BACKGROUND: Influenza vaccination of elderly individuals is recommended worldwide and has been targeted toward the elderly and those at serious risk of complications. OBJECTIVES: Our aim was to review the evidence of efficacy, effectiveness and safety of influenza vaccines in individuals aged 65 years or older. SEARCH STRATEGY: We searched the following databases on The Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effectiveness (Issue 1, 2006); MEDLINE (January 1966 to March Week 3 2006); EMBASE (Dialog 1974 to 1979; SilverPlatter 1980 to December 2005); Biological Abstracts (SilverPlatter 1969 to December 2004); and Science Citation Index (Web of Science 1974 to December 2004). SELECTION CRITERIA: We considered randomised, quasi-randomised, cohort and case-control studies assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. Any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo or with no intervention was considered. DATA COLLECTION AND ANALYSIS: We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching. We further stratified by co-administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines. We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications and deaths. MAIN RESULTS: Sixty-four studies were included in the efficacy / effectiveness assessment, resulting in 96 data sets. In homes for elderly individuals (with good vaccine match and high viral circulation) the effectiveness of vaccines against ILI was 23% (6% to 36%) and non-significant against influenza (RR 1.04: 95% CI 0.43 to 2.51). We found no correlation between vaccine coverage and ILI attack rate. Well matched vaccines prevented pneumonia (VE 46%; 30% to 58%), hospital admission (VE 45%; 16% to 64%) and deaths from influenza or pneumonia (VE 42%, 17% to 59%). In elderly individuals living in the community, vaccines were not significantly effective against influenza (RR 0.19; 95% CI 0.02 to 2.01), ILI (RR 1.05: 95% CI 0.58 to 1.89), or pneumonia (RR 0.88; 95% CI 0.64 to 1.20). Well matched vaccines prevented hospital admission for influenza and pneumonia (VE 26%; 12% to 38%) and all-cause mortality (VE 42%; 24% to 55%). After adjustment for confounders, vaccine performance was improved for admissions to hospital for influenza or pneumonia (VE* 27%; 21% to 33%), respiratory diseases (VE* 22%; 15% to 28%) and cardiac disease (VE* 24%; 18% to 30%); and for all-cause mortality (VE* 47%; 39% to 54%). The public health safety profiles of the vaccines appear to be acceptable. AUTHORS' CONCLUSIONS: In long-term care facilities, where vaccination is most effective against complications, the aims of the vaccination campaign are fulfilled, at least in part. However, according to reliable evidence the usefulness of vaccines in the community is modest. The apparent high effectiveness of the vaccines in preventing death from all causes may reflect a baseline imbalance in health status and other systematic differences in the two groups of participants.

Calculation of dose coefficients for radionuclides produced in a spallation neutron source utilizing NUBASE and the evaluated nuclear structure data file databases.

Based on a mercury spallation neutron source target, the UNLV Transmutation Research Program has identified 72 radionuclides with a half-life greater than or equal to a minute as lacking an appropriate reference for a published dose coefficient according to existing radiation safety dose coefficient databases. A method was developed to compare the nuclear data presented in the ENSDF and NUBASE databases for these 72 radionuclides. Due to conflicting or lacking nuclear data in one or more of the databases, internal and external dose coefficient values have been calculated for only 14 radionuclides, which are not currently presented in Federal Guidance Reports Nos. 11, 12, and 13 or Publications 68 and 72 of the International Commission on Radiological Protection. Internal dose coefficient values are reported for inhalation and ingestion of 1 microm and 5 microm AMAD particulates along with the f1 values and absorption types for the adult worker. Internal dose coefficient values are also reported for inhalation and ingestion of 1 microm AMAD particulates as well as the f1 values and absorption types for members of the public. Additionally, external dose coefficient values for air submersion, exposure to contaminated ground surface, and exposure to soil contaminated to an infinite depth are also presented.

Quality assurance methods and procedures used to verify consistency in calculating dose coefficients.

The development of a spallation neutron source with a mercury target will lead to the production of rare radionuclides. The dose coefficients for many of these radionuclides have not yet been published. A collaboration of universities and national labs has taken on the task of calculating dose coefficients for the rare radionuclides using the software package DCAL. The working group developed a procedure for calculating dose coefficients and a quality assurance (QA) program to verify the calculations completed. The first portion of this QA program was to verify that each participating group could independently reproduce the dose coefficients for a known set of radionuclides. The second effort was to divide the group of rare radionuclides among the independent participants in a manner that assured that each radionuclide would be redundantly and independently calculated, and the results subsequently be submitted for publication in a separate manuscript. The final aspect of this program was to resolve any discrepancies arising among the participants as a group. The output of the various software programs for six QA radionuclides, 144Nd, 201Au, 50V, 61Co, 41Ar, and 38S were compared among all members of the working group. Initially, a few differences in outputs were identified. This exercise identified weaknesses in the procedure, which has since been revised. After the revisions, dose coefficients were calculated and compared to published dose coefficients with good agreement. The present efforts involve generating dose coefficients for the rare radionuclides anticipated to be produced from the spallation neutron source should a mercury target be employed.

Partial inhibition of the growth of transplanted dunning rat prostate tumors with the long-acting somatostatin analogue sandostatin (SMS 201-995).

The growth-inhibiting effects of the long-acting somatostatin analogue Sandostatin on the transplanted Dunning R3327-H androgen-sensitive rat prostate tumor were investigated. Recipient animals were male Copenhagen x Fischer F1 rats (N = 36). When mean tumor volume reached 700 mm3 (20 weeks following transplantation), the rats were divided into four groups: control; Sandostatin (100 micrograms/kg s.c. twice a day); castrate; castrate/Sandostatin. Tumor size was assessed by magnetic resonance imaging 21, 42, 63, 105, and 138 days subsequently. Administration of Sandostatin was interrupted between days 43 and 62. As assessed by transplant volume, Sandostatin caused a moderate (up to 50%) but highly significant (P less than 0.001) suppression of tumor growth in the intact rats; the effect was reversed when drug administration was stopped. In the castrates, in which tumor growth was markedly less than in intact rats, no significant effect of Sandostatin was seen. Analysis of the tumor growth rate demonstrated that Sandostatin led to a 19% reduction (P less than 0.05) in growth rate in intact rats and a 9% decrease (not significant) in castrates. These findings extend previous reports of partial suppression of various types of tumors in vivo with Sandostatin and other somatostatin analogues. Their relevance with regard to the possible use of Sandostatin in the treatment of prostatic carcinoma in humans is discussed.

New developments in cardiovascular magnetic resonance imaging and spectroscopy.

Methodological improvements in nuclear magnetic resonance (NMR) imaging and spectroscopy have enabled the application of these techniques to the study of functional or dynamic biological processes. Because the techniques are non-invasive, repeated measurements can be made in the same animal at different time points, allowing disease progression and regression to be followed during drug therapy. In this review, Markus Rudin, Wolfgang Zierhut, André Sauter and Nigel Cook illustrate this concept by the use of NMR to evaluate cardiovascular function in the rat in various physiological and pathological situations. The possibility of using NMR to perform similar studies in both animals and humans should lead to the design of preclinical models with an improved clinical predictability.

Decreased lumen size after balloon injury despite inhibition of neointimal thickening and antivasospastic treatment.

OBJECTIVE: Both calcium antagonists and angiotensin converting enzyme (ACE) inhibitors are known to diminish the development of intimal thickening after a balloon catheter lesion. It was previously shown that narrowing of carotid artery lumen induced by balloon injury was not influenced by treatment, even though the two ACE inhibitors used inhibited neointimal thickening. The aim of the present study was to include a calcium antagonist as well, in order to investigate whether vasospasm contributes to the persistence of lumen narrowing in ACE inhibitor treated rats after a balloon lesion. METHODS: Six groups of 10 rats were subject to balloon lesion of the left carotid artery. They received spirapril (10 mg.kg-1 x d-1) or isradipine (30 or 100 mg.kg-1 x d-1) or both, given throughout the study in the food. Controls received no drug. Neointimal thickening was measured histologically two weeks after injury. The cross sectional carotid lumen area was measured in vivo by nuclear magnetic resonance imaging, both before and two weeks after balloon injury, and also postmortem by histological techniques. RESULTS: Two weeks after injury, the lumen area of the left carotid artery was significantly reduced following balloon injury, as measured by both techniques. Treatment did not modify the stenosis process as assessed by either method for measuring lumen size. Neointimal thickening, however, was inhibited by between 4% (low dose isradipine) and 59% (combined spirapril + high dose isradipine) in the various treatment groups. CONCLUSIONS: Since calcium antagonist treatment was not able to influence the reduction of lumen size, it is unlikely that the narrowing is due to reversible spasm of the carotid artery in the first two weeks after inducing a balloon lesion. Alternatively, chronic vasospasm of neointimal smooth muscle might not be very sensitive to calcium antagonists.

Treatment of hypertension with isradipine reduces infarct size following stroke in laboratory animals.

Earlier studies have shown isradipine to reduce the size of infarct in a rat model of embolic stroke (permanent occlusion of the left middle cerebral artery) (Sauter A, Rudin M: Stroke 1986; 17: 1228-1234). The greater the delay in isradipine administration after occlusion of the left middle cerebral artery, the less these effects until no effect on infarct size was obtained when isradipine was injected six hours after occlusion of the left middle cerebral artery. Blood pressure was dose-dependently reduced in spontaneously hypertensive rats (blood pressure more than 200 mm Hg), which received injections of isradipine subcutaneously 2.5, 5, and 10 mg/kg per day for six days, to approximately 150, 135, and 120 mm Hg, respectively. Twelve hours post-injection, the left middle cerebral artery was occluded. Isradipine also dose-dependently decreased infarct size, as measured by magnetic resonance imaging at 24 hours and histology five days later, by approximately 20, 40, and 60 percent, respectively, compared with vehicle-injected controls. These results suggest that isradipine, at doses required to normalize the high blood pressure in spontaneously hypertensive rats, will substantially reduce the infarct size caused by a later stroke.

Cerebrovascular, biochemical, and cytoprotective effects of isradipine in laboratory animals.

Dose-response curves of isradipine for blood pressure, total peripheral conductance, and regional cerebral conductances and blood flows were obtained in anesthetized cats and rabbits using the microsphere method. Cerebrovascular effects occurred at lower doses than systemic effects, and the effective duration was longer in the brain than in the periphery. In a rat model of embolic stroke (unilateral occlusion of the middle cerebral artery), isradipine has been shown to have cytoprotective efficacy (Sauter A, Rudin M: Stroke 1986; 17: 1228-1234; Rudin M, Sauter A, Wiederhold K-H: Therapie 1987; 42: 477-481; Sauter A, Rudin M, Wiederhold K-H: Neurochem Pathol 1989 [in press]). Using this model, dose-response curves for infarct size, measured by magnetic resonance imaging, and biochemical markers of infarction were obtained for various calcium antagonists. Isradipine showed the biggest improvements (50 to 60 percent at 2.5 mg/kg subcutaneously), followed by nimodipine (30 to 40 percent at 5 mg/kg subcutaneously), nitrendipine (30 to 40 percent at 10 mg/kg subcutaneously), darodipine (20 to 30 percent at 10 mg/kg subcutaneously), and nicardipine (10 percent at 10 mg/kg subcutaneously). It is concluded that isradipine differs in both efficacy and potency from the other calcium antagonists tested. The effects of isradipine, nimodipine, and darodipine on cerebral blood flow were further investigated in this model using the [14C]iodoantipyrine method. Despite systemic hypotension, cerebral blood flow was dose dependently increased in the normal and ischemic hemispheres. Isradipine elicited maximal improvements over a wider dose range than the other drugs tested (0.1 to 2.5 mg/kg), preferentially affecting cerebral blood flow in the ischemic areas, as further demonstrated using autoradiographic techniques. These effects are in good, quantitative agreement with the reductions in infarct size, observed by magnetic resonance imaging and histology, emphasizing the importance of cerebrovascular mechanisms for cytoprotection in stroke. The concurrence between cat, rabbit, and rat experiments suggests that the findings may also apply to humans.

Community-acquired acinetobacter pneumonia.

Acinetobacter calcoaceticus var anitratus, a nonfermentative grampnegative bacillus, has been infrequently reported as a cause of community-acquired pneumonia. In this paper we describe the course of six recent patients with community-acquired, bacteremic pneumonia due to this organism and review the six previously reported cases. Our experience suggests this organism is a more common cause of community-acquired pneumonia than previously thought. Acinetobacter pneumonia occurs in older persons with chronic disease, especially alcoholism. It is a fulminant illness with respiratory distress, hypoxemia, leukopenia and shock. Chest roentgenograms reveal a lobar or bronchopneumonic infiltrate which often becomes bilateral within 24 hours of admission to the hospital. Pleural effusions are common. The mortality rate is 43 per cent. Factors that predict a fatal outcome are granulocytopenia, empyema and therapy with inappropriate antibiotics. Therapy with appropriate antibiotics, especially carbenicillin and an aminoglycoside, increases survival.