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1.  How Does Joint Remodeling Work? 
Cell Adhesion & Migration  2007;1(2):102-103.
Remodeling of joints is a key feature of inflammatory and degenerative joint disease. Bone erosion, cartilage degeneration and growth of bony spurs termed osteophytes are key features of structural joint pathology in the course of arthritis, which lead to impairment of joint function. Understanding their molecular mechanisms is essential to tailor targeted therapeutic approaches to protect joint architecture from inflammatory and mechanical stress. This addendum summarizes the new insights in the molecular regulation of bone formation in the joint and its relation to bone resorption. It describes how inflammatory cytokines impair bone formation and block the repair response of joints towards inflammatory stimuli. It particularly points out the key role of Dickkopf-1 protein, a regulator of the Wingless signaling and inhibitor of bone formation. This new link between inflammation and bone formation is also crucial for explaining the generation of osteophytes, bony spurs along joints, which are characterized by new bone and cartilage formation. This mechanism is largely dependent on an activation of wingless protein signaling and can lead to complete joint fusion. This addendum summarized the current concepts of joint remodeling in the limelight of these new findings.
PMCID: PMC2633978  PMID: 19262161
joint remodeling; arthritis; bone formation; bone erosion; osteoblasts; osteoclasts; Dickkopf; wingless proteins
2.  E2F and retinoblastoma related proteins may regulate GL1 expression in developing Arabidopsis trichomes 
Plant Signaling & Behavior  2008;3(6):420-422.
This is an addendum to our recent paper published in The Plant Journal (52:352–61). The major findings were: (1) trichomes on the leaves of gl3-sst sim double mutants developed as large multi-cellular clusters whereas wild type trichomes are composed of single cells; (2) ectopic CYCD3;1 expression in gl3-sst trichomes also resulted in trichome cluster formation; and (3) that GL1 expression is prolonged in the gl3-sst sim trichome clusters. This addendum shows that ectopic CYCD3;1 expression in gl3-sst also enhanced GL1 expression. An analysis of the GL1 promoter found two overlapping potential E2F binding sites in a region of the promoter known to be essential for GL1 function. This finding indicates that GL1 may be directly regulated by the activity of a CYCD3/CDKA complex that phosphorylates E2F-RB bound to the GL1 promoter.
PMCID: PMC2634322  PMID: 19704586
plant cell cycle; endoreduplication; glabra1; plant development
3.  Cell communication and tissue engineering 
Gap junction intercellular communication (GJIC) is ubiquitous in the majority of cells and is indispensable for proper development and function of most tissues. The loss of gap junction mediated cell to cell communication leads to compromised development in many tissues and organs, and also facilitates tumorigenesis and autonomous cell behavior in cancerous cells. Because cells embedded in an extracellular matrix constantly interact through gap junctions to coordinate normal tissue functions and homeostasis, our group hypothesized that increasing cell to cell communication, via genetically engineering cells to overexpress gap junction proteins, could improve cell signaling and increase differentiation in interior regions of engineered tissue equivalents. In a recent paper,1 we presented a platform to regenerate full 3D equivalents of engineered tissue, providing a strategy to overcome a barrier in regenerative medicine. These findings suggest that both targeted delivery and cell-based strategies can be used as treatments to enhance communication in 3D living tissue.2 In this addendum, we address the effects of extracellular calcium (Ca2+e) on intracellular calcium (Ca2+i), GJIC and osteogenic differentiation under conditions in which bone marrow stromal cells (BMSCs) also exhibit higher cell-to-cell communication. As a key secondary messenger in many biological processes, the levels of Ca2+e and Ca2+i play a role in cell differentiation and may be a tunable signal in tissue regeneration. Higher cell-to-cell communication was achieved by both genetically engineering cells to overexpress connexin 43 (Cx43) and by a high density cell seeding technique, denoted micromass seeding (MM). The results presented in this addendum show that the intensity and duration of a second messenger, like calcium, can be augmented in a platform that enables higher cell-to-cell communication. The ability to modulate calcium signaling, combined with our previous approaches to modulate GJIC, may have an impact on tissue regeneration and therapies for communication incompetent cells, such as those associated with heart disease and certain types of cancer.
PMCID: PMC2881242  PMID: 20539784
connexin 43 (Cx43); gap junction intercellular communication (GJIC); calcium; micromass cultures; Bone
4.  Addendum: First injection technique recommendations for patients with diabetes, Forum for Injection Techniques India 
The forum for injection techniques, India recommendation, the first ever in the country on insulin injcetion techniques, have covered the science and the art of insulin injection technique in an exhaustive manner. However, a few gaps were identified in the document, which are addressed in the current addendum. This article focuses on insulin injection technique in special clinical situations, including geriatric people, women in pregnancy and those with dermatological or surgical disease who live with diabetes. The addendum also covers salient features of administration of insulin using the insulin pump.
PMCID: PMC3872676
Dermatology; geriatric diabetes; insulin pump; pregnancy; surgical disease
5.  A randomized phase II study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: A North Central Cancer Treatment Group Study, N0775 
Cancer  2012;119(3):586-592.
Increasing evidence shows chemotherapy in combination with VEGF inhibition is a clinically active therapy for patients with metastatic melanoma (MM).
A phase II trial was conducted in chemotherapy naïve patients with unresectable stage IV MM who were randomized to temozolomide (200 mg/m2 on d. 1–5) and bevacizumab (10mg/kg IV d. 1 and 15) every 28 days (Regimen temozolomide/bevacizumab [TB]) or nab-paclitaxel (100mg/m2 [80 mg/m2 post addendum 5-secondary to toxicity] days 1, 8 and 15), bevacizumab (10mg/kg on days 1 and 15), and carboplatin (AUC 6 day 1 [ AUC 5 post addendum 5]) every 28 days (Regimen ABC). Accrual goal was 41 patients per regimen. The primary aim of this study was to estimate progression-free survival rate at 6 months (PFS6) in each regimen. A regimen would be considered promising if its PFS6 rate was > 60%.
Ninety-three eligible patients (42 TB and 51 ABC) were enrolled. The majority of patients had M1c disease (20- TB & 26 ABC). The median PFS and overall survival (OS) times with ABC were 6.7 months and 13.9 months, respectively. Median PFS time and median OS with TB were 3.8 months and 12.3 months, respectively. The most common severe toxicities (≥grade 3) in both regimens were cytopenias, fatigue, and thrombosis. Among the first 41 patients enrolled onto each regimen, PFS6 rate was 32.8% (95% CI: 21.1–51.2%) for TB and 56.1% (90% CI: 44.7–70.4%) for ABC.
The addition of bevacizumab to nab-paclitaxel and carboplatin shows promising activity despite tolerability issues.
PMCID: PMC4089063  PMID: 22915053
metastatic melanoma; chemotherapy; VEGF inhibition; combination therapy; unresectable metastatic melanoma
6.  Molecular evolution of DNA-(cytosine-N4) methyltransferases: evidence for their polyphyletic origin. 
Nucleic Acids Research  1999;27(22):4501-4509.
DNA N4-cytosine methyltransferases (N4mC MTases) are a family of S-adenosyl-L-methionine (AdoMet)-dependent MTases. Members of this family were previously found to share nine conserved sequence motifs, but the evolutionary basis of these similarities has never been studied in detail. We performed phylogenetic analysis of 37 known and potential new family members from the multiple sequence alignment using distance matrix, parsimony and maximum likelihood approaches to infer the evolutionary relationship among the N4mC MTases and classify them into groups of orthologs. All the treeing algorithms employed as well as results of exhaustive sequence database searching support a scenario, in which the majority of N4mC MTases, except for M. Bal I and M. Bam HI, arose by divergence from a common ancestor. Interestingly, MTases M. Bal I and M. Bam HI apparently originated from N6-adenine MTases and represent the most recent addendum to the N4mC MTase family. In addition to the previously reported nine sequence motifs, two more conserved sequence patches were detected. Phylogenetic analysis also provided the evidence for massive horizontal transfer of MTase genes, presumably with the whole restriction-modification systems, between Bacteria and Archaea.
PMCID: PMC148735  PMID: 10536161
7.  An analysis of the Sargasso Sea resource and the consequences for database composition 
BMC Bioinformatics  2006;7:213.
The environmental sequencing of the Sargasso Sea has introduced a huge new resource of genomic information. Unlike the protein sequences held in the current searchable databases, the Sargasso Sea sequences originate from a single marine environment and have been sequenced from species that are not easily obtainable by laboratory cultivation. The resource also contains very many fragments of whole protein sequences, a side effect of the shotgun sequencing method.
These sequences form a significant addendum to the current searchable databases but also present us with some intrinsic difficulties. While it is important to know whether it is possible to assign function to these sequences with the current methods and whether they will increase our capacity to explore sequence space, it is also interesting to know how current bioinformatics techniques will deal with the new sequences in the resource.
The Sargasso Sea sequences seem to introduce a bias that decreases the potential of current methods to propose structure and function for new proteins. In particular the high proportion of sequence fragments in the resource seems to result in poor quality multiple alignments.
These observations suggest that the new sequences should be used with care, especially if the information is to be used in large scale analyses. On a positive note, the results may just spark improvements in computational and experimental methods to take into account the fragments generated by environmental sequencing techniques.
PMCID: PMC1513258  PMID: 16623953
8.  An Update on Cancer Cluster Activities at the Centers for Disease Control and Prevention 
Environmental Health Perspectives  2006;115(1):165-171.
The Centers for Disease Control and Prevention (CDC) continues to be aware of the need for response to public concern as well as to state and local agency concern about cancer clusters. In 1990 the CDC published the “Guidelines for Investigating Clusters of Health Events,” in which a four-stage process was presented. This document has provided a framework that most state health departments have adopted, with modifications pertaining to their specific situations, available resources, and philosophy concerning disease clusters. The purpose of this present article is not to revise the CDC guidelines; they retain their original usefulness and validity. However, in the past 15 years, multiple cluster studies as well as scientific and technologic developments have affected cluster science and response (improvements in cancer registries, a federal initiative in environmental public health tracking, refinement of biomarker technology, cluster identification using geographic information systems software, and the emergence of the Internet). Thus, we offer an addendum for use with the original document. Currently, to address both the needs of state health departments as well as public concern, the CDC now a) provides a centralized, coordinated response system for cancer cluster inquiries, b) supports an electronic cancer cluster listserver, c) maintains an informative web page, and d) provides support to states, ranging from laboratory analysis to epidemiologic assistance and expertise. Response to cancer clusters is appropriate public health action, and the CDC will continue to provide assistance, facilitate communication among states, and foster the development of new approaches in cluster science.
PMCID: PMC1797849  PMID: 17366838
cancer; cancer clusters; Centers for Disease Control and Prevention; environmental hazards; epidemiologic cluster investigations; state health departments
9.  Natural Ventilation for the Prevention of Airborne Contagion 
PLoS Medicine  2007;4(2):e68.
Institutional transmission of airborne infections such as tuberculosis (TB) is an important public health problem, especially in resource-limited settings where protective measures such as negative-pressure isolation rooms are difficult to implement. Natural ventilation may offer a low-cost alternative. Our objective was to investigate the rates, determinants, and effects of natural ventilation in health care settings.
Methods and Findings
The study was carried out in eight hospitals in Lima, Peru; five were hospitals of “old-fashioned” design built pre-1950, and three of “modern” design, built 1970–1990. In these hospitals 70 naturally ventilated clinical rooms where infectious patients are likely to be encountered were studied. These included respiratory isolation rooms, TB wards, respiratory wards, general medical wards, outpatient consulting rooms, waiting rooms, and emergency departments. These rooms were compared with 12 mechanically ventilated negative-pressure respiratory isolation rooms built post-2000. Ventilation was measured using a carbon dioxide tracer gas technique in 368 experiments. Architectural and environmental variables were measured. For each experiment, infection risk was estimated for TB exposure using the Wells-Riley model of airborne infection. We found that opening windows and doors provided median ventilation of 28 air changes/hour (ACH), more than double that of mechanically ventilated negative-pressure rooms ventilated at the 12 ACH recommended for high-risk areas, and 18 times that with windows and doors closed (p < 0.001). Facilities built more than 50 years ago, characterised by large windows and high ceilings, had greater ventilation than modern naturally ventilated rooms (40 versus 17 ACH; p < 0.001). Even within the lowest quartile of wind speeds, natural ventilation exceeded mechanical (p < 0.001). The Wells-Riley airborne infection model predicted that in mechanically ventilated rooms 39% of susceptible individuals would become infected following 24 h of exposure to untreated TB patients of infectiousness characterised in a well-documented outbreak. This infection rate compared with 33% in modern and 11% in pre-1950 naturally ventilated facilities with windows and doors open.
Opening windows and doors maximises natural ventilation so that the risk of airborne contagion is much lower than with costly, maintenance-requiring mechanical ventilation systems. Old-fashioned clinical areas with high ceilings and large windows provide greatest protection. Natural ventilation costs little and is maintenance free, and is particularly suited to limited-resource settings and tropical climates, where the burden of TB and institutional TB transmission is highest. In settings where respiratory isolation is difficult and climate permits, windows and doors should be opened to reduce the risk of airborne contagion.
In eight hospitals in Lima, opening windows and doors maximised natural ventilation and lowered the risk of airborne infection. Old-fashioned clinical areas with high ceilings and large windows provide greatest protection.
Editors' Summary
Tuberculosis (TB) is a major cause of ill health and death worldwide, with around one-third of the world's population infected with the bacterium that causes it (Mycobacterium tuberculosis). One person with active tuberculosis can go on to infect many others; the bacterium is passed in tiny liquid droplets that are produced when someone with active disease coughs, sneezes, spits, or speaks. The risk of tuberculosis being transmitted in hospital settings is particularly high, because people with tuberculosis are often in close contact with very many other people. Currently, most guidelines recommend that the risk of transmission be controlled in certain areas where TB is more likely by making sure that the air in rooms is changed with fresh air between six and 12 times an hour. Air changes can be achieved with simple measures such as opening windows and doors, or by installing mechanical equipment that forces air changes and also keeps the air pressure in an isolation room lower than that outside it. Such “negative pressure,” mechanically ventilated systems are often used on tuberculosis wards to prevent air flowing from isolation rooms to other rooms outside, and so to prevent people on the tuberculosis ward from infecting others.
Why Was This Study Done?
In many parts of the world, hospitals do not have equipment even for simple air conditioning, let alone the special equipment needed for forcing high air changes in isolation rooms and wards. Instead they rely on opening windows and doors in order to reduce the transmission of TB, and this is called natural ventilation. However, it is not clear whether these sorts of measures are adequate for controlling TB transmission. It is important to find out what sorts of systems work best at controlling TB in the real world, so that hospitals and wards can be designed appropriately, within available resources.
What Did the Researchers Do and Find?
This study was based in Lima, Peru's capital city. The researchers studied a variety of rooms, including tuberculosis wards and respiratory isolation rooms, in the city's hospitals. Rooms which had only natural measures for encouraging airflow were compared with mechanically ventilated, negative pressure rooms, which were built much more recently. A comparison was also done between rooms in old hospitals that were naturally ventilated with rooms in newer hospitals that were also naturally ventilated. The researchers used a particular method to measure the number of air changes per hour within each room, and based on this they estimated the risk of a person with TB infecting others using a method called the Wells-Riley equation. The results showed that natural ventilation provided surprisingly high rates of air exchange, with an average of 28 air changes per hour. Hospitals over 50 years old, which generally had large windows and high ceilings, had the highest ventilation, with an average of 40 air changes per hour. This rate compared with 17 air changes per hour in naturally ventilated rooms in modern hospitals, which tended to have lower ceilings and smaller windows. The rooms with modern mechanical ventilation were supposed to have 12 air changes per hour but in reality this was not achieved, as the systems were not maintained properly. The Wells-Riley equation predicted that if an untreated person with tuberculosis was exposed to other people, within 24 hours this person would infect 39% of the people in the mechanically ventilated room, 33% of people in the naturally ventilated new hospital rooms, and only 11% of the people in the naturally ventilated old hospital rooms.
What Do These Findings Mean?
These findings suggest that natural methods of encouraging airflow (e.g., opening doors and windows) work well and in theory could reduce the likelihood of TB being carried from one person to another. Some aspects of the design of wards in old hospitals (such as large windows and high ceilings) are also likely to achieve better airflow and reduce the risk of infection. In poor countries, where mechanical ventilation systems might be too expensive to install and maintain properly, rooms that are designed to naturally achieve good airflow might be the best choice. Another advantage of natural ventilation is that it is not restricted by cost to just high-risk areas, and can therefore be used in many different parts of the hospital, including emergency departments, outpatient departments, and waiting rooms, and it is here that many infectious patients are to be found.
Additional Information.
Please access these Web sites via the online version of this summary at
Information from the World Health Organization on tuberculosis, detailing global efforts to prevent the spread of TB
The World Health Organization publishes guidelines for the prevention of TB in health care facilities in resource-limited settings
Tuberculosis infection control in the era of expanding HIV care and treatment is discussed in an addendum to the above booklet
The Centers for Disease Control have published guidelines for preventing the transmission of mycobacterium tuberculosis in health care settings
Wikipedia has an entry on nosocomial infections (diseases that are spread in hospital). Wikipedia is an internet encyclopedia anyone can edit
A PLoS Medicine Perspective by Peter Wilson, “Is Natural Ventilation a Useful Tool to Prevent the Airborne Spread of TB?” discusses the implications of this study
PMCID: PMC1808096  PMID: 17326709
10.  The complex genetics of multiple sclerosis: pitfalls and prospects 
Brain  2008;131(12):3118-3131.
The genetics of complex disease is entering a new and exciting era. The exponentially growing knowledge and technological capabilities emerging from the human genome project have finally reached the point where relevant genes can be readily and affordably identified. As a result, the last 12 months has seen a virtual explosion in new knowledge with reports of unequivocal association to relevant genes appearing almost weekly. The impact of these new discoveries in Neuroscience is incalculable at this stage but potentially revolutionary. In this review, an attempt is made to illuminate some of the mysteries surrounding complex genetics. Although focused almost exclusively on multiple sclerosis all the points made are essentially generic and apply equally well, with relatively minor addendums, to any other complex trait, neurological or otherwise.
PMCID: PMC2639203  PMID: 18490360
multiple sclerosis; genetics; association; linkage
11.  Continuity and change?: Exploring reactions to a guided self-management intervention in a randomised controlled trial for IBS with reference to prior experience of managing a long term condition 
Trials  2007;8:6.
Self-care interventions are promoted as effective strategies for improving the quality of life and health outcomes for individuals with long-term health conditions. Outcome measures used in evaluations using Randomised Controlled Trials (RCTs) are not designed to consider patients' prior management strategies and experience of illness. Yet the experience of illness literature suggests that adjusting to living with chronic illness, together with broader contextual influences, are likely to be relevant to understanding responses to self-management initiatives. Using group and individual interview data we attempt to illuminate the transposition of IBS from a condition unsatisfactorily managed by medicine to one successfully managed within the life worlds of individuals. If routine embedding of complex interventions depends on the accomplishment of integration and workability in patients' everyday lives then the design and evaluation of such interventions should view participation as part of a process of continuity as well as change. Responses to formal self-management can be extended beyond psychological and other quantitatively measured outcomes. A useful addendum to trial outcomes for self-management education is an understanding of change as being inextricably linked to people's previous attempts to, and experience of, managing long-term conditions. We suggest that the benefits of understanding the prior experience of managing illness and contact with health services include the acceptability and workability of complex interventions in patients' everyday lives.
PMCID: PMC1819391  PMID: 17316438
12.  Overview of graduate medical education. Funding streams, policy problems, and options for reform. 
Western Journal of Medicine  1998;168(5):428-436.
In this article, we examine the financing mechanisms for graduate medical education (GME) in the United States. In so doing, we identify Medicare as the single largest contributor to GME and the most important barrier to producing a physician workforce that is appropriately sized, balanced, and skilled. Until passage of the 1997 Budget Reconciliation Agreement, the structure of Medicare payments promoted overproduction and skewed production toward training specialists in tertiary settings. We then examine the various reform proposals put forward by major health care organizations and policy bodies. These organizations generally agree on seven policy objectives: Remove incentives that promote expanded resident production; Base the GME subsidy on actual costs and distribute it more uniformly; Focus reductions on specialty residency positions; Provide GME payments for training provided in ambulatory, community, and managed care sites; Decouple Medicare GME reimbursement from payments to health maintenance organizations for patient care; Require all health insurers to contribute to GME; and Ensure that reductions in the GME subsidy do not reduce access to care for low-income persons. A myriad of different mechanisms for achieving these objectives have been recommended, many of which could be melded together to form a comprehensive approach to GME reform. The prospects for meaningful GME reform are dim in the absence of broader Medicare reform. The costs to stake-holders are too concentrated while the benefits to the public are too diffuse for GME reform to stand alone. But the political imperative to deal with the federal budget's short-term deficit and Medicare's long-term solvency will likely create an opportunity for GME reform. An addendum has been added that shows how the 1997 Budget Reconciliation Agreement addresses most of the major reform objectives identified but that several important issues remain unresolved.
PMCID: PMC1304986  PMID: 9614800
13.  The Electrophoretic Pattern of Hemoglobin in Newborn Babies, and Abnormalities of Hemoglobin F Synthesis in Adults 
On routine electrophoretic analyses on filter paper and starch gel in an alkaline or neutral medium, no abnormal hemoglobin fractions were found in the blood of 600 newborn infants or their mothers. Trace amounts of hemoglobin Barts were noted in many of the blood samples from newborns when the starch gels (phosphate buffer pH 7.0) were stained with a benzidine/H2O2 reagent. In one infant, precocious cessation of synthesis of hemoglobin F was postulated to account for the small amounts of this hemoglobin found in a cord-blood specimen. Analysis of 15,000 blood samples from adults revealed two instances in which the hemoglobin F level was 20 and 35%, respectively. The former was attributed to a hereditary persistence of hemoglobin F, while the latter was associated with acute leukemia.
In an addendum, the finding of an infant with an abnormal hemoglobin variant, resembling in many of its properties hemoglobin F Texas, is reported.
PMCID: PMC1935987  PMID: 6019054
14.  Production of Microbial Biomass Protein from Potato Processing Wastes by Cephalosporium eichhorniae 
The use of Cephalosporium eichhorniae 152 (ATCC 38255) (reclassified as Acremonium alabamense; see Addendum in Proof), a thermophilic, acidophilic, amylolytic fungus, for the conversion of potato processing wastes into microbial protein for use as animal feed was studied. The fungus was not inhibited by α-solanine or β-2-chaconine, antimicrobial compounds in potatoes, or by morpholine or cyclohexylamine (additives to steam used in the peeling process) at levels likely to be encountered in this substrate. Mixed effluent from holding tanks at a potato-processing plant contained about 109 bacteria per ml and inhibited fungal growth. The fungus grew well on fresh potato wastes containing up to 5% total carbohydrate and utilized both starch and protein at 45°C and pH 3.75. On potato homogenate medium containing 2% carbohydrate (about 14% fresh potato) supplemented with monoammonium phosphate (0.506 g/liter) and ferric iron (0.1 g/liter), with pH control (at 3.75) and additional nitrogen supplied by the automatic addition of ammonium hydroxide, typical yields were 0.61 g (dry weight) of product and 0.3 g of crude protein per g of carbohydrate supplied. An aerobic, spore-forming bacterium, related to Bacillus brevis, commonly contaminated nonsterilized batch cultures but was destroyed by heating for 15 min at 100°C.
PMCID: PMC203653  PMID: 16347277
15.  Impact of Chlorine and Heat on the Survival of Hartmannella vermiformis and Subsequent Growth of Legionella pneumophila 
Applied and Environmental Microbiology  1993;59(12):4096-4100.
Hartmannella vermiformis, a common amoebal inhabitant of potable-water systems, supports intracellular multiplication of Legionella pneumophila and is probably important in the transportation and amplification of legionellae within these systems. To provide a practical guide for decontamination of potable-water systems, we assessed the chlorine and heat resistance of H. vermiformis. H. vermiformis cysts and trophozoites were treated independently with chlorine at concentrations of 2.0 to 10.0 ppm for 30 min and then cocultured with L. pneumophila. Both cysts and trophozoites were sensitive to concentrations between 2.0 and 4.0 ppm and above (trophozoites somewhat more so than cysts), and 10.0 ppm was lethal to both forms. Hartmannellae treated with chlorine up to a concentration of 4.0 ppm supported the growth of legionellae. To determine whether heat would be an effective addendum to chlorine treatment of amoebae, hartmannellae were subjected to temperatures of 55 and 60°C for 30 min and alternatively to 50°C followed by treatment with chlorine at a concentration of 2 ppm. Fewer than 0.05% of the amoebae survived treatment at 55°C, and there were no survivors at 60°C. Pretreatment at 50°C appeared to make hartmannella cysts more susceptible to chlorine but did not further reduce the concentration of trophozoites.
PMCID: PMC195872  PMID: 16349110
16.  A study of stereotypic behaviours in Alzheimer's disease and frontal and temporal variant frontotemporal dementia 
Objective: To document the prevalence and pattern of stereotypic behaviour in patients with Alzheimer's dementia and frontal and temporal variants of frontotemporal dementia. Secondly, to examine the relationship between stereotypic and other neuropsychiatric behaviours.
Methods: Patients with the following were studied; Alzheimer's disease (n=28), frontal variant frontotemporal dementia (fvFTD, n=18), and semantic dementia—the temporal lobe variant of FTD (n=13). All patients were assessed using the Neuropsychiatric Inventory (NPI), the Mini-Mental State Examination, Addenbrooke's Cognitive Examination, and the Clinical Dementia Rating scale. Patients were also rated on the newly devised Stereotypic and Ritualistic Behaviour (SRB) subscale, which was designed as an addendum to the NPI.
Results: There was no significant difference across diagnostic groups in terms of age, sex, or severity of cognitive deficits. The overall NPI was significantly higher in patients with fvFTD compared with the other two groups, but fvFTD and semantic dementia showed a similar, and significantly increased, prevalence of stereotypic behaviours on the SRB subscale. Within the FTD group as a whole these behaviours were more likely to be complex, whereas in Alzheimer's disease, when present, such behaviours tended to be more simple stereotypies or stimulus bound repetitive behaviours. Stereotypic behaviours were not correlated with either disease severity or the extent of cognitive impairment in the fvFTD group, but were in the other two diagnostic groups.
Conclusion: Complex stereotypic behaviours are a core feature of the dementing syndrome in FTD and may reflect early and specific deficits in orbitofrontal circuitry and basal ganglia involvement.
PMCID: PMC1757381  PMID: 14570833
17.  ....Officiously to keep alive 
Journal of Medical Ethics  1977;3(4):189-193.
The case of a patient with an incurable condition which was bound to deteriorate is discussed in the light of two conceptions of medical care: the first, the traditional one of treating with all the means at the doctor's disposal until death `wins', the other to `let go' of his skills for the greater good of the patient and his family. The second course was adopted by the doctor looking after the patient described here after careful consultation with the daughter, who was living in her father's house and willing to look after him as long as was necessary. On the whole the doctor is commended by those contributing to the case conference, although it is recognized that the course of `action' adopted is still not yet fully accepted in modern society. (Both lay and medical opinion, however, seems to be moving towards that way of thinking.) Susan Thorne's contribution makes the suggestion that in cases where there seems to be a moral or ethical dilemma there might be some kind of counsellor available for those concerned in making the ethical and medical decisions, and in the addendum to the case conference a former general practitioner, now practising as a hospital doctor, points to the two different medical cultures exemplified by the attitudes of American and British doctors.
PMCID: PMC1154602  PMID: 604489
18.  Four families with immunodeficiency and chromosome abnormalities. 
Archives of Disease in Childhood  1979;54(7):518-523.
Six children, with severe deficiency of some or all of the immunoglobulins and minor somatic abnormalities, had chromosomal abnormalities: (1) 45,XY,t(13q/18q), (2) 46,XY,21ps +, (3) two brothers 46,XY (inv. 7) (4) 45,X,t(11p/10p)/46X,iXq,t(11p/10p) and, (5) in addendum, 45,XX,-18;46,XX, r18. The chromosome abnormalities were detected in B- as well as T-lymphocytes (as evidenced by using both PHA- and PWM-stimulated cultures) in all probands, but one was mosaic in PHA culture, although all his PWM-stimulated cells were abnormal. Chromosomal variants were also detected in relatives of three and immunodeficiency in relatives of two.
PMCID: PMC1545485  PMID: 314782
19.  California Medical Association 
California Medicine  1951;74(1):51-71.
Herewith is printed for the second time in California Medicine, the proposed C.M.A. Constitution introduced in the 1950 House of Delegates by Reference Committee No. 3 of that body.
Included in this document is an additional proposed section introduced by Reference Committee No. 3 as an addendum to its original introduction of the proposed Constitution.
Members of the Association, and especially members of the House of Delegates, are urged to give this proposed Constitution a thorough study. It contains various provisions which are different from existing constitutional provisions and which have been under discussion in the House of Delegates in the past.
PMCID: PMC1520824  PMID: 18731735
20.  Possible genetic influences in familial sarcoidosis 
Postgraduate Medical Journal  1974;50(589):664-670.
Five families (three English, one Irish, one West Indian) contained eleven members with sarcoidosis, nine of whom have been investigated and followed. Their multisystem involvement and course was similar to that of other patients attending the Sarcoidosis Clinic at the Royal Northern Hospital. There were three brother-sister and two mother-offspring relations; it was not observed in a father-offspring relationship. It is noted that the course of one sister was considerably worse than that of her brother. The evidence suggests a recessive mode of inheritance for sarcoidosis susceptibility. Four other families are reported on in an Addendum.
PMCID: PMC2496040  PMID: 4467866
21.  Library Orientation Methods: J. Hillis Miller Health Center Library Program 
Two orientation devices are described which are currently in use at the J. Hillis Miller Health Center Library.
One is a taped tour which requires a portable recorder with earphones attached. Tapes are now available for nursing students, physical therapy students, and Health Center staff. The tour includes location information and description of the card catalog and certain basic index and abstract services.
The second orientation device is a short instruction tape on the use of Index Medicus which is attached to the Index Medicus table. This is heard through a telephone apparatus.
It is anticipated that the tape technique will be expanded to apply to other students and other library tools. It is also believed that this technique may be used in other libraries.
Information about the supplies and equipment used is given as an addendum.
PMCID: PMC198636  PMID: 4112483
22.  Review of the Book Sniffy the Virtual Rat Pro Version 2.0 
Sniffy the Virtual Rat Pro Version 2.0 is the most recent update to the Sniffy the Rat program modules. It has an extensive set of simulations related to Pavlovian and operant conditioning. Many of the standard conditioning paradigms and phenomena are contained within this program. Pavlovian effects such as blocking, overshadowing, and stimulus competition are demonstrated in the data output. Operant manipulations allow shaping the behavior of the virtual rat, observing cumulative records of interval and ratio schedules, as well as conducting operant discrimination procedures. In both Pavlovian and operant paradigms, one can generate histograms that predict the degree to which various stimuli control the virtual rat's behavior. On-screen presentations may keep most users interested, but working with the generated data files sometimes can prove difficult. Overall, this program has a strong potential for facilitating the instruction in undergraduate conditioning courses, serving as an addendum to traditional undergraduate conditioning laboratories and as a supplement to the use of live animals.
PMCID: PMC1832165
Sniffy; virtual rat; instructional software; simulation
23.  Do pathogen-specific defense mechanisms contribute to wound-induced resistance in tomato? 
Plant Signaling & Behavior  2008;3(5):340-341.
A network of shared intermediates/components and/or common molecular outputs in biotic and abiotic stress signaling has long been known, but the possibility of effective influence between differently triggered stresses (co-protection) is less studied. Recent observations show that wounding induces transient protection in tomato (Solanum lycopersicum L.) to four pathogens with a range of lifestyles, locally and systemically. The contribution of ethylene (ET) in basal but also in wound-induced resistance to each pathogen, although dispensable, is demonstrated to be positive (Botrytis cinerea, Phytophthora capsici) or negative (Fusarium oxysporum, Pseudomonas syringae pv. tomato). Furthermore, the expression of several defense markers is influenced locally and/or systemically by wounding and ET, and might be part of that core of conserved molecular responses whereby an abiotic stress such as wounding imparts co-resistance to biotic stress. In this addendum, we speculate on some of the physiological responses to wounding that might contribute to the modulation of resistance in a more pathogen-specific manner.
PMCID: PMC2634277  PMID: 19841665
tomato; phytophthora; fusarium; wounding; ethylene; defense mechanisms; electric fields; zoospores; tylosis
24.  Antisense oligodeoxynucleotide inhibition as a potent diagnostic tool for gene function in plant biology 
Plant Signaling & Behavior  2008;3(5):328-330.
Antisense oligodeoxynucleotide (ODN) inhibition emerges as an effective means for probing gene function in plant cells. Employing this method we have established the importance of the SUSIBA2 transcription factor for regulation of starch synthesis in barley endosperm, and arrived at a model for the role of the SUSIBAs in sugar signaling and source-sink commutation during cereal endosperm development. In this addendum we provide additional data demonstrating the suitability of the antisense ODN technology in studies on starch branching enzyme activities in barley leaves. We also comment on the mechanism for ODN uptake in plant cells.
PMCID: PMC2634273  PMID: 19841661
antisense ODN; barley; SBE; SUSIBA2
25.  Actin-based cellular framework for glucose signaling by Arabidopsis hexokinase1 
Plant Signaling & Behavior  2008;3(5):322-324.
Glucose functions in plants both as a metabolic resource as well as a hormone that regulates expression of many genes. Arabidopsis hexokinase1 (HXK1) is the best understood plant glucose sensor/transducer, yet we are only now appreciating the cellular complexity of its signaling functions. We have recently shown that one of the earliest detectable responses to plant glucose treatments are extensive alterations of cellular F-actin. Interestingly, AtHXK1 is predominantly located on mitochondria, yet also can interact with actin. A normal functioning actin cytoskeleton is required for HXK1 to act as an effector in glucose signaling assays. We have suggested that HXK1 might alter F-actin dynamics and thereby influence the formation and/or stabilization of cytoskeleton-bound polysomes. In this Addendum, we have extended our initial observations on the subcellular targeting of HXK1 and its interaction with F-actin. We then further consider the cellular context in which HXK1 might regulate gene expression.
PMCID: PMC2634271  PMID: 19841659
Arabidopsis; F-actin; glucose signaling; hexokinase; hTalin; mitochondria; polysomes; protoplasts; transient expression assay; fluorescence microscopy

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