We treated a patient with a rare combination of ipsilateral fractures of the distal and proximal ends of the radius. A man aged 42 years had simultaneous fractures of the distal and proximal ends of the radius  following a roadside accident. The distal end fracture of the radius was treated with surgical reduction and T-plate volar fixation, and the undisplaced radial neck fracture was treated by an above elbow splintage for 2 weeks. The elbow mobilization was started at 2 weeks. The distal radius was protected for another 4 weeks in a below elbow functional brace. Ipsilateral proximal and distal radial fracture is an uncommon injury pattern. The series illustrates a number of problems associated with this combination. Firstly, one should be aware of this rare injury pattern and there should be greater emphasis on clinical examination of elbow in cases of wrist injuries and vice versa. Once diagnosed, one faces the dilemma of appropriate management in these cases. The appropriate management will depend on the injury characteristics including the age of the patient and the fracture pattern. One should try to preserve the radial head to prevent a possible proximal radial migration especially in younger patients. Fractures of the distal end of the radius are commonly encountered in clinical practice, while fractures of the proximal end of the radius occur mostly when an individual falls with the impact on the outstretched hand, with the elbow joint extended; these fractures should be treated with special attention to associated injury of the ulnar collateral ligament . HoweverA man aged 42 years presented with simultaneous fractures of the distal and proximal ends of the left radius   after a Fractures of the distal end of the radius are often associated with elbow joint dislocation, but rarely with fractures of the proximal end of the radius. Although the reason for this finding is not clear, a fracture of the distal end of the radius may reduce axial pressure applied to the radius, and, thereby, reduce the possibility of an additional fracture occurring at the proximal end of the same radius. Both fractures of proximal and distal radius are quite common individually in adults and children. In fact, distal radius fractures account for 14% of all extremity injuries and 17% of all adult fractures treated in emergency departments . SimilarA less common explanation for these types of injuries may be a direct blow producing a fracture at one radial site along with an axial force created by fall . LookingIpsilateral proximal and distal radial fracture is an uncommon injury pattern. The series illustrates a number of problems associated with this combination. Firstly, one should be aware of this rare injury pattern and there should be greater emphasis on clinical examination of elbow in cases of wrist injuries and vice versa. Once diagnosed, one faces the dilemma of appropriate management in these cases. The appropriate management will depend on the injury characteristics including the age of the patient and the fracture pattern. One should try to preserve the radial head to prevent a possible proximal radial migration especially in younger patients.The authors declare no competing interests.


Clinical holistic medicine has its roots in the medicine and tradition of Hippocrates. Modern epidemiological research in quality of life, the emerging science of complementary and alternative medicine, the tradition of psychodynamic therapy, and the tradition of bodywork are merging into a new scientific way of treating patients. This approach seems able to help every second patient with physical, mental, existential or sexual health problem in 20 sessions over one year. The paper discusses the development of holistic medicine into scientific holistic medicine with discussion of future research efforts.


Lactobacillus and Gardnerella vaginalis have shown that these organisms shared compatibility profiling for the majority of the normal bacterial constituents of the female genital tract. Dominance disruption appears to come from the addition of compatible co-isolates and presumed loss of numerical superiority. These phenomena appear to be the keys to reregulation of BFFGT. Lactobacillus appears to be the major regulator of both G. vaginalis and anaerobic bacteria. When additional organisms are added to the bacterial flora, they may add to or partially negate the inhibitory influence of Lactobacillus on the BFFGT. Inhibitor interrelationships appear to exist between coagulase-negative staphylococci and Staphylococcus aureus and the group B streptococci (GBS) and other beta hemolytic streptococci. Facilitating interrelationships appear to exist between S. aureus and the GBS and selected Enterobacteriaceae.Analysis of 240 consecutive vaginal swabs using the compatibility profile technique revealed that only 2 bacteria have the ability to be a sole isolate and as such a candidate to be a major aerobic regulator of the bacterial flora of the female genital tract (BFFGT). Compatibility profiles of


The chromosomes of 12 samples of cultured Chinese hamster kidney and prostate cells , whose tissue culture properties have already been described  have been examined for numerical change and for the appearance of abnormal markers. Six transformed kidney subclones contained a consistent telocentric marker not present in the normal parental cell, and Giemsa banding demonstrated this to be the centromere and the long (q) arm of the number 4 chromosome in all cases. Two transformed prostate subclones also contained a consistent telocentric marker, not present in similarly derived normal subclones or in the normal parental cell, and Giemsa banding demonstrated this to be a different fragment (the centromere and most of the p arm) of the number 4 chromosome. It is believed that the use of a mixed-serum culture medium, designed to stabilize the karyotype of cultured Chinese hamster cells, is at least partly responsible for the detection of these transformation-associated chromosome changes.


Broken screws after interlocking nailing of long bones are commonly seen in Orthopaedic practice. Removal of such screws can be difficult particularly the distal part which is often held within the bone. We describe a simple technique of using Steinman pin to aid removal of broken screws in a case of non-union fracture tibia with broken interlocking nail and screws. Steinman pin being easily available and the reproducible technique make it a useful aid for removal of broken interlocking screws. Broken interlocking screws are not an unusual problem in Orthopaedic practice and its causes can be varied ,2. WhileA 28 year old male presented with increasing leg pain and disability after a previous interlocking nailing procedure for tibia shaft fracture. Radiographs of his leg showed the broken interlocking nail and screws in the tibia along with the non-union of fracture. To proceed with any revised fixation of the fracture required removal of the original metal work in situ, including the broken interlocking screws.An appropriate incision was made over the screw and the head part of the broken screw removed after dissection. The blunt end of the Steinman pin was then passed down the screw track until it touched the broken end of retained screw Several techniques and methods have been described for removal of broken interlocking nails and screws ,3. The sWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.KS was involved with the initial writing of the manuscript including the literature search. GA is the senior author who described and used the technique. He also reviewed the article and suggested final changes before submission.


The solvolysis of the complex trans-- has been investigated by means of spectroscopic techniques in different solvents. We investigated theindazolium as well as the sodium salt, the latter showing improved solubility in water. Inaqueous acetonitrile and ethanol the solvolysis results in one main solvento complex. Thehydrolysis of the complex is more complicated and depends on the pH of the solution as wellas on the buffer system.The ruthenium(III) complex Hlnd


Sir,Despite the initial success of imatinib  in the treatment of chronic myeloid leukaemia (CML) (Two groups have recently published theoretical models to study the treatment response to imatinib. Our models remain valid given the currently available data. Further experimental and theoretical investigations are needed to increase the understanding of CML stem cell dynamics and to clarify the mechanism of their insensitivity to imatinib.


We produced specula for laryngomicroscopy to observe blind spots in the operating field. Use of these specula has facilitated detailed observation of the lower surface of the false vocal folds, laryngeal ventricle, and subglottis, which were previously in blind spots. The specula are useful in the following ways: 1) clarifying blind spots for improved diagnosis and providing more accurate surgical margins; 2) observing the lower lips of the vocal folds in phonosurgery; and 3) Vaporizing with laser reflection. The specula are cheap and easy to use and are well worth considering for application to laryngomicroscopy.


Genetic and environmental factors have been widely suggested to contribute to the pathogenesis of primary biliary cirrhosis (PBC), an autoimmune disease of unknown etiology leading to destruction of small bile ducts. Interestingly, epidemiologic data indicate a variable prevalence of the disease in different geographical areas. The study of clusters of PBC may provide clues as to possible triggers in the induction of immunopathology. We report herein four such unique PBC clusters that suggest the presence of both genetic and environmental factors in the induction of PBC. The first cluster is represented by a family of ten siblings of Palestinian origin that have an extraordinary frequency of PBC (with 5/8 sisters having the disease). Second, we describe the cases of a husband and wife, both having PBC. A family in which PBC was diagnosed in two genetically unrelated individuals, who lived in the same household, represents the third cluster. Fourth, we report a high prevalence of PBC cases in a very small area in Alaska. Although these data are anedoctal, the study of a large number of such clusters may provide a tool to estimate the roles of genetics and environment in the induction of autoimmunity.


Traction apophysitis of medial malleolus is very rare and presented in view of its rarity. A 13 years old boy presented with pain and swelling without history of trauma around left ankle of 3 months duration. The swelling was diffuse with tenderness on anterior aspect of medial malleolus. The overlying skin was normal. The X-rays revealed fragmented accessory ossification centre of medial malleolus an left side. MRI revealed multiple foci of hypointensity in T1 and T2 weighted images of left medial malleolus apophysis. Patient was treated in below knee plaster for three weeks with restriction of sports activities for 5 weeks. The patient became asymptomatic in 8 weeks. Traction apophysitis is a well-known entity and commonly seen in children involved in sports activities. Accessory ossification centers may appear as normal variant at the medial malleolus in growing children but traction apophysitis is very rare. We are reporting a case of traction apophysitis of medial malleolus in a child with review of the literature.A 13-year-old boy presented with pain and swelling around the left ankle region for three months. He was very active in outdoor sports activities. The pain used to increase on activity. There was no history of trauma. On examination there was diffuse swelling around the medial malleolus on the left side. Overlying skin was normal in appearance. Tenderness was present over the anterior aspect of the medial malleolus and there was pain on valgus stress applied to the ankle. Routine blood investigations were within normal limits. Plain X-ray of ankle showed accessory ossification center of the medial malleolus on both sides. The accessory ossification center on the right side showed uniform density with smooth margins and on the left side was fragmented . An MRI On the basis of clinical and radiological findings a diagnosis of traction apophysitis of the medial malleolus was made. Below the knee POP slab was applied on the left side for three weeks and sports activities were restricted for another five weeks. The patient became asymptomatic in eight weeks.The traction apophyses are sites of active growth in children consisting of columns of growth cartilage uniting tendon with bone. Injuries at the traction apophysis may result from a single episode of macro trauma with resultant frank avulsion of a portion of apophysis or may result from repetitive micro trauma with resulting pain, swelling and on occasion bony and cartilaginous overgrowth referred to as apophysitis.Another factor that is active in the occurrence of traction apophysitis is the growth process itself. Longitudinal growth occurs in the bones of the extremities and spine, with the soft tissue- muscle tendon units, ligaments and so on secondarily elongating in response to this growth. During this rapid growth, there can be a measurable increase in muscle-tendon tightness around the joints, with loss of flexibility and an enhanced environment for overuse injury. As the tight muscle tendon unit is subject to repetitive overload, there is an increased potential for repetitive tiny avulsion fractures at the weakest site in the muscle- tendon unit, the apophyseal growth cartilage.The final factor associated with the onset of most of the traction apophysitis is repetitive stress applied to the apophysis, often in the form of repetitive sports training or competition.The accessory centers of ossification of the medial malleolus are common in skeletally immature individuals.–5 They uMany of the ossification centers are identified accidentally when radiographs are taken to evaluate injury at the ankle or foot. At times they may be mistaken for fractures. A smooth appearance on both sides of the radiolucency usually obviates the diagnosis.There have been very few reports describing symptomatic accessory center at the medial malleolus with no history of trauma.45 Ogden 4Conservative management in the form of restriction of activities with or without immobilization leads to resolution of symptoms in one to six months depending on the severity of injury.5The case described in this report showed fragmentation of the accessory center on both the X-ray and MRI. Clinico-radiological diagnosis of apophysitis of the medial malleolus was made and conservative treatment was given in the form of plaster slab and rest which showed good results.Extra centers of ossification at the tip of the internal malleolus are common in children. Most of them remain asymptomatic and eventually fuse with the lower tibial epiphysis. A few of them become symptomatic in children involved in sports activities due to repetitive trauma. Conservative management in the form of restriction of activities and splintage gives good results.


Our previous studies, in specimens of large intestine resected for carcinoma, have shown abnormal patterns of mucous secretion in areas of apparently "normal" mucosa, where goblet cells produce mainly sialomucins as compared with the true normal colonic mucosa in which sulphomucins predominate. In the present work, large bowel cancer was induced in rats by the administration of 1,2-dimethylhydrazine-2HCl (DMH). We attempted to study the sequential histological and secretory abnormalities which developed in the colonic epithelium during carcinogenesis, and to correlate these changes with those described above in the human. The microscopical and histological lesions observed in the colonic mucosa of DMH treated rats confirmed the findings of other authors and resembled the human colorectal cancer. The earliest changes detected were small foci of hyperplasia accompanied from the 6th week onwards by several foci of dysplasia. Carcinoma in situ appeared at the 15th week and finally invasive carcinoma developed from the 19th week onwards. Changes in the type of mucous secretion, with predominance of sialomucins, were observed in the majority of the areas showing mild to moderate dysplasia whilst the surrounding normal epithelium produced suphated material. Mucous depletion was a common feature in areas of severe dysplasia and carcinoma. These findings correlated well with the similar variations in the mucin composition observed in human colonic mucosa in carcinoma and further supported our previous hypothesis that mucin changes characterized by an increase in sialomucins might reflect early malignant transformation. If this hypothesis proved to be correct, the use of a simple method for the identification of mucins in large bowel biopsies would be of great help in detecting early malignancy.


Distal colostography (DC), also called distal colography or loopography, is an important step in the reparative management of anorectal malformations (ARMs) with imperforate anus, Hirschsprung's disease  and colonic atresia (rarely) in children and obstructive disorders of the distal colon  in adults. It serves to identify/confirm the type of ARM, presence/absence of fistulae, leakage from anastomoses, or patency of the distal colon. We present a pictorial essay of DC in a variety of cases. Distal colostography (DC) is an important diagnostic investigation to delineate the altered anatomy of anorectal malformations and know the spectrum of associated fistulae between the blind rectum on the one hand and the bladder, urethra, perineum and vagina on the other. It remains a dependable test for a surgeon to plan surgical repair.Anorectal malformations (ARMs) occur with an incidence of 1 in 5000[About one month after colostomy or before the reparative surgery is planned, distal colostography (DC) is essential. It serves many purposes; it helpsFind the degree of fecal impaction and ectasia of the blind end of the rectum . Prior iJudge the distance of the blind rectum from the marker placed at the expected site of the anus (pouch-to-perineum distance)Detect precisely the various types of rectal fistulae4 Figure–7, cloacAccording to Durham, Keiller 7The technique followed by us is as follows:A marker is placed over the anal dimple or expected position of the anus. Another marker is placed at the point where urine or fecal material is seen to be discharging.After passing an indwelling catheter through the stoma leading to the distal colon, its balloon is inflated and it is pulled back during injection of the contrast to avoid any spillage. The distal blind end of the colon gets filled progressively and pressure is maintained till the contrast fills the fistulous tract.Water-soluble contrast is used.Images are obtained under fluoroscopy.The colostogram is obtained in the lateral position, with the femora overlapping as perfectly as possible, to determine the level of the blind end of the rectum and identify the type of ARM.In practice, DC is a very useful technique since it has a high specificity. Its sensitivity can be increased if proper care is taken to demonstrate the most distal end of the blind rectum and the fistula.Some surgeons perform a defunctioning colostomy for the management of the aganglionic colon. DC confirms the earlier diagnosis and helps in planning the further course of action .In dealing with strictures due to chronic colitis or complicated diverticulosis and malignant tumors of the rectosigmoid region a defunctioning colostomy and resection with anastomosis are undertaken. DC is useful to check for any leakage from the site of anastomosis before closure of the colostomy .


This paper provides a brief overview of the Canadian physical activity communications and social marketing organization "ParticipACTION"; introduces the "new" ParticipACTION; describes the research process leading to the collection of baseline data on the new ParticipACTION; and outlines the accompanying series of papers in the supplement presenting the detailed baseline data.Information on ParticipACTION was gathered from close personal involvement with the organization, from interviews and meetings with key leaders of the organization, from published literature and from ParticipACTION archives. In 2001, after nearly 30 years of operation, ParticipACTION ceased operations because of inadequate funding. In February 2007 the organization was officially resurrected and the launch of the first mass media campaign of the "new" ParticipACTION occurred in October 2007. The six-year absence of ParticipACTION, or any equivalent substitute, provided a unique opportunity to examine the impact of a national physical activity social marketing organization on important individual and organizational level indicators of success. A rapid response research team was established in January 2007 to exploit this natural intervention research opportunity.The research team was successful in obtaining funding through the new Canadian Institutes of Health Research Intervention Research  Funding Program. Data were collected on individuals and organizations prior to the complete implementation of the first mass media campaign of the new ParticipACTION.Rapid response research and funding mechanisms facilitated the collection of baseline information on the new ParticipACTION. These data will allow for comprehensive assessments of future initiatives of ParticipACTION. ParticipACTION was launched as a physical activity communications and social marketing organization in 1971 with financial support from the Government of Canada . The orgDuring its 30-year mandate, ParticipACTION became a catalyst for physical activity across Canada and was viewed internationally as an exemplar of a highly successful national physical activity social marketing organization, with many award winning campaigns  or who have a key interest in physical activity promotion  as well as locally based alliances to increase physical activity . The mandate of the new ParticipACTION is contextualized within the broader Integrated Pan-Canadian Healthy Living Strategy [Pan-Canadian Physical Activity Strategy [During its first year of operations, ParticipACTION focused on developing and launching the first in a series of annual mass media campaigns. In subsequent years, it is planned to expand activities to include knowledge transfer; ongoing and coordinated communication; and supportive activities to increase the capacity of Canada's physical activity and sport delivery system, comprised of governmental and non-governmental organizations at the national and provincial/territorial level whose primary mandate is physical activity  by gathering individual-level data on awareness of the brand, campaign recall, knowledge, understanding and physical activity behaviours before and during the early period after the launch of the revitalized ParticipACTION. Baseline data were also collected at an organizational level to assess the future impact of a sustained campaign through ParticipACTION on the overall capacity of the physical activity sector in Canada.http://www.researchnet-recherchenet.ca/rnr16/viewOpportunityDetails.do?prog=399&view=search&terms=intervention+research&org=CIHR&type=AND&resultCount=25). The combination of early knowledge of this ensuing natural intervention and the announcement of the CIHR funding program created a perfect opportunity to collect important baseline data before the official resurrection of ParticipACTION.During early discussions of the possible resurrection of ParticipACTION the lead author of this paper (MST) was appointed to the new Board of ParticipACTION and its Executive Committee. This privileged position allowed MST to facilitate strategic research planning extraneous to the operations of the Board and Executive. At the same time (early December 2006), though serendipitous to this strategic research planning, the Canadian Institutes of Health Research (CIHR) announced a new strategic funding opportunity titled the "Intervention Research  Funding Program". This program was targeted towards funding research that examines "natural interventions" which are out of the control of researchers yet provide important, time-sensitive research opportunities. Accordingly, this funding opportunity did not follow the typical application and review process, allowing for applications to be submitted whenever the natural intervention opportunity presented itself (e.g. no fixed application date) and providing a thorough though expedited review process  was convened in Saskatoon, Canada to discuss the appropriateness and viability of research possibilities to assess and study the impact of the revitalization and re-launch of ParticipACTION in the form of a natural intervention. The research team represented a good balance of experience with ParticipACTION, intervention research and natural experiments, and physical activity monitoring and measurement. The opportunity to collect pre-resurrection, baseline data at both individual and organizational levels was time-limited and required immediate action that this team could act upon. The objectives of this initial meeting were to:• Take advantage of a natural experiment opportunity• Test the new CIHR funding mechanism/opportunity• Test the viability and responsiveness of the research community RRRT concept• Link previously unlinked researchers and create networking opportunities• Challenge ParticipACTION's commitment to research and evaluation• Exploit and advance the learnings from the "Canada on the Move" initiative • Produce a letter of intent for the CIHR funding opportunityTwo letters of intent were generated at this initial meeting of the RRRT. One proposal focused on individual level data and a second on organizational level capacity (described further below). The cascade of events related to the preparation and outcome of this meeting are summarized below.Key dates:• CIHR funding announcement: December 8, 2006• ParticipACTION resurrection funding confirmed: December 8, 2006• Funding request to CIHR and ParticipACTION to host the initial RRRT meeting: December 19, 2006• Notice of support for meeting funding request: December 22, 2006• RRRT meeting: January 19-20, 2007• Record of Discussion of meeting completed: January 21, 2007• Two letters of intent submitted to CIHR: January 24, 2007• Approval of two letters of intent received by email: February 21, 2007• Two full research proposals submitted to CIHR: March 21, 2007• Notification that both proposals were funded: June 18, 2007• Data collection for both projects: August 2007 - February 2008Six months passed between conception of the idea and full research funding being approved and within 13 months of the RRRT first meeting, the research data collection was complete. This very rapid sequence of events was necessary to collect baseline data before the first campaign of the "new" ParticipACTION was widely recognized.The ParticipACTION proposals were the first to be reviewed through the new CIHR funding mechanism and although the process went reasonably smoothly (as indicated by the sequence of events summarized above) the CIHR made subsequent adaptations to the review procedures in an effort to further expedite the process. In summary, the new CIHR funding opportunity allowed for the successful completion of this research - an opportunity previously unavailable through traditional funding mechanisms in Canada. Both the CIHR and the RRRT benefited and learned from this novel funding mechanism. This is a good example of constructive and productive cooperation and collaboration between researchers and a research granting agency.To assess baseline awareness and understanding of ParticipACTION at an individual level, a population-based survey was conducted on a monthly basis over a period of six months from late August 2007 to February 2008. The survey consisted of a set of questions on the Physical Activity Monitor conducted by the Institute for Social Research at York University on behalf of the Canadian Fitness and Lifestyle Research Institute (CFLRI). The details of this project and the findings of the baseline data collection are described in the paper by Spence and colleagues .The examination of population based physical activity campaigns has been limited with a focus on dissemination and accuracy, the behavioural effect of messages, and/or the recall of media items by the general public -17. LessA sample of respondents from the quantitative survey  were conAn assessment of the inaugural mass communications campaign of the "new" ParticipACTION was completed using an internet-based survey conducted by Angus Reid Strategies. This survey evaluated awareness of ParticipACTION, its recent campaign and assessed the recall and interpretation of the campaign messaging in both the target market (parents with children aged 7-12 years) and others. The findings from this campaign evaluation are presented in the paper by Craig and co-workers .Finally, Bauman et al.  provide ParticipACTION has a distinguished history and can serve to inform future physical activity social marketing initiatives. The resurrection of ParticipACTION provided a unique research opportunity to establish baseline data to allow for future campaign assessments. A rapid response research team was established to exploit this opportunity and the new research funding opportunity of the CIHR allowed this opportunity to flourish. The findings from the baseline research are summarized in the papers that follow this brief introduction. This research provides a valuable platform for monitoring the future impact of ParticipACTION on the physical activity levels of Canadians. It is also hoped that this short series of papers informs the efforts of others attempting to assess the impact of physical activity communications and social marketing programs and campaigns elsewhere.The authors have been involved on various committees and advisory groups for both the previous and "new" ParticipACTION including the Board of Directors (MST). The Canadian Fitness and Lifestyle Research Institute (CFLRI) was previously contracted by the "new" ParticipACTION to perform research and surveillance - CLC is President of CFLRI but received no personal compensation for the contracted work.MST conceived of and initiated the study of the natural intervention of the re-emergence of the "new" ParticipACTION. MST and CLC co-wrote this manuscript.


Sir,Periodontitis is a destructive inflammatory disease of the supporting tissues of the teevth and is caused by specific microorganisms or group of specific microorganisms resulting in progressive destruction of periodontal ligament and alveolar bone with periodontal pocket formation, gingival recession or both.2 The hos


A versatile automated apparatus, equipped with an artificialintelligence has been developed which may be used to prepare andisolate a wide variety of compounds. The prediction of the optimumreaction conditions and the reaction control in real time, areaccomplished using novel kinetic equations and substituent effects inan artificial intelligence software which has already reported [1].This paper deals with the design and construction of the fullyautomated system, and its application to the synthesis of asubstituted N-amino acid. The apparatus is composedof units for perfoming various tasks, e.g. reagent supply,reaction, purification and separation, each linked to a controlsystem. All synthetic processes including washing and drying of theapparatus after each synthetic run were automatically performedfrom the mixing of the reactants to the isolation of the products aspowders with purities of greater than 98%. The automatedapparatus has been able to run for 24 hours per day, and the averagerate of synthesis of substituted N-amino acids hasbeen three compounds daily. The apparatus is extremely valuablefor synthesizing many derivatives of one particular compoundstructure. Even if the chemical yields are low under the optimumconditions, it is still possible to obtain a sufficient amount of thedesired product by repetition of the reaction. Moreover it waspossible to greatly reduce the manual involvement of the manysyntheses which are a necessary part of pharmaceutical research.


The immune response of the neonate is poor and is dependent on passive immunity provided by maternal Ig. However, here we show that exposure of the neonate to environmental antigens induces a germinal center (GC) reaction. In the peripheral blood of premature infants one finds IgG class switched B cells expressing a selected V-gene repertoire. These data suggest that restrictions in the repertoire rather than immaturity of the immune system is responsible for the poor immune responses of the neonate.


Radial nerve compression by a ganglion in the radial tunnel is not common. Compressive neuropathies of the radial nerve in the radial tunnel can occur anywhere along the course of the nerve and may lead to various clinical manifestations, depending on which branch is involved. We present two unusual cases of ganglions located in the radial tunnel and requiring surgical excision.A 31-year-old woman complained of difficulty in fully extending her fingers at the metacarpophalangeal joint for 2 weeks. Before her first visit, she had noticed a swelling and pain in her right elbow over the anterolateral forearm. The extension muscle power of the metacarpophalangeal joints at the fingers and the interphalangeal joint at the thumb had decreased. Sonography and magnetic resonance imaging of the elbow revealed a cystic lesion located at the area of the arcade of Frohse. A thin-walled ovoid cyst was found against the posterior interosseous nerve during surgical excision. Pathological examination was compatible with a ganglion cyst. The second case involved a 36-year-old woman complaining of numbness over the radial aspect of her hand and wrist, but without swelling or tumor in this area. The patient had slightly decreased sensitivity in the distribution of the sensory branch of the radial nerve. There was no muscle weakness on extension of the fingers and wrist. Surgical exposure defined a ganglion cyst in the shoulder of the division of the radial nerve into its superficial sensory and posterior interosseous components. There has been no disease recurrence after following both patients for 2 years.Compression of nerves by extraneural soft tissue tumors of the extremities should be considered when a patient presents with progressive weakness or sensory changes in an extremity. Surgical excision should be promptly performed to ensure optimal recovery from the nerve palsy. Compressive neuropathies are important and widespread debilitating clinical problems. The two most common compressive peripheral nerve disorders in the upper limb are carpal tunnel syndrome and cubital tunnel syndrome, however, radial tunnel syndrome occurs less frequently . The radA 31-year-old woman complained of difficulty in fully extending her fingers at the metacarpophalangeal joint for 2 weeks. Before her first visit, she had noticed swelling and pain in her right elbow over the anterolateral forearm. Examination revealed a tender swelling in the anterolateral region of the antecubital fossa but no clinical evidence of a mass. The extension muscle power of the metacarpophalangeal joints at her fingers and the interphalangeal joint at her thumb had decreased. The patient had full strength with resisted wrist extension and resisted supination. The radial nerve sensibility was normal. An electromyogram and nerve conduction study showed early partial neuropathy of the posterior interosseous nerve. Sonography revealed a mass continuous with the posterior interosseous nerve immediately distal to the radiocapitellar joint. Magnetic resonance imaging (MRI) of the elbow revealed a cystic lesion located at the area of the arcade of Frohse, which was attached to the anterior capsule of the radiocapitellar joint Figure . Due to A 36-year-old, right-handed woman complained of numbness over the radial aspect of her hand and wrist. She complained of pain in the lateral aspect of her elbow but did not notice swelling or tumor in this area. On physical examination, a mass could not be definitely detected by palpation. The patient had slightly decreased sensitivity in the distribution of the sensory branch of the radial nerve. There was no muscle weakness on extension of her fingers and wrist. Electrodiagnostic studies were consistent with the diagnosis of neuropathy of the sensory branch of the radial nerve. Ultrasonography and MRI each demonstrated a well-defined mass just anterior to the radiocapitellar joint Figure . SurgicaRadial nerve entrapment in the radial tunnel is uncommon in peripheral nerve compressive neuropathies. There are three different types of palsy in the radial tunnel syndrome: posterior interosseous nerve palsy, neuropathy of the sensory branch of the radial nerve, and neuropathy of both nerves ,3. The pet al. reported 14 patients presenting with posterior interosseous nerve (PIN) paralysis due to a ganglion at the elbow, located proximal to the proximal edge of the supinator muscle in 13 cases and distal in one [Our first case experienced lateral forearm pain that is initially often difficult to distinguish from lateral epicondylitis, synovitis of the radiocapitellar joint, and a muscle tear of the extensor carpi radialis brevis . Howeverl in one . These fCompression of the posterior interosseous nerve by a ganglion was first reported by Bowen in 1966 . He recoWhen a ganglion is not detected by palpation in cases with palsy of the posterior interosseous nerve or sensory branch, differential diagnosis of the cause of the palsy may be difficult. Compression of nerves by extraneural soft-tissue tumors of the extremities, although not common, should be considered when a patient presents with progressive weakness or sensory changes in an extremity. This is true whether or not a soft-tissue mass is found during examination, since an occult soft-tissue tumor was found in approximately one-third of patients at the time of operation in a report by Barber .Ultrasound and MRI have been used to detect space-occupying lesions causing nerve compression . UltrasoStandard surgical management for persistent neuropathy, refractory to non-surgical treatment, is open decompression of the radial nerve. This can be done through a variety of anterior or lateral approaches. The approach includes addressing all of the potential sites of compression in addition to excising the mass lesions described previously which may cause compression of the radial nerve.Radial nerve compression by a ganglion in the radial tunnel is an uncommon condition. We report two cases of posterior interosseous nerve and superficial sensory branch compression by a ganglion cyst. The value of this case report to the practicing physician is that it sheds light on the importance of familiarity with the possible presentation, anatomic location and differential diagnosis to facilitate corrective diagnostic approaches and timely management.Written informed consent was obtained from both patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.IMJ participated in the surgical interventions, contributed to the study concept and design and drafted the manuscript. HNW participated in the medical interventions, took the photographs and undertook the literature review. ISY was involved in reviewing the histological section of the case and proofreading of the manuscript. WRS participated in the surgical interventions and helped draft the final version of this manuscript to be published. All authors read and approved the final manuscript.


Oral potassium permanganate has been used in the management of terminal carcinoma in three patients. Symptomatic improvement occurred in all three, with elimination of oral foetor in one patient and diminished requirement of analgesics in the other two. The mental state of each patient was improved and normal activities were resumed.


Laser in vivo confocal microscopy noninvasively provides images that are equivalent to high quality histology. We have now applied this technique to identify pathological characteristics of traumatic recurrent corneal erosion (RCE).Six eyes of six patients with traumatic RCE were studied. Corneas were examined with a slit lamp biomicroscope and with a laser in vivo confocal microscope (Heidelberg Retina Tomograph II–Rostock Cornea Module or HRTII-RCM) at various times after the onset of the most recent recurrence of corneal erosion.Brightly reflective granular structures were detected by the HRTII-RCM system in the basal and wing cell layers of the corneal epithelium in all eyes affected by recurrent erosion. Activated keratocytes and scattered fine particles were also apparent in the shallow stroma of five of the six affected eyes. These features were not observed in the normal cornea.The HRTII-RCM system allows detection of characteristic abnormal structures in the cornea of individuals with traumatic RCE. The presence of granular structures in the corneal epithelium as well as persistent inflammation in the shallow stroma may contribute to the deterioration of the corneal epithelial cell alignment and to the weakening of adhesion between the basal epithelial cells and the basement membrane in RCE lesions. Recurrent corneal erosion (RCE) is characterized by repeated episodes of corneal epithelial defects that are usually accompanied by the sudden onset of eye pain upon awakening as well as by hyperemia, photophobia, and tearing . RCE is The development of confocal optics has allowed changes in corneal cells to be examined layer by layer ,6. FurthWe undertook a retrospective evaluation of six patients with traumatic unilateral RCE at Yamaguchi University Hospital, Ube, Yamaguchi Japan. We also examined 30 volunteers (30 eyes) without any apparent pathology of the cornea. The six patients were referred to our hospital by their local ophthalmologists for diagnosis or treatment of their corneal epithelial disorders. All patients had at least two episodes of corneal erosion since the last corneal trauma. Sex, age, best corrected visual acuity (BCVA) at the initial visit, date of onset of the most recent erosion episode, and corneal lesion findings by slit lamp biomicroscopy and in vivo confocal microscopy were recorded. All subjects were informed of the aims of the study, and their consent was obtained. The study was approved by the institutional review board of Yamaguchi University Hospital.In vivo confocal microscopy was performed with the HRTII-RCM system. Before examination, a drop of gel  was placed on the front side and inside of a TomoCap . One drop of topical anesthetic  and one drop of gel (Comfort Gel) were instilled into the lower conjunctival fornix of each eye. Corneal lesions were scanned by alternating vertical and horizontal movement of the applanating TomoCap from the upper edge of the lesion toward the lower edge. Several confocal microscopic images of tangential optical sections of the superficial, wing, and basal cell layers of the corneal epithelium, the stroma, and the endothelium were obtained for each eye. Oblique sections were also obtained when necessary. All in vivo confocal microscopy was performed by a single investigator (N.T.). No complications with the HRTII-RCM system were noted during examination.The clinical characteristics of the six patients with traumatic unilateral RCE are shown in Abnormal findings by in vivo laser confocal microscopy in the corneas affected by RCE  includedWe divided the six cases into three groups on the basis of the time between the onset of the most recent episode of RCE and examination by in vivo confocal microscopy. Cases 1 and 2 were in the early stage group because in vivo confocal microscopy was performed within two and three days after the onset of RCE, respectively. All of the abnormal findings for RCE with the exception of keratoprecipitates for case 1 were observed with the HRTII-RCM system in the corneas of these two cases. Cases 3 and 4 were in the mid-stage group because in vivo confocal microscopy was performed at 10 and 16 days, respectively, after the onset of RCE. The in vivo confocal microscopic images for cases 3 and 4 revealed enlarged basal cells, brightly reflective granular structures in the corneal epithelium and Bowman’s layer, activated keratocytes in the shallow stroma, and scattered fine particles in the shallow stroma. In contrast, gaps in the epithelial cell layers and inflammatory cell infiltration in the mid stroma were not observed in this group. Cases 5 and 6 constituted the late stage group in which in vivo confocal microscopy was performed 30 days or more after the onset of RCE, respectively. Both corneas of this group manifested brightly reflective granular structures in the corneal epithelium and Bowman’s layer whereas case 5 also exhibited activated keratocytes in the shallow stroma and scattered fine particles in the shallow stroma. The in vivo confocal microscopic findings for all cases are summarized in Corneal epithelial debridement was performed for the affected area in four patients . These four patients had not developed any recurrence of erosion, and no brightly reflective granular structures in the corneal epithelium were detected with the HRTII-RCM system one month after the treatment .We have identified candidate pathological characteristics of the lesions associated with traumatic RCE with the use of in vivo laser confocal microscopy. Among these characteristics, the irregularity of superficial epithelial cell alignment is suggestive of the active migration of epithelial cells to cover epithelial defects whereas the gaps in epithelial cell layers appear to reflect such defects or incomplete epithelial cell migration. The enlargement of basal epithelial cells likely represents a compensatory response to the lack of overlying epithelial cells. The absence or reduced number of subepithelial nerves suggests that the nerves are destroyed or damaged in association with the epithelial defect. Given that subepithelial nerves appeared normal in cases 5 and 6, it is possible that the damaged nerves regenerate with time after epithelial erosion. The infiltration of inflammatory cells in the mid stroma and the presence of keratoprecipitates on the endothelium are indicative of an acute inflammatory response secondary to epithelial defects. These characteristics were apparent in the early and mid stages of the erosion episodes and are likely not specific to RCE. In contrast, the brightly reflective granular structures in the corneal epithelium and Bowman’s layer were observed at all stages of RCE in the cases studied. These structures likely represent deposition of hyperreflective material, most probably cell debris. In vivo confocal microscopy performed after LASIK has also revealed brightly reflective particles at the corneal interface ,12,13. TThe cause of RCE after traumatic injury is thought to be the failure to recover tight adhesion between the wounded corneal epithelial cells and the underlying stroma. RCE can also result from loss of adhesion due to a defect in the basement membrane in the cornea of individuals with epithelial basement membrane dystrophies . In suchEven in asymptomatic stages of traumatic RCE as exemplified by cases 4, 5, and 6, we observed brightly reflective granular structures in the basal and wing cell layers of the corneal epithelium as well as a persistent mild inflammatory response in the shallow stroma. Although RCE can occur in patients with epithelial basement membrane dystrophies and after traumatic injury, its pathology appears to differ between the two types of case. Even though the present study includes only a small number of cases, our findings provide a basis for speculation on a possible mechanism for traumatic RCE. This condition may thus result from a failure of reconstruction of cell-cell or cell-matrix adhesion structures at the lesion site. This failure may contribute to deterioration of the corneal epithelial cell alignment and to the weakening of adhesion between basal cells and the basement membrane. It may also lead to mild inflammation involving the activation of keratocytes in the shallow stroma and the consequent operation of a vicious cycle involving the epithelium and shallow stroma.The HRTII-RCM system allows detection of abnormal structures in the cornea. Indeed, in vivo laser confocal microscopy noninvasively provides high resolution images that are equivalent to high quality histology, having been termed “in vivo biopsy.” A longitudinal study of patients with RCE is required to provide insight into the natural course of the pathological changes associated with this condition. Furthermore, the efficacy of treatments for RCE such as debridement and bandage contact lenses warrants evaluation with the HRTII-RCM system.In conclusion, in vivo laser confocal microscopy reveals pathological characteristics of RCE. Although the diagnosis of RCE should be made on the basis of clinical progress and careful examination with a slit lamp biomicroscope, the in vivo laser confocal microscope is a powerful tool that can contribute to the diagnosis and management of RCE.


Objective: Avulsion injuries of the dorsum of the foot and ankle present difficult reconstructive problems especially in pediatric patients. Usually, there is exposure of bones, joints, tendons, or ligaments, which requires coverage by flaps. The best skin for coverage is the local skin, but the remaining intact skin is usually limited. Usage of such local skin necessitates elevation of long and narrow skin flaps. These flaps need delay to survive. Method: This study included 8 children who sustained avulsion injuries to their feet and ankles in road traffic accidents. Debridement and delaying flaps using bipedicled flap elevation technique were done in the first session. Dressing of the raw areas was done while the flaps were being delayed. The delayed flaps were elevated in the second session to cover any exposed bone, joints, or ligaments. Split thickness skin grafts were applied to the donor site and to the granulating raw areas. Results: Complete survival of the flaps and complete take of the skin grafts with minimal donor site morbidity. Conclusion: This technique of delaying flaps from the intact skin adjacent to the defect is safe, successful and allows minimal hospital stay. The skin of the dorsum of the foot and ankle is vulnerable to avulsion trauma, because it is thin and loosely attached to the underlying tendons, ligaments, and bones.Eight pediatric patients who sustained avulsion injuries to their foot and ankle in road traffic accidents were managed. They were 7 male and 1 female. They ranged in age between 4 and 12 years. They presented with avulsion injuries involving the dorsum of the foot and lateral ankle regions. There was fracture of lower tibia and fibula in one case that necessitated external fixation. There were different combinations of exposure of bones, tendons, ligaments, and joints. The edges of the wounds showed friction burns. The preoperative photo of one of the patients on admission is shown in Figure The 2-week delay in coverage of the raw area allowed granulation of most of the bed except exposed bone at the ankle joints. The 2-week gap in addition allowed healing of the friction burns at the edges of the wound. The delayed flaps survived completely and provided adequate coverage. The take of the split-thickness skin grafts over the donor site of flaps and over the granulated raw area was 100%. The donor site of split-thickness skin grafts healed in 2 weeks. The splints provided stability of the ankle joint in a right-angle position and prevented shearing of the split-thickness skin grafts. Loss of the dorsi-flexors of the lateral toes in trauma did not constitute a major functional deficit. The aesthetic outcome was acceptable because there was no donor site morbidity in any region away from the site of injury. Apart from the patient who had external fixation, the patients became ambulatory after complete wound healing. No subsequent breakdown of the grafted skin or unstable scars with regular wearing of shoes were found. There were hypertrophic scars in 3 patients, which necessitated wearing pressure garments for 3 months. The patients walked without noticeable limping after 2 to 3 months. The relatively short follow-up period did not allow investigating the effect on growth (limb-length discrepancy). The postoperative photos of 2 children are shown in Figures Reconstruction of the soft tissue defect on the dorsum of the foot and ankle is challenging. Local skin flaps are limited by the area of the remaining nonavulsed skin on the dorsum of the foot. Reverse-flow fasciocutaneous flaps have the disadvantages of sacrificing an important artery in the leg and the obvious contour deformity of the donor site.The remaining intact skin on the dorsum of the foot can be used for reconstruction, but the risk of impaired vascularity is high because the flap will be long and narrow. To avoid this risk, the flap was delayed. A surgical delay increases the survival length of a flap by allowing the choke vessels to dilate between adjacent perforators.4The advantages of the local delayed flaps are numerous. They include safe flap elevation regarding vascularity, no donor site morbidity in leg, and no flap crossing the ankle joint. One sheet graft can be applied to both raw area and the adjacent donor site of flap. It is a narrow and thin skin flap and will not add any bulk or produce obvious dog ears. The contracture, which is expected to happen in skin graft on the long term, compensates for the loss of dorsiflexors of lateral toes.This technique is advised to be used by surgeons who do not have free-flap expertise or who cannot achieve high success rate. Thin free cutaneous flaps surely will provide total coverage with no need for skin graft and better local aesthetic results.


Bos gaurus (H. Smith) (Artiodactyla: Bovidae) and Asian elephant, Elephas maximus Linnaeus (Proboscidea: Elephantidae), is reported from the moist forests of Western Ghats, in South India. The dominance of dwellers over rollers, presence of many endemic species, predominance of regional species and higher incidence of the old world roller, Ochicanthon laetum, make the dung beetle community in the moist forests of the region unusual. The dominance of dwellers and the lower presence of rollers make the functional guild structure of the dung beetle community of the region different from assemblages in the moist forests of south East Asia and Neotropics, and more similar to the community found in Ivory Coast forests. The ability of taxonomic diversity indices to relate variation in dung physical quality with phylogenetic structure of dung beetle assemblage is highlighted. Comparatively higher taxonomic diversity and evenness of dung beetle assemblage attracted to elephant dung rather than to gaur dung is attributed to the heterogeneous nature of elephant dung. Further analyses of community structure of dung beetles across the moist forests of Western Ghats are needed to ascertain whether the abundance of dwellers is a regional pattern specific to the transitional Wayanad forests of south Western Ghats.The community structure of dung beetles attracted to dung of gaur,  Rollersnesters) .Dung beetles have a variety of effects on the ecosystem. By burying dung and carrion as food for their offspring, dung beetles may increase the rate of soil nutrient cycling  and redue.g., according to their diet and their resource-relocation behavior). Dung beetle communities are strongly influenced by dung type and they change in relation to the availability of different dung types  and elephants is the preferred resource for several dung beetle species  and gaur, Bos gaurus (H. Smith) (Artiodactyla: Bovidae), are the major mega-mammalian herbivores in the moist forests of Western Ghats  (n° 53′ N latitude and 76°01′  E longitude), 100 km North of Calicut, Kerala state  provide a wide choice of resource materials for grazers and browsers . Earlier studies on the succession pattern of dung beetles showed that dung pats that were 3–7 days older attracted a subset of species that were not attracted to fresh dung , Calicut and Indian Agricultural Research Institute (IARI), New Delhi.Rainfall data was collected from the records of Kerala State Electricity Board at Thirunelly. Humidity and forest floor temperature were assessed with thermo-hygrometer. Slope of the terrain was calculated using the trigonometric formula ‘tanθ’ (where ‘θ’ is the angle of inclination).+) and variation in taxonomic distinctness (Λ+) indices  with respect to the master list values were estimated by drawing 95% confidence funnels using Primer package  and two first reports from the Western Ghats (Onthophagus laevis and O. brutus) , and Drepanocerus setosus, a dweller (10.5%), dominated the assemblage  (P = 0.09). 21 species belonging to 10 genera, six tribes and three nesting guilds were collected from elephant dung  were lower in comparison to elephant dung beetle assemblage . Values of both taxonomic diversity indices fell within the 95% limits of the probability funnel indicating that taxonomic diversity of both the assemblages did not vary significantly from the regional species pool.As shown in  brutus) . Beetlessemblage . Tunneleundance) . Smallerant dung . Bray CuA taxonomic diversity index is a measure of biodiversity that indicates how different the species in a habitat are from each other . The taxThe first report of the community structure and diversity of dung beetles in a moist forest locality in Western Ghats and South Asian region is provided. Most conspicuous is the difference observed in the guild structure of the community, when compared to dung beetle assemblages from other moist forests of the Afrotropical region. Dwellers are the dominant functional guild after tunnelers, and rollers are lower in richness and abundance. Such high abundance of dwellers is reported previously only from the moist forests of Ivory Coast in Africa.Onthophagus laevis and O. brutus) from Western Ghats and high abundance of endemics (32.6 %) indicate that further characterization of the dung beetle faunal diversity of other forests of Western Ghats down to more local scales may reveal more details of the regional variation in endemism and localised distribution patterns.Combining the 37 species recorded from the present study along with 7 species reported exclusively from elephant dung  leads toO. laetum, whose overall abundance is very low in south east Asian forests . Dominance by a few tunneler, roller or guild unspecified species  in the range of 56.7 % to 29.4% or tunneler species alone in the range of 34% 40.5%, is a general pattern of tropical moist forest dung beetle communities. Moist forests of the Ivory Coast . A similar situation exists in the moist forests of Ivory Coast in Western Africa with the abundance of Oniticellus pseudoplanatus (Oniticellini) and is attributed to the availability of undisturbed elephant dung pats in the region  and large rollers (Gymnopleurus) are abundant in the middle and low elevation  moist forests  values indicate the presence of a phylogenetically closely related dung beetle assemblage. Analysis of taxonomic evenness by truncating the tree at various places and by removing the speciose genera showed that both taxonomic evenness and diversity of gaur dung beetle assemblage equaled that of elephant when species distribution under the genera Onthophagus and Caccobius were made even in both assemblages. High unevenness in taxonomic structure of the gaur dung beetle assemblage arises from the overrepresetation of Onthophagus and Caccobius species. The presence of 24 species of Onthophagus and 3 species of Caccobius in gaur dung (65% of the species attracted to gaur dung from genus Onthophagus and 73% from genus Onthophagus and Caccobius) compared to the presence of 7 Onthophagus species (33.3%) and the absence of Caccobius in elephant dung, reduced the taxonomic evenness of gaur dung beetle assemblage. This variation is distinctly shown by Λ+, as the variation in taxonomic distinctness index is sensitive to variations in taxonomic evenness of the assemblage and the presence of speciose genera reduces the taxonomic evenness of the assemblage which is reflected as higher Λ+ values.Although species richness was higher in the dung beetle assemblages attracted to gaur dung pats, high Λ+ of the assemblages showed lesser variations than Λ+, as Δ+ considers only the relatedness between individual member species involved and not the taxonomic evenness properties of the assemblage.he overrepresentation of closely related species, and the resulting high uneveness of the taxonomic struture of dung beetles attracted to gaur dung in comparison to elepahnt dung, we relate to the coarse and fine dung preferences of dung beetles , and to O. andrewesi, an endemic of the Western Ghats, and D. setosus recorded only from the Indian continent, and the higher incidence of the old world roller O. laetum, makes dung beetle assemblage in the moist forests of this region unusual. The dominance of dwellers (Oniticellini) over rollers makes the functional guild structure of dung beetle assemblage of the Wayanad forests more similar to the dung beetle community of the Ivory Coast forests of Western Africa and different from those of south East Asian (Borneo) and Neotropical forests. Furthermore, the current study reiterates that the abundance of dwellers is an indicator of the availability of undisturbed dung pats and herbivore abundance in moist forests. However, not enough data exists to establish that the predominance of dwellers, and the low abundance and species richness of rollers, is a general pattern applicable to entire moist forests of Western Ghats. Further studies are necessary to ascertain whether it is a regional pattern specific to the transitional Wayanad forests of Western Ghats alone.In summary, the present study provides for the first time data about community structure of dung beetles from moist forests of Western Ghats, as well from a South Asian region. Though with low species richness, elephant dung attracts a more taxonomically diverse and even dung beetle assemblage than gaur dung that is likely to be related to the more heterogenous physical nature of elephant dung with both fluid and fibrous dung particles. The presence of many endemics (27 %), predominance of


Neurons in the cortex exhibit a number of patterns that correlate with working memory. Specifically, averaged across trials of working memory tasks, neurons exhibit different firing rate patterns during the delay of those tasks. These patterns include: 1) persistent fixed-frequency elevated rates above baseline, 2) elevated rates that decay throughout the tasks memory period, 3) rates that accelerate throughout the delay, and 4) patterns of inhibited firing (below baseline) analogous to each of the preceding excitatory patterns. Persistent elevated rate patterns are believed to be the neural correlate of working memory retention and preparation for execution of behavioral/motor responses as required in working memory tasks. Models have proposed that such activity corresponds to stable attractors in cortical neural networks with fixed synaptic weights. However, the variability in patterned behavior and the firing statistics of real neurons across the entire range of those behaviors across and within trials of working memory tasks are typical not reproduced. Here we examine the effect of dynamic synapses and network architectures with multiple cortical areas on the states and dynamics of working memory networks. The analysis indicates that the multiple pattern types exhibited by cells in working memory networks are inherent in networks with dynamic synapses, and that the variability and firing statistics in such networks with distributed architectures agree with that observed in the cortex. Persistent elevation in firing rates of cortical neurons during retention of memoranda has been suggested to represent the neuronal correlate of working memory While the mechanism(s) by which the patterns of activity are initiated and maintained in working memory are undetermined, a number of plausible hypothesis have been proposed. With respect to persistent elevated-rate patterns, prevailing ideas which have emerged from computational and theoretical studies are that the activity arises as stable states in recurrent attractor networks A potential source of these and other difficulties Functional architecture is a second consideration of potentially fundamental importance to the dynamics of working memory networks. Typically, efforts have focused on studying working memory within the framework of local modules or networks that exist at various specific or general locations in the cortex. However, while working memory and/or working memory-correlated neuronal activity may be maintainable within local networks (or even cellularly), considerable evidence from neurophysiological and imaging studies have shown that working memory involves widely distributed cortical networks across multiple cortical areas Recent work has indicated that working memory networks incorporate dynamic synapses. One study Several computational efforts have attempted to address various aspects of the issues described above. For example, one study demonstrated that persistent activation with realistic frequencies might be achieved if working memory corresponds to attractor states on the unstable branch, and have proposed mechanisms by which such states might be stabilized While working memory models have mostly concentrated on bistable persistent activation, some efforts have also addressed the issue of cue- or response-coupled patterns of activity that steadily increase and decrease during delay periods. For example, graded activity in recurrent networks with slow synapses has been modeled In this work we examine a cortical model of working memory incorporating dynamic synapses both within a local and a distributed cortical framework. We investigate the mechanism of dynamic synaptic facilitation in the generation of all of the different patterns of persistent activity associated with working memory and the effect of a distributed cortical architecture on the dynamics of working memory patterns. We first examine a firing rate model incorporating dynamic synapses representing a working memory network residing locally in a given cortical area. We analyze the statistics and firing-rate-patterns of this network during simulated working memory and compare the results with that of real cortical neurons recorded from parietal and prefrontal cortex of monkeys performing working memory tasks. A reduction of this model to a 2-dimensional system enables an analysis to completely characterize the states of the system. We then examined a distributed firing rate model consisting of 2 and 4 locally interconnected networks, analyzing the possible states as a function of different long-range connectivity schemes and strengths. The expansion of the architecture to multiple networks allows the incorporation of possible heterogeneity. We compare the output of these models  with the activity of the database of real cortical neurons recorded extracellularly from the prefrontal and parietal cortex of primates performing working memory tasks. The model expands on previous work examining the ability of population models with dynamic synapses to produce bistable memory states, or rate changing states (either cue dependent during the stimulus period—i.e. Barak and Tsodyks F(X) given bymτ is the membrane time constant, and b is a parameter inversely proportional to the noise. This form of the firing rate function mimics the firing rate of a class I neuron in the presence of noise (∼1/b) C in equation (1) is the strength of feedback connections in the population,sτ is the decay constant for synaptic activity, w corresponds to the synaptic facilitation, and θ is the threshold. I(t) corresponds to an external current which increases during memorandum (cue) presentation in the simulated working memory task.We start with a firing rate model of a local network . While tw) is incorporated in the model according to wτ is the decay constant, γ is a proportionality constant controlling the amount of facilitation as a function of intra-cellular calcium, and Ca is the calcium concentration. oCa is a reference parameter controlling the level of intracellular calcium at which facilitation begins to increase. The calcium concentration dynamics are given by caτ is the decay constant, and F(x) is of the form given in equation (2).Dynamic synaptic facilitation  and Calcium dynamics satisfy equations similar to (3) which are:The two populations can be considered to reside in different cortical areas  or two populations within the same area. For convenience of description we can consider the populations to represent networks in different cortical areas, which for purposes of association with the real cortical data we take as prefrontal cortex (population 1) and parietal cortex (population 2). In these equations then, The distributed architecture is further extended to one consisting of four populations , by recuS), facilitation (W), and calcium concentration (Ca). A reduction of this model to 2 dimensions is achieved by assuming steady state calcium (dCa/dt = 0) allowing the system to be rigorously analyzed. While assuming steady state calcium does not have an immediate justification from a neurophysiological standpoint, it produces a system with the same attractor structure as the 3-dimensional system and thus allows the rigorous analysis. We carried out analysis of the dynamics and the stability of states of the model using XPPAUT Wmax) to range over values less than the value of the baseline facilitation (Wmin) in equation (3).We begin the analysis first from the single population model. The single population possesses 3-dimensional dynamics in the variables for synaptic activity .thus obtaining the correspondence between the mean field and spiking models (as the parameter I(t) is an external current occurring during the presentation of memoranda, and amp is the amplitude of the Weiner noise. The synaptic activity of a unit js in equation (10) increases with each afferent spike according to β corresponds to the increase in synaptic activity from a single afferent spike, mjt is the time of incidence of the mth afferent spike on the jth neuron, and τs is the decay constant. The dynamics of the synaptic facilitation jw in equation (10) is given by Ca corresponds to the intercellular calcium concentration which modulates the change in facilitation and increases with each spike according to The membrane potential dynamics of a unit in the spiking model is given by the equation The 2-population spiking network consisted of two “local” networks of 100 neurons each with all-to-all connectivity, and with average weaker recurrent connectivity between populations than within the populations. The activation properties of each individual network reflect that of the single populations of the firing rate models.I(t) was applied for 300 ms. The external current raises the firing rate of many units in the populations, simulating the activity observed during presentation of the memorandum in working memory tasks. The current input and increased firing rate triggers dynamic facilitation through equations (11–13). After the cue period, the delay period begins. For the spiking model simulations, unit activity was analyzed over an 11-second delay period which is proportional to the delay period of the working memory tasks during which the parietal and prefrontal cells of the database were recorded. PSTH histograms of units were generated to analyze the patterns and firing rate statistics of the units. Average PSTH histograms were generated for each unit over 10 simulated working memory task trials. Pattern types appearing in the average PSTH histograms were determined and the distribution of patterns in the network were compared to the distribution of patterns observed in the parietal and prefrontal neuron populations of the database. Variability in working memory patterns occurring across trials for each unit was analyzed and compared between the 2- and 4-population networks and the neuronal populations.For the 2- and 4-population spiking networks, working memory task simulations were conducted similarly to those for the firing rate model, and the firing rate patterns and statistics were analyzed. During the baseline period of the simulated working memory task, facilitation in the models was kept low such that the firing rate of the populations was near the baseline fixed-point attractor state inherent in the model . After 20 seconds, the baseline period ended and an external current To examine the effect of network size on patterns exhibited in the networks across trials and their variability, we generated 2- and 4-population networks consisting of 2000 spiking units. For these networks the distribution of pattern types exhibited on each of 20 simulated working memory task trials was obtained and the average distribution across all 20 trials was determined. These distributions were compared to the distributions obtained with the 200 unit networks as well as that observed in the parietal and prefrontal neuron populations of the database. Variability in firing rate within trials was determined through an analysis of the coefficient of variation (CV) of the ISI's during the baseline and delay periods. Variability in working memory patterns occurring across trials for each unit was analyzed and compared to that observed in the 2- and 4-population networks of 200 units.The database with which the different models' activity is compared consists of 812 neurons recorded extracellularly from the parietal cortex  and prefrontal cortex  of monkeys performing working memory tasks. In parietal cortex, 521 cells were recorded from monkeys during performance of a haptic delayed matching-to-sample task S and W for synaptic activity and facilitation respectively) and thus phaseplane and rigorous mathematical analysis was carried out. The nullclines of the system (ds/dt = dw/dt = 0). The steady states of the system are defined by the points at which these 2 curves intersect. For sufficiently low self connectivity strengths (or low maximum facilitation), only one such point is present, corresponding to the baseline firing rate of the population  significantly determines the fixed points of the system (where the facilitation nullcline intersects the synaptic activity nullcline). While this parameter is varied over a large percentile range , the resulting change in actual facilitation realized by the network is within the range of 10% to 60%–within the range of reported increases  that are less the background value (Wmin) in equation (3). For sufficiently small values of synaptic depression, as was the case for facilitation, the network exhibits the non-responsive pattern. As synaptic depression is increased the network exhibits the inhibitory pattern which is the mirror image of decaying memory cells , and inhibitory-inhibitory (I-I). Slightly different values for self-feedback connections strengths within the two populations were chosen.As was the case for the single-population model the PSTH histograms reveal that the 2-population model exhibits the excitatory patterns of memory and decaying-rate or ramping cells with a continuum of rate differences. The inclusion of inhibitory connections results in the presence of parameter ranges in which all of the inhibitory patterns (mirroring the excitatory ones) occur. These inhibitory patterns can occur purely as a function of inhibitory inter-population connectivity, without incorporating dynamic synaptic depression as was the case for the single population. In addition the inhibitory pattern of increasing inhibition throughout the delay (mirroring the excitatory ramping cells) which was absent in the single population model, now can occur .In the phase diagrams of the 2-populations  it can bWe next consider the effect on the states of the network when the model is extended to 4 populations. In the 4-population model all of the patterned activities continue to be present over a continuum range of increases and decreases in firing frequencies. However the distributed architecture results in a “specialization” of pattern activity within specific populations. As can be seen in the phase diagrams  C and 6DWe next examine the statistics and dynamics of the spiking version of the distributed mean-field models. In the spiking network version of the 2-population mean field model we first replace the populations with two networks of 100 spiking units each, whose activity averaged across units approaches the activity of the populations in the mean field model . We firsAs is the case in real cortical cells, the specific pattern exhibited by a unit in the spiking network in any given trial can vary from the predominant pattern observed in the average PSTH histogram We next examine the range of statistic and memory pattern types occurring in the activity of units in a spiking network with four populations of 50 neurons each. In the spiking network we replace the four populations of the mean field model with four networks of 50 spiking units each whose activity averaged across units is the same as the activity of the populations of the mean field model. We first analyze the range of memory pattern types in the spiking networks during simulated working memory tasks. Average PSTH histograms over 20 simulated trials of a working memory task were generated and examined for each unit in the network. As was the case in the 2-network spiking model, the range of excitatory and inhibitory patterns, in addition to the non-responsive pattern are exhibited by the units in the network. The specific baseline frequencies, delay frequencies and deltas (changes in frequency from baseline to delay period) exhibited by the units for each pattern fall within the ranges observed in the real parietal and prefrontal cells . Figure As was the case in the 2-population spiking model, the specific pattern exhibited by a unit in the 4-population spiking network in any given trial of the simulated working memory task can vary from the predominant pattern observed in the average PSTH histogram . Figure We next examine the dependence of pattern type, firing rate statistics and variability as a function of population size. To do this we produced a 2- and 4-population spiking model as above consisting of 2000 units. We first analyze the range of memory pattern types in the spiking networks during simulated working memory tasks. Average PSTH histograms over 20 simulated trials of a working memory task were generated and examined for each unit in the network. As was the case in the 2- and 4 population spiking networks consisting of 200 units, the range of excitatory and inhibitory patterns, in addition to the non-responsive pattern are exhibited by the units in the network . The speThe firing rate model produces a trajectory in the phase plane which corresponds to a specific pattern type. Depending on the connections and other parameters, the stimulus causes the trajectory to remain above or below the separatrix of the phase space. In terms of the spiking model the firing rate model trajectory corresponds to the mean of the trajectory of all units. Depending on how close to the separatrix that mean trajectory is after the stimulus, fluctuations about the mean from various sources of stochasticity in the spiking model will result in a probability that units will make transitions to trajectories corresponding to pattern types different than that of the mean trajectory. The resulting pattern types will have a distribution reflecting this. Conversely the closer the system is to one of the stable attractors of the system, the less probable it is for a given level of noise that the system trajectory will depart from the pattern of the mean trajectory.There are 3 primary sources of stochasticity in the spiking model networks, not present in the mean field model that produce fluctuations resulting in units behavior departing from the single pattern type of the mean trajectory: 1) heterogeneity in the connections between units, 2) heterogeneity in the maximum facilitation, and 3) the noise present in all the units' activity. Increasing population size reduces the source of noise resulting from heterogeneous connections, and thus reduces the overall amplitude of fluctuations. A reduction in the source of variability due to noise present in all neurons during simulation—i.e. the Weiner noise–can be achieved by averaging across trials. An analysis of the intra-trial variance of firing rate in the model units revealed high variability in the distribution of ISIs during both baseline and delay periods of the model . The CV The results of this study demonstrated that recurrent networks with dynamic synapses inherently produce the different persistent firing rate patterns observed in real cortical neurons during working memory. The persistent patterns produced are robust with respect to variations of the parameters in the network. That is, the different patterns occur over a wide range of values of the parameter space, and given patterns do not occur only for a very narrow set of parameter values. Further, the statistics of those patterns fall within the ranges of variation observed in firing rate pattern behavior of real cortical neurons. For example the changes in firing rate from baseline to the delay period can take values along an apparent continuum with absolute changes in firing rate of less than 100% of the baseline rate. For the majority of persistently activated cells recorded from parietal and prefrontal cortex of primates during working memory this corresponds to changes in firing rate of less than 10 Hz. The present network demonstrates a mechanism beyond previous solution for achieving these realistic low delay firing rates Bistable firing rates are one of the possible activities of the model. However, the present work has focused on the range of working memory-correlated patterns of firing rate and their simultaneous, complementary occurrences in the working memory network as opposed to only fixed states that the networks or their neuronal constituents may adopt. The spiking networks exhibited all of the general patterns correlated with working memory that are observed in the database of microelectrode recordings of parietal and prefrontal cortical neurons. In addition, the statistics and firing rates of the units fall within the ranges observed in real cells, with the occurrence of the different pattern types similar in proportion to that observed in the cortical populations. In terms of the behavior of individual neurons, bistable activity is typically only observed as an average over many trials of a working memory task. Across trials, cells exhibit different average frequencies, and even within individual trials, cells exhibit significant variability in firing rather than a single stable rate While the firing pattern varies from trial to trial in cells, there are also significant variations from trial to trial in the delay frequencies for any particular patterns exhibited. The concept of a network with fixed connectivity and bistability between units is not indicated by such activity, and thus a dynamic connectivity is reasonable to consider. The idea of bistable activity corresponding to fixed attractor states may apply at the level of a population of neurons, and could be the essential neuronal correlate of working memory. However, the majority of persistent activity patterns observed consists of cells whose firing rates decay or accelerate during working memory (cue-coupled or response-coupled), and these populations should be taken into account in addition to bistability. In the present model, as stated above, bistable attractor states are present and could correspond to working memory. Here however, a second additional role is suggested for these states in terms of modulating the firing rate activity, resulting in decaying and ramping firing patterns. That is, without necessarily representing memory states in and of themselves, the attractor states allow the network, which represents working memory and its complementary functions, to become active and behave with the necessary dynamics to mediate cross-temporal contingencies. The key component, resulting here from facilitation and observable in the phase plane, is the presence of the bottleneck through which the trajectories of the system pass. The bottleneck modulates the rate at which the trajectories approach the stable attractors, thus creating the patterned activities within the actual range of frequencies observed in the cortex. This mechanism might be present and modulate activity through other components of the network in addition to facilitation. For example Durstewitz The dynamic synaptic facilitation is the component of this model which creates the bottleneck in the phase plane, and gives it its unique characteristics. Specifically it is facilitation which determines the amount of persistent activation, which, since it can adopt a continuous range of values, enables the change in firing rate from baseline to memory period to fall along a continuum. The bottleneck determines the rate at which the firing rates decay towards the baseline attractor (or increases towards the higher firing rate attractor) to adopt the continuum of firing rate values. The decay rate can be sufficiently slow such that no decay or acceleration of firing is observed for the duration of a memory period. Thus the result is an apparent or virtual bistability, which for all intents and purposes can be extended for as long as working memory is defined by the parameters of a working memory task. The fact that the rate at which persistent activation waxes or wanes is highly adjustable is consistent with the behavior of cells in the cortex during working memory. It has been observed in working memory experiments Another prediction from the dynamics of the model is that the rate of persistent activation correlates with baseline rate. In the majority of delay activated cells, the magnitude of firing rate increases are less than 100% of baseline, with the magnitude of the delay period firing rate change increasing nonmonotonically with baseline rate increases. The largest magnitude increases in delay period frequency are in those cells with the largest baseline firing rates, while the largest percentage changes are those with low baseline rates. This is naturally incorporated in the present model. The range of rates over which the population can exhibit memory cell behavior is bounded by the saddle separatrix. Once facilitation pushes the system's trajectory beyond the separatrix, further increasing facilitation (or judiciously adjusting other parameters) does not result in further continuous increases in persistent activation delay rates, but rather a change in the activation pattern itself. The parameters of the model can be adjusted however, raising the frequency of the baseline state and incrementing the entire range of frequencies within its basin of attraction. Thus both baseline and delay rates increase in a correlated fashion, and due to the nonlinearity of the nullcline of the synaptic activity, the proportional increase in frequency is nonmonotonic.The specific simultaneous patterns which may be exhibited in the populations are dependent on the relative strength of the inter-population connection strength, the intra-population connection strength, and whether the inter-population connectivities are mutually net inhibitory, or a combination of excitatory and inhibitory. The phase diagram of the 2-population firing rate model reveals a number of behavioral trends. For an excitatory-inhibitory connectivity between populations, the networks can exhibit a range of concomitant activities which includes memory cell activity in both populations, and simultaneous cue-coupled/response-coupled behavior. In contrast, with a mutually inhibitory connectivity between populations these particular behaviors are absent, and simultaneously occurring fixed-rate-memory/response-coupled behavior is present over only an extremely narrow range of the parameters. Thus memory being maintained simultaneously in both cortical areas occurs in the 2-population model only within the E-I connectivity scheme. During working memory, the simultaneous presence of memory cells in prefrontal cortex and another cortical area important to the sensory modality of the memorandum has been indicated by numerous studies. In addition to prefrontal cortex, memory cells have been observed for example in posterior association cortex including inferotemporal cortex As the network becomes more distributed, increasing to four populations, simultaneous memory cell behavior and cue-coupled/response-coupled behaviors becomes more robust with these concomitant behaviors occurring over a wide continuous range of the parameters as can be observed by the increased areas of those respective behaviors over larger continuous ranges of the parameters in the phase diagrams . While tIn addition to a distributed architecture affecting the stability of memory pattern behavior and modulating activity enabling the occurrence of complimentary patterned behaviors, certain working memory pattern behaviors apparently are exclusively a function of a distributed architecture rather than the facilitation mechanism alone. Particularly the ramping delay inhibition pattern which is observed in the cortical data was present only in the distributed versions of the model. Another phenomenon is the existence of large regions of the parameter space in which one population exhibits the non-responsive pattern, while the other population exhibits memory cell behavior . In the database of real cells, the majority of neurons from parietal and prefrontal cortex exhibit the non-responsive pattern of behavior. Interspersed within these populations of non-responsive cells are neurons that exhibit the other patterns. From the models we see that the non-responsive pattern is a common part of a working memory network coexisting with the other patterned behaviors. Studies of patterns in spike sequence of such cells It should be noted that the present analysis supplements the general attractor picture rather than replacing, or invalidating it. Cells with apparent bistable activity with high firing rates above baseline, while apparently rare in the cortex


Prions are believed to be the causative agents of a group of rapidly progressive neurodegenerative diseases called transmissible spongiform encephalopathies, or prion diseases. They are infectious isoforms of a host-encoded cellular protein known as the prion protein. Prion diseases affect humans and animals and are uniformly fatal. The most common prion disease in humans is Creutzfeldt-Jakob disease (CJD), which occurs as a sporadic disease in most patients and as a familial or iatrogenic disease in some patients. Whether prions are infectious proteins that act alone to cause prion diseases remains a matter of scientific debate. However, mounting experimental evidence and lack of a plausible alternative explanation for the occurrence of prion diseases as both infectious and inherited has led to the widespread acceptance of the prion hypothesis.Interest in prion disease research dramatically increased after the identification in the 1980s of a large international outbreak of bovine spongiform encephalopathy  in cattle and after accumulating scientific evidence indicated the zoonotic transmission of BSE to humans causing variant CJD. In recent years, secondary bloodborne transmission of variant CJD has been reported in the United Kingdom.Prions: The New Biology of Proteins describes the current state of knowledge about the enigmatic world of prion diseases. The book is organized into 12 mostly brief chapters, which nicely summarize the various types of prion diseases and the challenges associated with their diagnosis and treatment. These sections review the biology of prions, the underlying hypotheses for prion replication, and the biochemical basis for strain diversity. Chapters 2 through 5 describe the various characteristic features of prions, including the historical evolution of the prion hypothesis, a detailed description of the possible mechanisms by which the normal prion protein is converted into the pathogenic form, and the cellular biology and putative functions of the normal prion protein. The author’s lucid descriptions of the various topics are supported by diagrams and key references. Subsequent chapters describe prion disease laboratory diagnostic tools that are available or under development. Chapter 9 succinctly summarizes the most likely target sites, from the formation of the infectious agent to its effects on neurodegeneration, which can be exploited for likely therapeutic development. The same chapter describes the various antiprion compounds that have been or are being tested as therapeutic interventions for prion diseases.The book is unusual because its entire content was exclusively authored by 1 person, resulting in a paucity of in-depth information in some areas, which may have been provided by multiple authors. However, all things considered, the book can be a valuable resource for scientists beginning to understand the world of prion diseases, the underlying biochemical mechanism of disease occurrence, and the challenges associated with the diagnosis and treatment of prion diseases.


Intraperitoneal diffusion chambers have been used to investigate changes in humoral factors during the development of myeloid leukaemia in mice. Normal mouse bone marrow cells form colonies of granulocytes and macrophages when cultured in semi-solid agar medium within intraperitoneal diffusion chambers. The use of mice bearing transplanted myeloid leukaemia as Agar Diffusion Chamber (ADC) hosts enhances colony formation from normal marrow. The humoral basis for this stimulation has been shown by the colony stimulating activity of the fluid entering the diffusion chambers when assayed against normal mouse bone marrow cells in agar culture in vitro. The stimulus to colony growth in ADCs and the in vitro colony stimulating activity depend on the phase in the development of the leukaemia investigated, and the stimulation was abolished by splenectomy. There was no apparent relationship between the growth of the leukaemic cell population in vivo and the level of the stimulating factor detected in leukaemic mice.


Chlamydia trachomatis (CT) infections of the female genital tract, although frequently asymptomatic, are a major cause of fallopian-tube occlusion and infertility. Early stage pregnancy loss may also be due to an unsuspected and undetected CT infection. In vitro and in vivo studies have demonstrated that this organism can persist in the female genital tract in a form undetectable by culture. The mechanism of tubal damage as well as the rejection of an embryo may involve an initial immune sensitization to the CT 60 kD heat shock protein (HSP), followed by a reactivation of HSP-sensitized lymphocytes in response to the human HSP and the subsequent release of inflammatory cytokines. The periodic induction of human HSP expression by various microorganisms or by noninfectious mechanisms in the fallopian tubes of women sensitized to the CT HSP may eventually result in tubal scarring and occlusion. Similarly, an immune response to human HSPexpression during the early stages of pregnancy may interfere with the immune regulatory mechanisms required for the maintenance of a semiallogeneic embryo.


Host responsiveness to a progressively growing methylcholanthrene (MC) induced tumour (MC6/2) was studied at varying intervals following subcutaneous (s.c.) tumour implantation by monitoring the in vitro incorporation of tritiated thymidine (3H-TdR) into lymph node cells (LNC) undergoing stimulation in vivo and concurrently determining the total numbers of the lymphoid cells present in these organs at each of the time intervals. It was found that an initial period of rapidly increasing stimulation of DNA synthesis in lymph nodes was soon followed by the onset of a stage of decrease of this activity. Within limits, the larger the tumour inoculum the stronger the initial response. The suppression of stimulation of DNA synthesis that ensued appeared to be directly related to the tumour mass and to the dose of tumour cells implanted. The total numbers of the cells accumulating in nodes also increased initially but remained elevated during the subsequent period of tumour growth. Continued presence of the tumour was essential for the increased DNA synthesis in lymph nodes since tumour removal leads to a rapid decrease to levels found in tumour-free animals. These findings demonstrate that the failure to eradicate an antigenic tumour by its host may not be solely due to "desensitizing" and "blocking" factors but that other important mechanisms are also involved. We suggest that the inability to reject the tumour in this situation is dependent in considerable measure on the development of a state of hyporeactivity in the host due to the partial inhibition of the DNA synthetic response, possibly in T cells of the tumour host, due to "suppressor factor(s)" interacting with the immunocompetent cells.