Anatomic obstruction by granulomas or distortion of the normal anatomy by fibrosis surrounding the reproductive tract structures is the commonest cause of infertility. The diagnosis is usually based on a suggestive history along with evidence of granulomatous infection on a tissue sample. The management depends on the site of obstruction and surgery is usually helpful only in cases with discrete ejaculatory duct obstruction. However, most other patients are candidates for  Tuberculosis of the male reproductive tract can result in infertility. The infection can involve any part of the reproductive tract including the testis, epididymis, vas deferens, seminal vesicles, prostate and the ejaculatory ducts. Infertility usually results from the inflammation and scarring that follow the infection, resulting in distortion of the normal anatomy and causing obstruction. Infertility may be the first presentation of genitourinary tuberculosis and patients may have no recollection of any other symptoms. InvolvemThe site of infection and the resultant scarring determine the manifestation of reproductive tract tuberculosis. In infertile men, determination of the site is critical for deciding the line of management and the potential fertility outcome.The epididymis is one of the favored sites for tuberculous infection. In a recent review of 69 patients diagnosed with genital tract tuberculosis, the epididymis was found to be involved in over 78%. In anothUnlike other parts of the reproductive tract that are usually infected secondarily due to a retrograde spread of infection from the bladder, the globus minor of the epididymis tends to get infected primarily through a hematogenous spread of the bacilli. The high vascularity of the globus minor may be one of the reasons for this preferential involvement. Chronic epididymitis is, in fact, one of the typical manifestations of genitourinary tuberculosis.et al., however, believe that this trend of bilateral involvement in now decreasing.[Tubercular epididymitis may manifest as an acute infection, chronic infection or infertility. Acute inflammation is usually a combined epididymo-orchitis with pain, tenderness and swelling. This may be the commonest manifestation in up to 40% cases. The othecreasing.The testis is a rare site for tuberculous involvement. One of the reasons for this may be the presence of a bloodtestis barrier that may impede seeding of the testicular parenchyma. Testicular involvement usually occurs contiguous to the epididymal involvement.et al.,[Infertility results from either a direct obstruction by granulomatous masses in the epididymis or vas deferens or from scarring and distortion of normal anatomy. The patients may have no recollection of an acute infection and, in fact, the infection may never have had an acute manifestation. The diagnosis is suspected on finding nodules within the epididymis or nodularity in the vas deferens. This often needs confirmation with a percutaneous fine needle aspiration biopsy or excision of the epididymis. In a retrospective study of 11 cases of confirmed and treated epididymal tuberculosis, Gueye et al., found thet al.,et al.,[An ultrasonographic examination of the scrotum may reveal diffuse hypoechogenicity in epididymal and testicular inflammation. Chung et al., evaluateInvolvement of the vas deferens is considered one of the principal sources of genital tuberculosis. Retrograde spread of infection may occur due to bacterial invasion or reflux of urine through the ejaculatory ducts and into the vas deferens. Clinically, this manifests as multiple nodules in the palpable, scrotal part of the vas and is often bilateral. Infertility results from the direct obstruction caused by these nodules.The seminal vesicles, prostate and the ejaculatory ducts exist in such close association that it is usually not possible to isolate the involvement of one from the other in the causation of infertility. Clinically, this involvement may manifest in one of two manners.Inflammation and scarring may occasionally be restricted to a discrete terminal portion of the ejaculatory ducts near their opening into the prostatic urethra. Obstruction at this level results in dilatation of the proximal ductal system including the vas deferens and seminal vesicles. Seminal vesicle secretions make up the bulk of the ejaculate, contain fructose and alkalinize the ejaculate. Obstruction at the level of the ejaculatory ducts prevents seminal vesicle secretions from reaching the ejaculate. The patients thus present with azoospermia and a low-volume ejaculate or may be aspermic. Further, the ejaculate is acidic and lacks fructose. In such patients, other causes of low-volume azoospermia need to be excluded. These include congenital absence of vas deferens and retrograde ejaculation. The former can be excluded through a good clinical examination while thet al.,[Tuberculous infection of the seminal vesicles or the prostate may be diffuse and result in aspermia without a demonstrable obstruction of the ejaculatory ducts. These patients will have a clinical manifestation similar to that described for a discrete obstruction; however, the proximal ductal system will not be dilated. The disease often results in calcification of the seminal vesicles, prostate and the vas deferens. Fraietta et al., reportedet al.,[Fibrotic, atrophic seminal vesicles with ejaculatory duct obstruction have even been considered a diagnostic feature for tuberculosis. Paick et al., reviewedet al., Pryor anet al.,et al.,[Mycobacterium gastri infection of the seminal vesicles in a diabetic patient that resulted in infertility. Semen parameters of this patient improved after antitubercular chemotherapy.Rarely, non-tuberculous mycobacteria may also be responsible for causing seminal vesicle infection and infertility. Indudhara et al., reportedTuberculous involvement of the penile shaft and the glans penis can result in severe disfigurement, ulcers and bulbous enlargement. This mayManagement of tuberculous infertility consists of two parts. The primary aim is to treat the infection and requires antitubercular therapy. Rarely, in patients with an early diagnosis of the disease who have not developed bulky granulomas causing an obstruction, this therapy may result in restoration of fertility.In the majority of cases, the presentation is late and antitubercular therapy does not improve the fertility status. Infertility here usually results from anatomic obstruction and therapy depends on the site and feasibility of reconstruction.While the diffuse, fibrotic type of tuberculous lesions of the ejaculatory duct and seminal vesicles are not amenable to surgery, patients with discrete obstructions at the distal end of the ejaculatory duct may benefit. The surgery in these cases involves resection of the obstructed terminal segment and marsupialization of the dilated portion of the ducts into the urethra.The ejaculatory ducts open as paired structures on either side of the verumontanum. In normal individuals, these are not visible on a cystourethroscopic examination. During a transurethral resection of the ejaculatory ducts (TURED), the location of these openings can be identified by instilling a colored dye into the seminal vesicles through an ultrasound guided needle. This needle is used to first aspirate the seminal vesicle fluid to confirm the presence of sperms and then to instill the dye, immediately prior to the TURED. In the lithotomy position, the assistant places a finger in the patient's rectum and applies pressure over the seminal vesicles, forcing the dye to extrude through the opening. Once the opening is identified, it is resected with a cautery loop using a resectoscope. The resection is often carried deep and laterally into the prostatic tissue to ensure a wide-mouthed opening. An alternative method of dye instillation is through a vasotomy incision made for performing a vasogram. This technique, however, has a greater likelihood of causing inflammation within the vas deferens.An alternative technique uses a combined incision-resection (TUIRED) process to avoid the instillation of dye into the seminal vesicles. During urethroscopy, delicate cuts are made with a cold knife, lateral to the verumontanum at the expected site of the ejaculatory ducts. A finger may be placed in the patient's rectum to apply pressure over the seminal vesicles to help extrude the collected seminal secretions and also help gauge the depth of the incision and prevent rectal injury. Entry into the ejaculatory ducts is confirmed when thick secretions emanate from the incision. The opening is then widened either using the cold knife or resected using the resectoscope and loop. A Foley type catheter is left in the bladder for the first postoperative day. We usually recommend examination of the semen within the first week. Presence of sperms confirms the adequacy of incision and diagnosis.TURED or TUIRED incisions have a propensity to close over a period of time. We therefore routinely advise patients with a successful procedure to follow up regularly with semen analysis and proceed to assisted reproduction with an Intrauterine insemination (IUI), In-vitro fertilization (IVF) if the initial few attempts at spontaneous pregnancy fail.Obstruction to the epididymis may be due to the presence of nodules and masses or may be the result of a distorted anatomy. Patients with palpable masses usually require excision of the epididymis, both for diagnosis and therapy of tuberculosis. This precludes surgical reconstruction in most cases.Patients who have obstructive azoospermia with normal volume, fructose-positive ejaculate may have discrete obstruction either within the vas deferens or at the vaso-epididymal junction. These patients should undergo surgical exploration for a possible microsurgical reconstruction.If a nodule is palpable in the vas deferens, the vas is incised proximal and distal to the site of the nodule. Distal patency of the vas is confirmed either through the injection of saline or a formal vasogram is obtained using contrast material. Fluid from the proximal part of the vas is sampled for the presence of sperms. Presence of sperms and a patent distal vas is an indication for a vasovasal anastomosis. However, this is feasible in an extreme minority of cases as the most common lesion is a multiple site obstruction that is not amenable to reconstruction. Occasionally, it is possible to bypass multiple segmental obstructions including one at the vaso-epididymal junction by performing a vasoepididymal anastomosis between the epididymal tubule and the patent distal vas deferens.in-vitro fertilization or Intracytoplasmic sperm injection (ICSI). The site of sperm harvest depends on the site of infection and the degree of destruction. Fortunately, the testis is usually spared in these cases and testicular sperm is almost always available for aspiration. Tuberculous obstruction of the genital tract does not adversely influence the outcome of assisted reproduction techniques using epididymal or testicular sperm. In a comparison of outcomes of ICSI in seven men with tuberculous obstruction versus another 37 with other indications for ICSI, the rates of fertilization and pregnancy were found to be similar.[et al.,[The majority of patients with tuberculous infertility will require assisted reproduction. Since the most common manifestation of tuberculous infertility is azoospermia, the intervention has to be either  similar. Kondoh e.[et al., similarlTuberculosis is an uncommon cause of male infertility, however, its diagnosis is important for managing not just infertility but also the systemic ramifications of the disease. In the absence of discrete nodules or granulomas, the diagnosis is based on a suggestive history and bacteriologic examination. Most cases of tuberculous infertility are not amenable to surgical correction. A rare exception is discrete ejaculatory duct obstruction that may respond to transurethral resection. Most other cases will require assisted reproduction which provides results comparable to those in men without this disease.


The presence in the thymus of hemopoietic cells other than thymocytes has been known formany years, but the extent of the hemopoietic activity of the thymus and the possiblefunctional implications have only recently begun to receive much attention. This reviewsummarizes the literature in this field, especially in the light of current cytokine andthymic-factor knowledge, and includes clinical relevance where possible.


The incidences of malignant melanoma recorded by 59 population-based cancer registries were investigated to determine the effects of racial and skin-colour differences. White populations exhibited a wide range of melanoma incidences and females commonly, though not invariably, had a higher incidence than males. Non-white populations experienced in general a much lower incidence of melanoma although there was some overlap of white and non-white rates. No predominant sex difference emerged among non-whites. Populations of African descent were found to have a higher incidence than those of Asiatic origin, but it was concluded that this was due largely to the high frequency of tumours among Africans on the sole of the foot. A clear negative correlation between degree of skin pigmentation and melanoma incidence emerged for the exposed body sites. These data provide strong support for the hypotheses that UV radiation is a major cause of malignant melanoma and that melanin pigmentation protects against it. Further research is required to elucidate the aetiology of melanoma of the sole of the foot.


This review summarizes bladder cancer studies dealing with both  Thus, array technologies represent high-throughput means to identify molecular targets associated with these biological and clinical phenotypes by comparing samples representative of distinct disease states.AQMicroarrays constitute a group of technologies characterised by the common availability of measuring hundreds or thousands of items, including DNA sequences, RNA transcripts or proteins, within a single experiment using miniaturised devices. The appropriate experimental design and the use of well-characterised Hybridisation-based methods and the microarray format constitute together an extremely versatile platform provide for both static and dynamic views of DNA structure, as well as RNA and protein expression patterns in cultured cancer cells and tumour tissues. The most widespread use of this technology to date has been the analysis of gene expression  are often found mixed with genes of known function.This represents the traditional approach of assigning a functional role to a gene when overexpressed, and observing the effect(s) of its expression on known pathways or processes. Such an approach has been especially useful in identifying the downstream targets of transcription factors. The genes identified as either up- or downregulated in these experiments are likely to play important roles in the signalling network in which the gene under investigation participates.This is one of the most promising and powerful applications of expression profiling with expression microarrays. The integration of gene expression patterns is providing complementary tools to histopathological criteria for classifying tumours into biologically meaningful and clinically useful categories. In addition, expression profiling of well-annotated tumour specimens has the potential of identifying target genes for novel diagnostic, prognostic or therapeutic approaches. High-throughput transcriptome analysis will become a means at improving cancer treatment by an early and accurate diagnosis of tumour subtype and determining the most effective therapeutic intervention.gene and pathway discovery in bladder cancer. Tumour cell growth inhibition mediated by genistein was produced to the susceptible bladder tumour line TCCSUP. Expression profiling was then analysed at various time points, using cDNA chips. Induction of genes involved in cell growth and cell cycle, such as EGR-1, was observed, and these events were related to the proliferation and differentiation effects of treatment  or for assigning tumours to known classes (class prediction). Reports using different microarray platforms and analysing specific cancer subgroups are finding consensus on subclasses and signatures of the disease with predictive utility.in vitro and in vivo models are warranted to functionally characterise the pathways by which many of the targets are already identified to be involved in tumorigenesis or bladder cancer progression. The utility of the application of microarrays has not yet estimated many clinical issues. Identification of Ta-T1-IS subtypes within the superficial disease and patients more likely to develop positive lymph nodes or distant metastases are critical subclassification questions to be answered.Overall, the use of microarray technologies for the study of bladder cancer remains a new research field. The results reported so far represent preliminary data that need to be contrasted by different groups using different series of patients. Creation of international tumour banks represents an option that might facilitate interactive research among different laboratories. Further efforts using An area that will provide critical targets for clinical intervention is that of pharmacogenomics. Studies evaluating biological markers  to predict the drug efficacy or the relative risk of adverse effects in individual patients are still needed for many tumour types. In the near future, gene profiling will provide an effective means of predicting the response against specific therapeutic regimes based on the molecular signatures of the tumours associated with their chemosensitivity or resistance to anticancer drugs. Moreover, the discovery of molecular pathways altered in cancer progression, as well as the identification of molecule-susceptible targets, would lead to the development of novel alternative therapies. The combined information revealed by these studies allows also identification of new molecular determinants involved in the progression of the disease with clinical diagnostic or predictive utility. The classical tumour marker concept of an individual biological determinant will be substituted by the use of cluster of genes as predictive classifiers. These genetic signatures will allow a better chance of cure by opting for the most appropriate treatment, while maintaining the quality of life.


Objective: Group B streptococcus  is an important cause of neonatal sepsis. Prevention is possible by intrapartum screening for maternal GBS carriership and antimicrobial treatment of colonized women with risk factors during labor. The conflicting results of diagnostic performance are reported both for the newly developed rapid GBS antigen tests and Gram's stain.Methods: The value of Gram's stain in GBS screening was investigated prospectively in 1,020 women. Intrapartum Gram's stains of the cervix from these women and of the introitus from 510 of them were compared with cultures of the cervix, introitus, and anorectum in a semiquantitative way.Results: The sensitivities of the cervical and introital Gram's stains were 25% and 31%, respectively, and the specificities 99% and 98%, respectively. Higher sensitivities  were found in heavily colonized parturients. No significant influence of rupture of the membranes was detected. There was a poor correlation between the number of gram-positive cocci in the Gram's stain and the growth density.Conclusions: We do not recommend the routine use of the Gram's stain for intrapartum GBS detection because of both the limited sensitivity and positive predictive value.


The system used by the National Nosocomial Infection Surveillance (NNIS) program to measure risk of surgical site infection uses a score of 3 on the American Society of Anesthesiologists (ASA)-physical status scale as a measure of underlying illness. The chronic disease score measures health status as a function of age, sex, and 29 chronic diseases, inferred from dispensing of prescription drugs. We studied the relationship between the chronic disease score and surgical site infection and whether the score can supplement the NNIS risk index. In a retrospective comparison of 191 patients with surgical site infection and 378 uninfected controls, the chronic disease score and ASA score were highly correlated. The chronic disease score improved prediction of infection by the NNIS risk index and augmented the ASA score for risk adjustment.


Single Nucleotide Polymorphisms, among other type of sequence variants, constitute key elements in genetic epidemiology and pharmacogenomics. While sequence data about genetic variation is found at databases such as dbSNP, clues about the functional and phenotypic consequences of the variations are generally found in biomedical literature. The identification of the relevant documents and the extraction of the information from them are hampered by the large size of literature databases and the lack of widely accepted standard notation for biomedical entities. Thus, automatic systems for the identification of citations of allelic variants of genes in biomedical texts are required.. Here we describe the development of a new version of OSIRIS  which incorporates a new entity recognition module and is built on top of a local mirror of the MEDLINE collection and HgenetInfoDB: a database that collects data on human gene sequence variations. The new entity recognition module is based on a pattern-based search algorithm for the identification of variation terms in the texts and their mapping to dbSNP identifiers. The performance of OSIRISv1.2 was evaluated on a manually annotated corpus, resulting in 99% precision, 82% recall, and an F-score of 0.89. As an example, the application of the system for collecting literature citations for the allelic variants of genes related to the diseases intracranial aneurysm and breast cancer is presented.Our group has previously reported the development of OSIRIS, a system aimed at the retrieval of literature about allelic variants of genes OSIRISv1.2 can be used to link literature references to dbSNP database entries with high accuracy, and therefore is suitable for collecting current knowledge on gene sequence variations and supporting the functional annotation of variation databases. The application of OSIRISv1.2 in combination with controlled vocabularies like MeSH provides a way to identify associations of biomedical interest, such as those that relate SNPs with diseases. In the last years the focus of biological research has shifted from individual genes and proteins towards the study of entire biological systems. The advent of high-throughput experimentation has led to the generation of large data sets, which is reflected in the constant growth of dedicated repositories such as sequence databases and literature collections. For instance, MEDLINE indexes more than 17 million articles in the biomedical sciences by April 2007), and it's increasing at a rate of more than 10% each year  AND "Polymorphism, Single Nucleotide" [MeSH] AND "Humans" [MeSH] AND hasabstract [text] AND English [lang] AND ("2004/01/01" [PDAT] : "2005/01/01" [PDAT]) AND "Chemicals and Drugs Category" [MeSH]This set is focused to a field of interest to our group and limited to years 2004 and 2005. As a first step in the annotation process, the set of abstracts was carefully reviewed to determine if it contained explicit mentions of sequence variants in the text that allow their mapping to a dbSNP identifier: the position of the variation in the sequence, one or both alleles, and the gene to which the variation is mapped to. Only 311 abstracts included this information and were retained in the corpus. Thus, these abstracts contained mentions of variations that could potentially be normalized to dbSNP identifiers . The next step consisted in the manual annotation of gene and sequence variant occurrences with their database identifiers. Since the process of manual annotation is very laborious and time consuming, a subset consisting of the first 105 abstracts (in terms of date of publication) was selected to perform the full annotation. The quality of the annotation was prioritised in front of the size of the corpus. Nevertheless, the size of the corpus (n = 105) is similar to other corpora used in other evaluations carried out in the field .The annotation of the abstracts consisted in manual identification of mentions of genes and variations and their disambiguation to database identifiers. The NCBI Gene database was used in the case of genes and HgenetInfoDB in the case of variations. The text inspection was performed at the level of title and abstract and the resulting annotations were recorded in the corpus as an XML file using the Vex editor  in the fThe search queries used to select the set of articles related to the diseases of interest are detailed below. Results presented in this article correspond to searches conducted on MEDLINE database updated to August 2007.For intracranial aneurysm and subarachnoid haemorrhage: OR "intracranial aneurysm" [MeSH Terms] OR cerebral aneurysm [Text Word]("subarachnoid hemorrhage" [TIAB] NOT MEDLINE [SB]) OR " subarachnoid hemorrhage" [MeSH Terms] OR subarachnoid hemorrhage [Text Word]For breast cancer:("breast neoplasms" [TIAB] NOT Medline [SB]) OR "breast neoplasms" [MeSH Terms] OR Breast Cancer [Text Word]The search query used for compiling the corpus was:"Pathological Conditions, Signs and Symptoms" [MeSH] AND "Polymorphism, Single Nucleotide" [MeSH] AND "Humans" [MeSH] AND hasabstract [text] AND English [lang] AND ("2004/01/01" [PDAT] : "2005/01/01" [PDAT]) AND "Chemicals and Drugs Category" [MeSH]LIF participated in the design of the system, implementation, evaluation and analysis of the results and prepared the manuscript document. HD and MHA contributed to the design of the system, and HD contributed to the database design and implementation. FS participated in the design and coordination of the work. All authors contributed to the manuscript, and read and approved its final version.


Increased amounts of intestinal endotoxin are absorbed in obstructive jaundice. The precise mechanism is not known but the increased absorption may arise from alterations in the luminal contents, in the intestinal flora, in the gut wall or in interactions between all three. To examine the effects of the intestinal flora we have compared the morphological changes in the small intestine in obstructive jaundice in germ free and conventional rats while the effects of bile constituents have been examined by addition of bile constituents to the diet of bile duct ligated rats. Changes in the intestine were examined, histologically, by enzyme histochemistry, and by transmission and scanning electron microscopy. The results showed no differences in response between germ free and conventional rats. Feeding of diets containing bile salts exacerbated the lesion. Feeding of diets containing cholesterol, however, reduced the degree of intestinal changes produced by cholestasis and completely antagonised the increase in damage caused by feeding of bile salts.


Three recent outbreaks of locally acquired malaria in densely populated areas of the United States demonstrate the continued risk for mosquitoborne transmission of this disease. Increased global travel, immigration, and the presence of competent anopheline vectors throughout the continental United States contribute to the ongoing threat of malaria transmission. The likelihood of mosquitoborne transmission in the United States is dependent on the interactions between the human host, anopheline vector, malaria parasite, and environmental conditions. Recent changes in the epidemiology of locally acquired malaria and possible factors contributing to these changes are discussed.


Results using the same drug in phase II studies of treatment in ovarian cancer vary widely. An analysis of five phase II studies with a total of 93 patients was carried out to determine whether factors other than the efficacy of the drug affect response. The drugs for the phase II studies were chosen on the basis of in vitro activity or previous activity in humans. Univariate analysis showed that several factors were of significance in predicting response. The most significant was interval from the end of previous treatment to entry into a phase II study. Others were the original presenting stage of the patient, the second line treatment given and the best previous response to therapy. In multivariate analysis, however, only two factors were shown to be of importance which were interval and the FIGO stage of the patient. Using these two variables the discriminant analysis predicted 89% of those who did not respond and 75% of those who did, with an overall correct prediction of 85%. The importance of interval is emphasised by the observation that the response rate for those patients who progressed on treatment or who relapsed within 3-6 months of primary therapy had a response rate of less than 10%. Future phase II studies should probably exclude patients in this category, since the chance of their responding is very low.


Saccharomyces cerevisiae genome. The collection was produced by the transatlantic yeastgene deletion project, a collaboration involving researchers in the USA, Canada andEurope. The European effort was part of EUROFAN  where some of the strains could feed into various functional analysis nodesdealing with specific areas of cell biology. With approximately 40% of human genesinvolved in heritable disease having a homologue in yeast and with the use of yeast invarious drug discovery strategies, not least due to the dramatic increase in fungalinfections, these strains will be valuable in trans-genomic studies and in specialised intereststudies in individual laboratories. A detailed analysis of the project by the consortium is inpreparation, here we discuss the yeast strains, reported findings and approaches to usingthis resource.In the year 2001 a collection of yeast strains will be completed that are deleted in the 6000open reading frames selected as putative genes by the initial bioinformatic analysis of the


High energy tibial plateau fractures along with calcaneal fractures individually produce several challenges for the orthopaedic surgeon. The principles of bony reconstruction include anatomic reduction and rigid internal fixation of intra-articular fractures and accurate restoration of the coronal, sagittal and transverse mechanical axes. Due to the tenuous nature of the soft tissue and devitalisation of the comminuted fragments with open reduction, external fixation of type 6 tibial plateau fractures is recommended. We report a case with ipsilateral high energy tibial plateau and calcaneal fractures both of which were managed with an ilizarov ring fixator.A 55-year-old Kashmiri female presented to our department with an ipsilateral fracture of the tibial plateau and the calcaneum. Both were closed reduced and stabilized with an ilizarov ring fixator.The circular wire fixator provides a viable method to manage such fractures especially if they are co existent. This is especially true in situations where the soft tissue is compromised. Fractures of the tibial plateau and the calcaneum sometimes occur together in the same patient because of the common causative axial load mechanism. Fractures of the calcaneus account for approximately 60% of tarsal injuries and usually are the result of a fall from height. It is necessary for other injuries of the appendicular skeleton be ruled out in all patients presenting with either a calcaneal or a tibial plateau fracture. The goal of the treatment in either fracture is the restoration of the articular congruity and axial alignment as also the achievement of joint stability and functional motion. This has to be done while allowing early range of motion and minimising wound complications. Closed manipulation restores the overall shape of the calcaneus, with emphasis on restoring the Bohler angle, obtaining facet congruency and re-establishing the normal heel width. This method is useful in patients who are not candidates for open treatment .High energy tibial fractures are often associated with a high incidence of severe complications with traditional internal fixation .We describe the management of a patient with high energy tibial and calcaneal fracture of the same limb, with an ilizarov fixator. The method provided manifest advantages in the management of the two high energy ipsilateral fractures sustained by our patient.A 55-year-old female presented to the out patient department of our hospital with a history of a fall from height. The patient had experienced immediate pain and swelling in the knee and ankle area of the limb. On removing the splint used to transport this patient and examining the patient, swelling of the knee, upper tibia and heel were noticed. Palpation produced crepitus of the upper tibia. Significant tenderness was elicited on palpation at the knee as well as the heel.Radiographs of the knee in the anterioposterior and lateral plane showed a type VI Schatzker fracture of the tibial plateau. Radiographic examination of the calcaneum showed a tongue type fracture of the calcaneum with complete loss of the Bohler angle  & 2.The patient's limb was placed in a well padded splint and observed for compartment syndrome. Over a period of three days the patient developed significant ecchymosis around the upper tibia.In view of the compromised soft tissue envelope, age of the patient and complexity of the trauma, it was decided to manage both the fractures in a ring fixator .The patient was anaesthetised and placed on a traction table. The proximal fragments were approximated with manual pressure under image intensifier control. Ilizarov wires were placed to obtain compression in the coronal plane. A cancellous transverse lag screw was placed to obtain further stability. An additional ring was placed and affixed to the bone, below the metaphysiodiaphysial comminution. This ring was affixed to the diaphyseal bone with two Schanz pins placed at right angles to each other. The foot was immobilised with a Schanz pin attached to this fixator. This Schanz pin was placed in the first metatarsal  & 5.A Schanz pin was placed into the tongue shaped calcaneal fragment, starting posteriorly. This pin was attached to the second ring by means of a plate and two threaded rods. By gradual distraction and lateral pressure under image intensifier control, the Bohler angle was restored. The Schanz pin was kept in this position in the distraction mode. The patient was allowed range of motion exercises of the knee from the first post operative day. At 10 weeks the fixator was removed and patient allowed partial weight bearing crutch walking. 12 weeks post fixation full weight bearing was allowed  & 7. At High energy fractures of the tibial plateau and the calcaneum challenge the orthopaedic surgeon due to the difficulties in restoring the complex bony architecture and the tenuous nature of the soft tissues.Cotton and Wilson in 1916 wrote that the man who breaks his heel bone is done . The manClosed manipulation of the calcaneum has been recommended . Paley eLow energy tibial plateau fractures have excellent clinical outcomes with few complications with contemporary internal fixation, however in high energy fractures; these methods produce severe complications . The metThe principles of bony reconstruction, particularly in weight bearing joints, include anatomic reduction and rigid internal fixation of intra-articular fractures and accurate restoration of coronal, sagittal and transverse mechanical axes. . High enThe advantages of using hybrid fixation with a circular small wire external fixator are numerous, with minimal additional devitalisation, capture of very small metaphyseal and sub chondral fragments with lag effect ,10. HoweIn our case the fixator was able to manage both fractures simultaneously. The fixator permitted early range of motion, adjustability and observation. The Ilizarov fixator can be an important methodology in the management of such coexisting injuries.The circular wire fixator provides a viable method to manage such fractures especially if they are co existent. This is especially true in case the soft tissue envelop is compromised.


Earlier studies have demonstrated an unexplained depletion of the epidermal growth factor receptor (EGFR) protein expression in prostatic cancer. We now attribute this phenomenon to the presence of a variant EGFR (EGFRvIII) that is highly expressed in malignant prostatic neoplasms. In a retrospective study, normal, benign hyperplastic and malignant prostatic tissues were examined at the mRNA and protein levels for the presence of this mutant receptor. The results demonstrated that whilst EGFRvIII was not present in normal prostatic glands, the level of expression of this variant protein increased progressively with the gradual transformation of the tissues to the malignant phenotype. The selective association of high EGFRvIII levels with the cancer phenotype underlines the role that this mutant receptor may maintain in the initiation and progression of malignant prostatic growth, and opens the way for new approaches in the management of this disease including gene therapy. © 2000 Cancer Research Campaign


Infant mortality is a major public health problem in the State of Michigan and the United States. The primary adverse reproductive outcome underlying infant mortality is low birthweight. Visualizing and exploring the spatial patterns of low birthweight and infant mortality rates and standardized incidence and mortality ratios is important for generating mechanistic hypotheses, targeting high-risk neighborhoods for monitoring and implementing maternal and child health intervention and prevention programs and evaluating the need for health care services. This study investigates the spatial patterns of low birthweight and infant mortality in the State of Michigan using automated zone matching (AZM) methodology and minimum case and population threshold recommendations provided by the National Center for Health Statistics and the US Census Bureau to calculate stable rates and standardized incidence and mortality ratios at the Zip Code (n = 896) level. The results from this analysis are validated using SaTScan. Vital statistics birth  and linked infant death  records obtained from the Michigan Department of Community Health and aggregated for the years 2004 to 2006 are utilized.For a majority of Zip Codes the relative standard errors (RSEs) of rates calculated prior to AZM were greater than 20%. Spurious results were the result of too few case and birth counts. Applying AZM with a target population of 25 cases and minimum threshold of 20 cases resulted in the reconstruction of zones with at least 50 births and RSEs of rates 20–22% and below respectively, demonstrating the stability reliability of these new estimates. Other AZM parameters included homogeneity constraints on maternal race and maximum shape compactness of zones to minimize potential confounding. AZM identified areas with elevated low birthweight and infant mortality rates and standardized incidence and mortality ratios. Most but not all of these areas were also detected by SaTScan.Understanding the spatial patterns of low birthweight and infant deaths in Michigan was an important first step in conducting a geographic evaluation of the State's reported high infant mortality rates. AZM proved to be a useful tool for visualizing and exploring the spatial patterns of low birthweight and infant deaths for public health surveillance. Future research should also consider AZM as a tool for health services research. Infant mortality refers to infants born alive who die within their first year of life. In 2006, Michigan's infant mortality rate was 7.6 infant deaths per 1,000 live births with African American infants at substantially higher risk (17.7) than white infants (5.2) of death  was the adjusted expected number of cases within the window under the null-hypothesis. C-E [c] was the expected number of cases outside the window. I  was an indicator function. When SaTScan scans for clusters with high rates, I  was equal to 1 when the window had more cases than expected under the null-hypothesis, and 0 otherwise . HypotheThe authors declare that they have no competing interests.SCG originated the study and participated in the planning of the study, analysis of the data and writing of the brief. HE contributed to the preparation of the data, analysis of the data, and writing of the brief.


In recent years proteomic techniques have started to become very useful tools in a variety of model systems of developmental biology. Applications cover many different aspects of development, including the characterization of changes in the proteome during early embryonic stages. During early animal development the embryo becomes patterned through the temporally and spatially controlled activation of distinct sets of genes. Patterning information is then translated, from gastrulation onwards, into regional specific morphogenetic cell and tissue movements that give the embryo its characteristic shape. On the molecular level, patterning is the outcome of intercellular communication via signaling molecules and the local activation or repression of transcription factors. Genetic approaches have been used very successfully to elucidate the processes behind these events. Morphogenetic movements, on the other hand, have to be orchestrated through regional changes in the mechanical properties of cells. The molecular mechanisms that govern these changes have remained much more elusive, at least in part due to the fact that they are more under translational/posttranslational control than patterning events. However, recent studies indicate that proteomic approaches can provide the means to finally unravel the mechanisms that link patterning to the generation of embryonic form. To intensify research in this direction will require close collaboration between proteome scientists and developmental researchers. It is with this aim in mind that we first give an outline of the classical questions of patterning and morphogenesis. We then summarize the proteomic approaches that have been applied in developmental model systems and describe the pioneering studies that have been done to study morphogenesis. Finally we discuss current and future strategies that will allow characterizing the changes in the embryonic proteome and ultimately lead to a deeper understanding of the cellular mechanisms that govern the generation of embryonic form. The wor century . Both doDuring the early period of experimental embryology, fundamental concepts have been formulated despite the lack of any knowledge about the molecular basis of development. One of the most influential theories was certainly the proposal of morphogens as inducers of patterning ,5. MorphIt appears now that in several species, including the "classic" model systems Drosophila melanogaster and Xenopus laevis, a reasonably "complete" list of genes that are involved in early pattern formation has emerged. This undertaking has become even more feasible in recent years, since the genomes of several model animals have been completely sequenced, including fruit fly, nematode and sea urchin, and other genomes are close to completion and/or large cDNA and EST databases have been built -19. TherTo study morphogenesis essentially means to ask how cells and tissues translate the positional information they have received into regional specific cell behaviors to give the embryo its defined shape. In animals, the first global cell rearrangements occur as gastrulation is initiated. Gastrulation is defined as the internalization of the prospective endoderm and mesoderm into the embryo and, while different species use different means and mechanisms to achieve internalization, the result is always the same: the endoderm forms the inner layer, the ectoderm remains on the outside and the mesoderm is located in between. After gastrulation, the three germ layers are in close apposition to each other; but they are clearly separated and mixing between the different layers rarely occurs, indicating that these cells can distinguish "similar" cells from "different" cells. This ability was demonstrated in dissociation and reaggregation experiments. Cells from early amphibian embryos can easily be separated by removal of calcium from the culture medium. Mixing of cells from the different germ layers and restoring of the calcium levels will lead first to a ball of mixed cells, but then cells will not only reaggregate according to their germ layer affiliation, but also assume the same position as in the embryo: ectoderm on the outside, mesoderm next and endoderm on the inside. These classical experiments led to the proposal of differential affinity between germ layer cells and later to the concept of differential adhesion to explain the ability of cells of different tissues to remain separate from each other -29. One Likewise, our understanding of the molecular mechanisms that drive the cellular movements and cell shape changes during embryogenesis is still very fragmented. In several species gastrulation movements have been characterized in great detail and employed to develop general models of coordinated cell movements and shape generation -41. ThesProteomic approaches have already strongly contributed to many research areas in the medical sciences and in biology. Such areas include for example the study of cellular organelles -60 and pDuring embryogenesis, discrete regions in the embryo display specific morphogenetic activities. The sum of these activities produces the final shape of the embryo. Regionalization of morphogenetic behavior poses an important challenge for the application of proteomic tools, mainly because sufficient amounts of a given tissue -that undergoes a specific movement- have to be obtained for subsequent analysis. Tissue formation and thereby the related cell behavior is under the control of upstream patterning signals and, to obtain large amounts of starting material, the manipulation of such signals has been employed to obtain mutant embryos that are either deficient or enriched in a certain tissue.In Drosophila gastrulation begins with the internalization of mesodermal precursor cells on the ventral side of the embryo. This movement is initiated by shape changes of ventral cells that lead to the formation of a furrow. To study changes in the protein composition of ventral cells during this period of development the group of Jonathan Minden compared mutant embryos which are strongly ventralized to embryos where the ventral cells have adopted a lateral fate . By diffA second study compared gastrulation stage zebrafish embryos that consisted mainly of cells of ectodermal respectively mesendodermal character . In zebrAnother possibility is to interfere specifically with signals that have been found to be involved in the control of tissue movements and to identify thereby downstream signaling events. This approach has been used to study Fyn/Yes dependent signal transduction during zebrafish axis formation . During The last decades have provided a large pool of mutants and antisense tools to manipulate patterning and morphogenetic events in the embryo. Combined with the continuous improvements of proteomic techniques and the increasing availability of proteomic facilities this will certainly lead to an increase in comparative proteome studies of mutant or knock down embryos. In addition, comparative studies on isolated tissues of an embryo might also be possible. Most notably, amphibian embryos like Xenopus laevis are known for the ease with which relatively high amounts of different tissues can be manually isolated. Manual isolation has been employed in many different contexts, e.g. to construct tissue specific libraries, to compare expression of marker genes or for antibody-based comparison of protein levels -105 and The examples cited above illustrate how comparative studies can provide novel candidates for proteins that participate in the regulation and execution of morphogenetic movements. 2D-gel-based approaches were used most commonly for good reasons, but it might be beneficial to additionally use peptide-based approaches to detect changes in protein concentration that are underrepresented in 2D-gels -82. Thisin vivo imaging, to decipher how these signals are coordinated to produce the forces that shape a complete organism from an undifferentiated ball of cells.Within just a few years proteomic techniques have been used in a variety of model organisms of developmental biology and in applications ranging from the development of species specific protein databases down to the isolation and identification of single proteins of interest. These pioneering studies demonstrate the usefulness of proteomic approaches and with increasing availability of proteomic facilities and technical expertise, such approaches offer exciting possibilities in many areas of embryology. These new possibilities -we believe- will strongly influence the study of morphogenesis. So far our understanding of the driving forces behind morphogenetic movements is largely based on detailed descriptions of changes in cell shape and protrusive activity as well as explantation/ablation techniques to elucidate their relative contribution to the forces that form the embryo. However, cell biology has already made incredible progress in the characterization of the protein components that determine the mechanical attributes of a cell, its internal architecture and its external interactions. Drawing from the immense wealth of cell biological studies, morphogenetic studies have also been extended to the investigation of some of the molecular regulators of cell mechanics. Proteomics provide now the means to systematically study the regulatory events that link patterning signals to the structural changes that determine tissue specific cell behavior. In the short term this will provide new candidate regulators of morphogenesis. In the longer term, the continuing improvements in proteomic techniques and data analysis and presentation will provide a more comprehensive picture of time and tissue specific protein composition and posttranslational modifications. This will allow for a systematic analysis of the active signaling networks in a given tissue at a given time point and form the necessary basis for a multidisciplinary approach that includes e.g. biomechanics and The authors declare that they have no competing interests.WER and CAM co-wrote the manuscript and approved the final version.


The operative methods of total uterine mucosal ablation (TUMA) as well as new abdominal and vaginal hysterectomy techniques are described. Classic intrafascial serrated edged macro-morcellator (SEMM) hysterectomy (CISH) by pelviscopy or laparotomy and intrafascial vaginal hysterectomy (IVH) are techniques that allow the nerve and the blood supply of the pelvic floor to remain intact, mainly because only the ascending branches of the uterine arteries are ligated. TUMA avoids the removal of the uterus altogether and is reserved for hypermenorrhea or menorrhagia without major enlargement of the uterus. Both CISH and IVH reduce the physical trauma of hysterectomy considerably and have the advantages of the supravaginal technique. Prophylaxis against cervical stump carcinoma is assured by coring out the cervix with the SEMM. In patients in whom both procedures are possible, IVH is preferred because it combines the minimal trauma and short operative time of vaginal hysterectomy. The decreased diameter of the cervix after coring out greatly simplifies this type of vaginal hysterectomy, the technique that has always been favored because of its short operative times and minimal trauma.


This special supplement to the Archives of Oral Biology reflects a collaborative initiative within the area of oro-facial growth and development. A Workshop was held in Liverpool in November 2007 to establish an International Collaborating Centre in Oro-facial Genetics and Development. This issue contains papers from that Workshop refereed by colleagues from the wider dental community.In bringing this group of colleagues together we have been inspired by the statue in Lisbon  which ceAs a basis for that future development this issue contains a series of papers which are either critical perspectives on specific topics or which report new studies in the area.The initial group of papers sets the scene. The first paper considers the multifactorial, multilevel, multidimensional and time related interactions which occur during normal and abnormal dental development. In the second paper a particular aspect of the multifactorial effects, the role of human sex chromosomes in dental development is reviewed while from the multilevel effects the third paper focuses on epithelial histogenesis during tooth development. This initial overview section closes with a consideration of multidimensional and time dependant effects by developing a current, clinically relevant update of the morphogenetic fields concept, incorporating a synthesis of the clone theory and the odontogenic homeobox code.The next section of papers considers the multifactorial effects on the initiation and morphogenesis phases of dental development. It begins with a critical evaluation of studies involving twins to determine genetic and environmental influences on human dental development. There follows a series of new studies on variation and anomalies of human tooth number, size and shape. These begin with family studies, first on the aetiology of hypodontia and then on the tooth dimensions in a family with hypodontia associated with an identified PAX 9 mutation. The contrasting tooth dimensions in patients with hypodontia and supernumerary teeth compared with controls are examined in the next study. There follows a paper reporting the detailed investigation of multiple crown size variables of upper incisor teeth in patients with supernumerary teeth compared with controls. This group of new studies concludes with the examination of variability and patterning of permanent tooth size in four human ethnic groups.The third group of papers consists of three new studies on the differentiation and biomineralisation phases of human dental development. The first of these examines enamel defects in extracted and exfoliated teeth from patients with Amelogenisis Imperfecta using the extended Enamel Defect Index and image analysis. This is followed by a study of the patterns of enamel hypoplastic defects in two archaeological populations and the section concludes with an investigation of demineralisation rates in pre-natal, neo-natal and post-natal enamel.The fourth section considers first the crucial role of critical evaluation of measurement studies of the phenotype resulting from the dental developmental process. It concludes with a consideration of innovative 3D methodologies to allow more detailed definition of dental phenotypes in order to enhance discrimination between individuals and to provide further insight into the aetiology of dental anomalies in the future.I am grateful to several people for their input to the preparation of this issue. Rebecca Griffin has been highly efficient and supportive as Assistant Guest Editor. Karen Barnes provided substantial and valuable administrative support in the organisation of the International Workshop. The Editor-in-Chief of the Archives of Oral Biology, Rex Holland, has given firm and clear guidance on the editorial process and has carefully and appropriately overseen the refereeing process. On the production side Nick Dunwell, Account Executive for Elsevier Pharma Solutions has been helpful and encouraging.This issue both makes available papers from the International Workshop to the wider research community and acts as a basis for future collaborative work. It is made possible by generous financial support from the Wellcome Trust, for those papers arising from the Wellcome Programme on Biomineralisation, from Boots plc and from the University of Liverpool. The Workshop was funded by donations from Boots plc, the Universities of Adelaide and Liverpool and Scantron Ltd. We are most grateful for this generous support.


The dual properties of genetic instability and clonal expansion allow the development of a tumour to occur in a microevolutionary fashion. A broad range of pressures are exerted upon a tumour during neoplastic development. Such pressures are responsible for the selection of adaptations which provide a growth or survival advantage to the tumour. The nature of such selective pressures is implied in the phenotype of tumours that have undergone selection. We have reviewed a range of immunologically relevant adaptations that are frequently exhibited by common tumours. Many of these have the potential to function as mechanisms of immune response evasion by the tumour. Thus, such adaptations provide evidence for both the existence of immune surveillance, and the concept of immune selection in neoplastic development. This line of reasoning is supported by experimental evidence from murine models of immune involvement in neoplastic development. The process of immune selection has serious implications for the development of clinical immunotherapeutic strategies and our understanding of current in vivo models of tumour immunotherapy. © 2000 Cancer Research Campaign


The continued northwards spread of Rhodesian sleeping sickness or Human African Trypanosomiasis (HAT) within Uganda is raising concerns of overlap with the Gambian form of the disease. Disease convergence would result in compromised diagnosis and treatment for HAT. Spatial determinants for HAT are poorly understood across small areas. This study examines the relationships between Rhodesian HAT and several environmental, climatic and social factors in two newly affected districts, Kaberamaido and Dokolo. A one-step logistic regression analysis of HAT prevalence and a two-step logistic regression method permitted separate analysis of both HAT occurrence and HAT prevalence. Both the occurrence and prevalence of HAT were negatively correlated with distance to the closest livestock market in all models. The significance of distance to the closest livestock market strongly indicates that HAT may have been introduced to this previously unaffected area via the movement of infected, untreated livestock from endemic areas. This illustrates the importance of the animal reservoir in disease transmission, and highlights the need for trypanosomiasis control in livestock and the stringent implementation of regulations requiring the treatment of cattle prior to sale at livestock markets to prevent any further spread of Rhodesian HAT within Uganda. Human African Trypanosomiasis (HAT) or sleeping sickness is a parasitic disease of humans, transmitted by the tsetse fly. There are two different forms of HAT: Rhodesian (in eastern sub-Saharan Africa), which also affects wild and domestic animals, and Gambian . Diagnosis and treatment of the two diseases differ, and disease characterisation is based on prior knowledge of known geographical disease distributions. Presently, the two forms of HAT do not overlap in any area: Uganda is the only country which sustains active transmission of both types.In recent years, Rhodesian HAT has spread into areas of Uganda that had not previously been affected, thus narrowing the gap between areas of Rhodesian and Gambian HAT transmission. This spread has raised concerns of a potential overlap of the two types of the disease, which would severely complicate their diagnosis and treatment. Earlier work indicated that Rhodesian HAT was introduced to Soroti district due to the movement of untreated cattle from affected areas. Here we show that the continued spread of HAT in Uganda (to a further 2 districts) may also have occurred due to cattle movements, despite legal requirements to treat livestock from affected areas prior to sale at markets. These findings can assist in the targeting of HAT control efforts in Uganda and show that the stringent implementation of animal treatments at livestock markets should be a priority. Trypanosoma brucei rhodesiense causes an acute disease in eastern sub-Saharan Africa and has a reservoir in wild and domestic animals while Trypanosoma brucei gambiense causes a chronic form of the disease in western and central sub-Saharan Africa. Uganda has had the misfortune to sustain active transmission of both types of the disease: T. b. gambiense in the north west and T. b. rhodesiense in the south east T. b. rhodesiense) was introduced into Tororo District in 1987, the disease has persistently spread northwards into previously unaffected areas of Uganda T. b. rhodesiense focus is a persistent concern. The Northwards spread of disease has narrowed the area between the active foci of Rhodesian and Gambian HAT, with an estimated 150 km now separating the two forms of the disease Human African trypanosomiasis (HAT), or sleeping sickness, is caused by two sub species of a hemoflagellate parasite that are transmitted by tsetse flies. It is essential that the dynamics of disease spread are understood if HAT is to be controlled in Uganda. A comprehensive understanding of the factors involved in the disease's spatial distribution and movements will enable more effective targeting of control efforts. The spatial distribution of HAT is driven by complex interactions of many factors. The occurrence of disease in an area is dependent on the establishment of disease transmission, which in turn is reliant on the suitability of an area for the disease. Within affected areas, a spatially varying intensity of transmission can result in the heterogeneous village level prevalence of disease. These two processes giving rise to i) the establishment of HAT transmission and ii) the heterogeneous prevalence of HAT in an area are likely to be driven by different environmental, climatic and social factors associated with the presence and density of tsetse flies Spatial analysis and geographic information systems (GIS) have been applied increasingly to infectious disease epidemiology in recent years, including to the analysis of HAT T. b. rhodesiense HAT in two newly affected districts of Uganda (Kaberamaido and Dokolo) was examined in relation to several environmental, climatic and social variables. Prevalence of HAT was then predicted spatially to highlight areas with the potential for high prevalence and to enable the targeting of future control efforts. The utilities of two different methodologies were compared: a two-step regression method and a traditional one-step regression method. The two-step regression was used to allow the separate analysis of factors governing the occurrence and prevalence of HAT. The prevalence analysis in the two-step regression model was conducted solely on areas that had a high predicted probability of occurrence. This was anticipated to provide an increase in predictive accuracy  due to the exclusion of large areas with little or no HAT transmission.The spatial distribution of T. b. rhodesiense). Kaberamaido (Eastern region) and Dokolo (Northern region) districts lie to the north of Lake Kyoga with a combined area of approximately 2740 km2. The main economic activities within the study area are agriculture and fishing, with the majority of the population engaged in subsistence farming The study area included Kaberamaido and Dokolo districts in Uganda see , two of A handheld global positioning system  was used to geo-reference the central point of all villages within the study area with guidance from local government staff. Coordinates were taken in the WGS84 geographical coordinate system in decimal degrees . Comprehensive HAT hospital records were collected in collaboration with the Ugandan Ministry of Health from the two HAT treatment centres serving the study area; Lwala Hospital (Kaberamaido district) and Serere Health Centre IV (Soroti district). To maintain anonymity of subjects and patient confidentiality and to adhere to the International Ethical Guidelines for Biomedical Research Involving Human Subjects, no patient names were recorded within the database or as part of the data collection process. The hospital records were matched with the geo-referenced villages by cross-referencing each case's village of residence with the names from the geo-referenced villages. This resulted in a spatially referenced dataset of all patients residing within the study area who had received a diagnosis of HAT .T. b. rhodesiense in the reservoir, the control programme resulted in an altered epidemiology of HAT within the study area in the subsequent year and so may have affected the results of the regression analyses.Cases occurring from February 2004 (when the first cases were reported) to December 2006 were included in the analysis. Cases diagnosed later than December 2006 were excluded because a control programme was instigated in September 2006 that involved the mass treatment of cattle in the study area and adjoining districts. By decreasing the prevalence of human infective The geo-referenced HAT case data were visualised using ArcMap 9.1 . External covariate datasets as listed in Several temporal Fourier-processed indices were obtained from Advanced Very High Resolution Radiometer (AVHRR) imagery: land surface temperature (LST), NDVI and middle-infrared . NDVI is a measure of the amount of green vegetation Predicted tsetse suitability maps were obtained from the Food and Agricultural Organization Distances to physical features (in km) were calculated. Land cover data In addition, distances to the closest livestock market and health centre (of any type) were calculated using the coordinates of each of these features that were obtained during fieldwork. The distance to the closest health centre (of any type i.e. not necessarily trained or equipped to diagnose or treat HAT) was used to deal with the confounding effect of access to health care. The distance to the closest livestock market was included to investigate the possibility that cattle movements in this area may have caused or contributed to the introduction and establishment of HAT transmission, as was found in a neighbouring district Exploratory analysis was conducted for each of the covariates: i) scatter plots to examine relationships with HAT prevalence; ii) box and whisker plots to examine the distributions of covariate data in villages which have had cases of HAT compared to villages which have not and iii) visualisation of the geographical distributions of the outcome variables in relation to the external covariates. Seventeen covariates were selected for use in the regression analyses  based onThe statistical modelling was carried out using logistic regression: a generalised linear model used for the analysis of binomial data such as disease occurrence  or disease prevalence (where the outcome is bounded between zero and one) An OR of one indicates no association, an OR greater than one indicates a positive association with the odds of disease and an OR less than one indicates a negative association This methodology comprised two logistic regression models applied sequentially  as well as prevalence (how intense was the transmission within affected areas) which are confounded in a one-step approach.Forwards stepwise addition beginning with the null model (no explanatory variables) was used in the model fitting. At each step the variable resulting in the greatest reduction in deviance was selected. A Chi-squared likelihood ratio test was used to compare models, and additional explanatory variables were accepted only if this test was significant and the covariate was significant within the model. Any variables that lost significance in subsequent steps were removed from the model. The stepwise addition of plausible interaction terms (if interaction is present the effect of one variable on odds of disease changes in relation to the effect of another variable) was then carried out in the same manner after the variables were centred .The sensitivity (true positive rate) and specificity (true negative rate) of the fitted model were calculated for a variety of cut-off points  using the predicted and observed values, and plotted against the cut-off points. The cut-off point where the sensitivity and specificity crossed was selected as a suitable cut-off point for the classification of case and non-case villages: this point maximises both the specificity and the sensitivity of the classification of locations. A 10-fold cross-validation  was performed using ten random sub-divisions of the dataset. The area under the receiver operator characteristic curve (AUC) was calculated; this value gives a measure of the overall performance of the model in classifying villages. An AUC of 1 indicates perfect discrimination between case and control villages, and an AUC of 0.5 illustrates a model that is in effect worthless for discrimination purposes.2 (including the study region) and a 1.1 km cell size . All villages within the study area lying within an area of high predicted probability of occurrence  were extracted for use in the second step of the analysis.The resulting regression equation (probability of occurrence as a function of the explanatory variables) was used to predict probability of occurrence of HAT across a grid with an area of 30,000 kmThe outcome variable for the second step of the two-step regression was defined as prevalence of HAT (number of cases divided by village population). Prevalence data from all villages within areas of high predicted probability of occurrence were included in the model, including those with no reported cases . Forwards stepwise addition was used in the model fitting procedure, as for the first step. For this section of the analysis, the distance to health centre variable was forced into the model (regardless of it's significance) to ensure that access to health care was controlled for in the final results. The fitted model was used to predict the prevalence of Rhodesian HAT across the same area as was used in the first step.For the one-step analysis  as shown in Four covariates were found to influence significantly the occurrence of HAT across the study area . The predicted suitability for transmission across the study area using the specified model is illustrated in The prediction was used to create a mask over the study area; all areas with a predicted probability of occurrence less than 0.2 were excluded. 279 villages lay within the area defined as having a high probability of occurrence. However, seven of those villages had no population data and so were excluded from the remaining analysis leaving 272 villages. The results from the second  model are shown in p = 0.05, variable forced into the model). Prevalence was negatively correlated with distance to the closest livestock market with every additional kilometre resulting in a 20% decrease in odds of disease. This was shown to interact with distance to the closest area of woodland, which in turn showed a positive correlation with prevalence. In addition, HAT prevalence was negatively correlated with distance to the closest area of bush and maximum NDVI and positively correlated with NDVI phase of annual cycle, NDVI annual amplitude, LST phase of annual cycle, LST annual amplitude and minimum LST.HAT prevalence was significantly correlated with nine variables in addition to distance to the closest health centre that was negatively correlated and of borderline significance . The model had a small tendency to over predict prevalence with a median error of 0.05% . The mean absolute error for the predicted prevalence per 100 population was 0.24%. The scatter plot of predicted prevalence against observed prevalence  shows a Nine variables were shown to be significantly associated with prevalence of HAT across the study area using the one-step regression, as shown in The correlation between predicted and observed prevalence values was 0.58 indicating a modest linear association. The model was slightly biased with a very small tendency to over-predict prevalence (median error = 0.02%) and the mean absolute error was 0.13% . The scatter plot of predicted prevalence against observed prevalence values  illustraTo allow a direct comparison of the predictive accuracy of the two methodologies, the one-step model was used to calculate predicted prevalence for the villages with high predicted probabilities of occurrence from the two-step analysis (i.e. excluding areas with a predicted probability of occurrence of less than 0.2). The correlation between predicted and observed prevalence was 0.50, lower than that for the two-step regression method (0.57). Again, the model was shown to have a tendency to over predict prevalence, with a median error of 0.05% . The mean absolute error was 0.24%, equal to the mean absolute error from the two-step regression methodology.Spatial determinants for HAT are poorly understood across small areas. This study examined the relationships between Rhodesian HAT and several environmental, climatic and social factors in two newly affected districts, Kaberamaido and Dokolo. The application of a two-step regression approach for the prediction of HAT prevalence in a newly affected area of Uganda allowed the investigation of factors influencing the occurrence and prevalence of HAT separately, and overall resulted in a slight increase in predictive accuracy when compared to a one-step analysis in areas with high predicted probability of occurrence. Each of the models has illustrated an increased risk of HAT in villages closer to livestock markets than in villages further away, suggesting the persistent spread of Rhodesian HAT in Uganda may have resulted from the continued movement of untreated cattle.The two-step regression model gave a slight increase in predictive accuracy in comparison with the one-step analysis with a correlation between fitted and observed prevalence values of 0.57 for the two-step regression and 0.50 for the one-step regression analysis (when looking only at areas with a high predicted probability of occurrence). Both models tended to predict higher prevalence than was observed, particularly in villages of zero prevalence, with a median error of 0.05% for both models. The mean absolute error was equal for the two methods (0.24%). The difference in predicted prevalence of HAT from the two methods was small over the majority of the prediction area, with divergences mainly occurring in areas of high predicted prevalence outside of the study area see .There were only two health centres trained and equipped to diagnose and treat HAT serving the study population during the study period. It has been shown previously that levels of geographical accessibility to treatment facilities can have an effect on the observed spatial distribution of HAT, with smaller numbers of cases reported from areas which are further from the treatment centres T. b. rhodesiense endemic areas in the south east, through the study area and neighbouring districts, to the T. b. gambiense endemic areas in the far north west of Uganda towards southern Sudan. Clearly, this increases the risk of overlap of the two subspecies, particularly if the regulations regarding the treatment of cattle being moved from T. b. rhodesiense endemic areas continue to be broken. The stringent implementation of regulations requiring the treatment of cattle prior to sale at livestock markets should be a priority for the Ugandan Government and tsetse control efforts may be more efficiently targeted to areas surrounding livestock markets to prevent the establishment of transmission in previously unaffected areas as occurred in Soroti district in the late 1990s and Kaberamaido and Dokolo districts in 2004.Distance to the closest livestock market was an important predictor in the one-step regression and in both steps of the two-step regression, with decreasing odds of infection at increasing distances. Previous research has confirmed the introduction of HAT to a previously unaffected area via the introduction of untreated, infected livestock Other variables that were also significantly correlated with HAT prevalence and/or occurrence included distance to the nearest health centre, maximum Normalised Difference Vegetation Index (NDVI), NDVI phase of annual variation, NDVI annual amplitude, minimum Land Surface Temperature (LST), LST phase of annual variation, LST annual amplitude, mean LST, distance to the closest area of woodland and distance to the closest area of bush. The significance of these variables highlights the importance of climatic and environmental conditions for HAT transmission. Distance to the closest health centre was also a significant factor in each model, with decreasing prevalence observed at increasing distances. This suggests a confounding relationship due to accessibility of health services as has been previously reported Each of the regression models (the one-step regression model and each step of the two-step regression models) included maximum NDVI (negative association) and minimum LST (positive association) as significant predictors. These are likely to relate to the habitat and environmental requirements of the tsetse fly vector of disease. The additional variables found to be significantly correlated with HAT prevalence in each analysis are probably also linked to the suitability of an area for the tsetse fly vector , and so will influence the intensity of transmission and observed prevalence of HAT.Analysis of the residual variation (after accounting for the covariate effects) indicated that there was some spatial autocorrelation in the residuals from the one-step regression and the probability of occurrence analysis . For the two-step regression, the probability of occurrence regression was carried out partially to provide a mask over areas with low predicted probability of occurrence to enable the focusing of the prevalence analysis, and so the small amount of spatial autocorrelation in the residuals is not seen as problematic as it would have a negligible effect on the final prevalence model. However, for the one-step regression, the small amount of spatial autocorrelation in the residuals may lead to inflated statistical significance for some of the covariates. Further research is underway to address this autocorrelation in the residuals and to assess any increase in the predictive accuracy using a model-based geostatistics approach T. b. rhodesiense infected livestock from endemic areas through livestock markets within the study area occurs periodically. A complex interaction of factors is involved in the establishment of transmission following such an occurrence. In addition to the variables included in the current analysis, tsetse and livestock densities, human-cattle-tsetse contact and also to a large degree, chance, may play roles. Further research is planned to build upon these findings, incorporating detailed livestock market data and cattle trading networks to give a more thorough understanding of the spatial and temporal dynamics of HAT within Uganda.From these and previous findings


Human genetic variation produces the wide range of phenotypic differences that make us individual. However, little is known about the distribution of variation in the most conserved functional regions of the human genome. We examined whether different subsets of the conserved human genome have been subjected to similar levels of selective constraint within the human population. We used set theory and high performance computing to carry out an analysis of the density of Single Nucleotide Polymorphisms (SNPs) within the evolutionary conserved human genome, at three different selective stringencies, intersected with exonic, intronic and intergenic coordinates.We demonstrate that SNP density across the genome is significantly reduced in conserved human sequences. Unexpectedly, we further demonstrate that, despite being conserved to the same degree, SNP density differs significantly between conserved subsets. Thus, both the conserved exonic and intronic genomes contain a significantly reduced density of SNPs compared to the conserved intergenic component. Furthermore the intronic and exonic subsets contain almost identical densities of SNPs indicating that they have been constrained to the same degree.Our findings suggest the presence of a selective linkage between the exonic and intronic subsets and ascribes increased significance to the role of introns in human health. In addition, the identification of increased plasticity within the conserved intergenic subset suggests an important role for this subset in the adaptation and diversification of the human population. Although it is widely accepted that genome changes have driven evolution, there is still a lack of consensus as to what aspect of genome function are most affected to bring about phenotypic change. Many conjecture that changes within exonic coding regions are most important ,2 whilstOne method to address the question of where the majority of functional polymorphisms lie within the human genome is to examine the densities of polymorphisms within the different functional components of the conserved human genome. Thus, functional portions of the genome under the strongest selective pressure will contain less polymorphisms due to removal of less fit individuals from the population at an early age. The advantages of examining the conserved genome to select for functional importance is that mechanistic bias towards particular subsets is removed and the importance of a particular sequence to survival is defined by its retention through evolution. Once these conserved sequences have been identified they can be divided into functional subsets and densities of polymorphisms within these subsets can be compared. Thus, if one portion of the conserved genome contains a lesser density of polymorphisms, despite being conserved to an identical degree, it can be assumed that this portion has been subjected to a higher degree of purifying selection within the human population and is consequently more important in maintaining species fitness and conferring disease susceptibility prior to reproductive age if compromised.In order to determine the densities of polymorphisms, in the form of SNPs  across tUsing this simple but unique set theory approach we have been able to demonstrate that, in keeping with the current understanding of its importance in evolution and health, the conserved exonic subset has a significantly reduced density of SNPs and has therefore been subjected to greater selective pressures than other areas of the genome. Unexpectedly, comparison of the SNP densities between the intergenic and intronic components, both previously considered "junk DNA", demonstrated significant differences in SNP densities, such that the intronic portion had a statistically identical SNP density to the exonic component and the intergenic component contained a significantly higher SNP density. These observations demonstrate that the conserved intronic subset of the human genome has been subjected to identical levels of purifying selection as the exonic component within the human population. These novel and far reaching observations point to a critical role for conserved intronic sequences in the maintenance of species fitness and human health and give added weight to the analysis of intronic polymorphisms in the search for the causes of human genetic disease. In addition, the higher SNP density within the intergenic subset is indicative of its important role in driving the adaptive changes that reflect diversity within the human population.The genomic data of chromosomal positions for transcripts and the positions of exons within those transcripts were downloaded from the UCSC genome browser through the table browser portal  from theThese data were held on a MySQL database implemented on a 56 node High Performance Cluster (HPC) IBM blade array operated by Microsoft compute cluster server 2003. All programs were written in Visual Basic .net on the Microsoft .net 3.5 framework, in a parallel design using the database to pass messages and data to the worker nodes. The database was designed so that the queries were optimized during the analysis process, and also to optimize subsequent analysis of the results. In utilizing set theory, each chromosome was considered as a set with its members being its base pairs. Each chromosome was considered separately as an entity of DNA of independent evolutionary path. The bases of each chromosome were categorized according to their position with respect to the different annotation information gathered.All autosomal chromosomes were analysed , although the × and Y chromosomes were removed from the analysis due to being under different selective pressures and being represented differently within the population. The mitochondrial genome was also removed from the analysis. We also removed repetitive regions  as the repetition, frequency and random nature of these repeat regions present problems when using pairwise alignment analyses. Un-sequenced regions of the genome, such as centromere regions of each chromosome were also removed from the analysis as no alignments or SNPs can be mapped to these regions . From the starting genomic annotations, set algebra was used to define subsets for further investigation, as described in Table The analysis was carried out on each chromosome with pairwise alignments of each species aforementioned at three different selective "stringencies" of 70%, 80% and 90% over 100 base pairs. However at the higher level of stringencies the size of conserved genome for large evolutionary depth was small and the number of SNPs reduces to a very small number. Therefore, in order to keep the analysis statistically valid across all species the 70% data was selected for the majority of the analysis in this paper although the 80% and 90% data demonstrated a similar trend. Statistical analyses of the results were carried out in MATLAB version 7.1 (Mathworks) and Microsoft Excel 2003. Tests of normality were undertaken using the Jarque-Bera test (JB test) on the mean SNP density counts for all regions as described in Table et al. we have compared SNP data from 2003 to that held within dbSNP in 2009 , and have determined that the major reservoirs of human SNP variation within the human genome conserved at three different stringencies within amniotes are to be found within the non-coding portion of the genome (the intergenic and intronic subsets) (Table We sought to determine if there was a relationship between SNP density and evolutionary depth as it has been shown that highly conserved sequences in the human genome are indicative of functionally important sequences within genes , intronsThe results of this analysis demonstrated that SNPs occur at a significantly lower rate in the most highly conserved regions, conserved since the common ancestors of humans and birds, amphibians and fish, as confirmed by one-way ANOVA analysis . The obsBecause they had been conserved to the same degree we initially hypothesised that SNPs would occur with equal density throughout the conserved genome, irrespective of the identity of the conserved subset. We carried out ANOVA analysis to determine whether there were significant differences in the densities of SNPs within the intergenic, intronic or exonic subsets at three different comparative stringencies. However, comparisons between the SNP densities for the exonic and intergenic subsets demonstrate significant differences in the SNP distribution between these subsets Table .These data suggest that, despite selecting on the basis of conservation, conserved intergenic and conserved exonic sequences appear to be subjected to different strengths of selective pressure within the human population. We considered the possibility that the differences observed in SNP density between the conserved exonic set and the conserved intergenic set reflects differences in the functional mechanism of these sets. The exonic sequences are functionally dependent on a mechanism involving the three base pair codon usage required for coding proteins, whilst intergenic regions and intronic regions are non-coding. Interestingly, comparison of the exonic and intronic subset by ANOVA analysis Table  shows thBy contrast, the SNP density within the conserved intergenic subset is consistently higher than in either the conserved coding or intronic subsets irrespective of the species under comparison (see Table A number of large scale bioinformatic studies have previously explored SNP densities throughout the human genome ,24, and , and 24,The current study also poses a fascinating contradiction. Before the start of this study we predicted that subsets of the genome that had been conserved to the same degree must contain similar densities of SNPs. However, we demonstrate that SNP density between the three subsets analysed is not the same and the intergenic subset contains significantly higher SNP density to either the intronic or exonic subset. This fascinating observation suggests that the variation seen within extant human populations has been selected for in a different way to the variation that has driven vertebrate evolution.We suggest two alternative hypotheses that might explain why the conserved human intergenic genome contains a higher SNP density than either the exonic or intronic genome. The first hypothesis is that the majority of the sequence within the conserved intergenic genome consists of "junk"; DNA that plays little or no functional role and has been conserved by chance. However, a number of recent studies demonstrating the important role played by conserved intergenic sequence in gene regulation argue against this hypothesis . A seconThe present study suggests the presence of a selective linkage between the exonic and intergenic subsets and ascribes increased significance to the role of introns in human health. In addition, the identification of increased plasticity within the conserved intergenic subset suggests an important role for this subset in the adaptation and diversification of the human population.SD undertook the design, computer analysis and statistical analysis of the study. AS and AM conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.


The pathological findings in 50 patients with Hodgkin's disease following laparotomy for diagnostic purposes are described. Forty-four patients had laparotomy before treatment and within a few months of the original diagnosis, while 6 patients had delayed laparotomies. The Rye histological classification was applied to the original lymph node biopsy, the abdominal lymph node and Hodgkin's tissue in the spleen. The variation in appearance both of these tissues and of the liver biopsies is discussed.


The influence of anthracyclines on membrane permeability functions has been investigated in HeLa cells by monitoring the efflux of fluorescein. Release of the fluorescent dye, dependent on the metabolic energy supply, occurs after the intracellular accumulation and enzymatic hydrolysis of the non-fluorescent substrate fluorescein diacetate (FDA). Flow cytometric evaluation of the efflux kinetics showed that adriamycin (ADR), N-trifluoroacetyladriamycin-14-valerate (AD-32) and daunorubicin (DNR) inhibited the permeability process. The degree of inhibition was dependent, though to different extent, on the intracellular concentration of each drug. An increase in the efflux rate was always observed when the cells were treated with the drugs in the presence of 20 mM glucose. Relationship of these effects with energetic metabolism was supported by the finding that ATP levels were lowered by the drugs and increased by glucose. Evaluation of the cytotoxicity induced by each drug showed that the intracellular amount necessary to inhibit cell survival by 50% was of the same order of magnitude as that which decreases to 50% membrane permeability to fluorescein. These results indicate a correspondence in the concentrations of anthracyclines required for inducing cytotoxicity and for inhibiting membrane permeability functions dependent on the metabolic energy supply.


The presence or absence of lymphocytic mucopolysaccharides (MPS) is studied in 223 subjects: 100 normals (controls); 8 cancer patients cured for more than 6 years; 30 cancer patients at the start of their treatment; and 85 relatives of first degree consanguinity of these last patients. The data are studied by statistical and genetic analysis. The results confirm the findings reported earlier and show that the difference in the probability of a high frequency of leucocytic MPS between the relatives of cancer patients and the controls is highly significant. Furthermore, this probability in a relative of first degree of consanguinity of a cancer patient is more than three times greater than in an individual of the general population. Genetic segregation analysis shows that the high leucocytic MPS trait segregates in the families of cancer patients after a classic pattern of dominant autosomal inheritance. Applying Falconer's nomogram it is concluded that the whole of this phenotypic variation is of genetic origin. Its interrelationships with cancer are discussed and it is postulated that this disturbance of the lymphocytic MPS represents a subclinical variant, not known until now, of the clinical mucopolysaccaridoses.


A total of 1,834 cases of colorectal cancers were divided into two diagnostic groups and studied. The ratio of smaller, less advanced carcinomas to the total number of colorectal cancers diagnosed by electronic videoendoscopy has increased as compared to the ratio in cases diagnosed by fiberscopy. This seems to be largely influenced by concomittent developments such as the implementation of colorectal cancer screening assisted by the popularization of immunological fecal occult blood tests and the increase in number of examinees. On the other hand, the use of the electronic videoendoscopy has been accompanied by increases in the diagnosis of minute carcinomas measuring 5 mm or less and flat carcinomas which were previously difficult to diagnose. Under these circumstances, endoscopic mucosal resection has gained popularity, widening the spectrum of therapeutic options. Nonetheless, endoscopic treatment also has been associated with increases in cases requiring laparotomy when carcinoma was found in the resected margin or those demonstrating invasion in the submucosa. This may be one result of the more aggressive application of endoscopic treatment, but the histologically recognized inability to detect carcinoma in the resected intestinal tract leaves room for improvement.