Growing cells push back under pressure.

In both plants and animals, the interplay between mechanical force generation and mechanical sensing plays a stabilizing role in many developmental processes. Uyttewaal et al. now demonstrate that cells in the Arabidopsis shoot apical meristem respond to local mechanical stresses by reorienting their growth, thereby guiding morphogenesis. Notably, the mechanism underlying such guidance is amplification--not suppression--of growth-rate heterogeneity.

Viscosupplementation with High Molecular Weight Hyaluronic Acid for Hip Osteoarthritis: a Systematic Review and Meta-Analysis of Randomised Control Trials of the Efficacy on Pain, Functional Disability, and the Occurrence of Adverse Events.

PURPOSE OF THE STUDY: Hip osteoarthritis (OA) has a prevalence of around 6.4% and is the second most commonly affected joint. This review aims to assess the clinical outcomes of intra-articular high molecular weight hyaluronic acid (HMWHA) in the management of hip osteoarthritis. MATERIAL AND METHODS: We conducted a comprehensive search across PubMed, Google Scholar, and the Cochrane Library for randomised trials investigating the effectiveness of high molecular weight hyaluronic acid (HMWHA) in the treatment of hip osteoarthritis. Quality and risk of bias assessments were performed using the Cochrane RoB2 tool. To synthesise the data, we utilised the Standardised Mean Difference (SMD) for assessing pain relief through the Visual Analogue Scale (VAS) and the Lequesne index (LI) for evaluating functional outcomes. Risk Ratio (RR) was calculated to assess the occurrence of complications. RESULTS: A total of four studies involving HMWHA and control groups were included. The standardised mean difference (SMD) for the Visual Analogue Scale (VAS) (SMD -0.056; 95% CI; -0.351, 0.239; p = 0.709) and the Lequesne index (SMD -0.114; 95% CI; -0.524, 0.296; p = 0.585) were not statistically significant. Analysis for complications demonstrated an overall relative risk ratio (RR) of 0.879 (95% CI; 0.527, 1.466; p = 0.622), and was not statistically significant. DISCUSSION AND CONCLUSIONS: Intra-articular HMWHA in hip OA can significantly reduce pain and improve functional recovery when compared with the condition before treatment. However, there is no significant difference between HMWHA, or saline, or other therapeutic treatments. Currently, available evidence indicates that intra-articular HMWHA in hip OA would not increase the risk of adverse events. KEY WORDS: hip osteoarthritis, hyaluronic acid, intra-articular, molecular weight, viscosupplementation.

A Systematic Review and Meta-Analysis of the Outcomes of Reconstruction with Vascularised vs Non-Vascularised Bone Graft after Surgical Resection of Primary Malignant and Non-Malignant Bone Tumors.

PURPOSE OF THE STUDY: Vascularised bone grafting (VBG) and non-vascularised bone grafting (NVBG) are crucial biological reconstructive procedures extensively employed in the management of bone tumours. The principal aim of this study is to conduct a comparative analysis of the post-resection outcomes associated with the utilisation of vascularised and non-vascularised bone grafts. MATERIAL AND METHODS: A comprehensive and systematic literature review spanning the years 2013 to 2023 was meticulously executed, utilising prominent online databases including PubMed/Medline, Google Scholar, and Cochrane Library. Inclusion criteria were restricted to comparative articles that specifically addressed outcomes pertaining to defect restoration following bone tumour resection via vascularised and non-vascularised bone grafting techniques. The quality of research methodologies was assessed using the Oxford Quality Scoring System for randomised trials and the Newcastle Ottawa Scale for non-randomised comparative studies. Data analysis was conducted using SPSS version 24. Key outcome measures encompassed the Musculoskeletal Tumour Society Score (MSTS), bone union duration, and the incidence of post-operative complications. RESULTS: This analysis incorporated four clinical publications, enrolling a total of 178 participants (comprising 92 males and 86 females), with 90 patients subjected to VBG and 88 to NVBG procedures. The primary endpoints of interest encompassed MSTS scores and bone union durations. Although no statistically significant distinction was observed in the complication rates between the two cohorts, it is noteworthy that VBG exhibited a markedly superior bone union rate (P<0.001). CONCLUSIONS: Our systematic evaluation revealed that VBG facilitates expedited bone union, thereby contributing to accelerated patient recovery. Notably, complication rates and functional outcomes were comparable between the VBG and NVBG groups. Moreover, the correlation between bone union duration and functional scores following VBG and NVBG merits further investigation. KEY WORDS: reconstruction techniques, vascularised bone grafting, non-vascularised bone grafting, bone tumor, resection.

Mitochondrial DNAs provide insight into trypanosome phylogeny and molecular evolution.

BACKGROUND: Trypanosomes are single-celled eukaryotic parasites characterised by the unique biology of their mitochondrial DNA. African livestock trypanosomes impose a major burden on agriculture across sub-Saharan Africa, but are poorly understood compared to those that cause sleeping sickness and Chagas disease in humans. Here we explore the potential of the maxicircle, a component of trypanosome mitochondrial DNA to study the evolutionary history of trypanosomes. RESULTS: We used long-read sequencing to completely assemble maxicircle mitochondrial DNA from four previously uncharacterized African trypanosomes, and leveraged these assemblies to scaffold and assemble a further 103 trypanosome maxicircle gene coding regions from published short-read data. While synteny was largely conserved, there were repeated, independent losses of Complex I genes. Comparison of pre-edited and non-edited genes revealed the impact of RNA editing on nucleotide composition, with non-edited genes approaching the limits of GC loss. African tsetse-transmitted trypanosomes showed high levels of RNA editing compared to other trypanosomes. The gene coding regions of maxicircle mitochondrial DNAs were used to construct time-resolved phylogenetic trees, revealing deep divergence events among isolates of the pathogens Trypanosoma brucei and T. congolense. CONCLUSIONS: Our data represents a new resource for experimental and evolutionary analyses of trypanosome phylogeny, molecular evolution and function. Molecular clock analyses yielded a timescale for trypanosome evolution congruent with major biogeographical events in Africa and revealed the recent emergence of Trypanosoma brucei gambiense and T. equiperdum, major human and animal pathogens.

Quantitative relations between transient BOLD responses, cortical energetics, and impulse firing in different cortical regions.

The blood oxygen level-dependent (BOLD) functional magnetic resonance imaging signal arises as a consequence of changes in blood flow (cerebral blood flow) and oxygen usage (cerebral metabolic rate of oxygen) that in turn are modulated by changes in neuronal activity. Much attention has been given to both theoretical and experimental aspects of the energetics but not to the neuronal activity. Here we use our previous theory relating the steady-state BOLD signal to neuronal activity and amalgamate it with the standard dynamic causal model (DCM, Friston) theory to produce a quantitative model relating the time-dependent BOLD signal to the underlying neuronal activity. Unlike existing treatments, this new theory incorporates a nonzero baseline activity in a completely consistent way and is thus able to account for both positive and negative BOLD signals. It can reproduce a wide variety of experimental BOLD signals reported in the literature solely by adjusting the neuronal input activity. In this way it provides support for the claim that the main features of the signals, including poststimulus undershoot and overshoot, are principally a result of changes in neuronal activity.NEW & NOTEWORTHY A previous model relating the steady-state blood oxygen level-dependent (BOLD) signal to neuronal activity, both above and below baseline, is extended to account for transient BOLD signals. This allows for a detailed investigation of the role neuronal activity can play in such signals and also encompasses poststimulus undershoot and overshoot. A wide variety of experimental BOLD signals are reproduced solely by adjusting the neuronal input activity, including recent results regarding the BOLD signal in patients with schizophrenia.

Quantitative relations between BOLD responses, cortical energetics, and impulse firing.

The blood oxygen level-dependent (BOLD) functional magnetic resonance imaging signal arises as a consequence of changes in blood flow and oxygen usage that in turn are modulated by changes in neural activity. Much attention has been given to both theoretical and experimental aspects of the energetics but not to the neural activity. Here we identify the best energetic theory for the steady-state BOLD signal on the basis of correct predictions of experimental observations. This theory is then used, together with the recently determined relationship between energetics and neural activity, to predict how the BOLD signal changes with activity. Unlike existing treatments, this new theory incorporates a nonzero baseline activity in a completely consistent way and is thus able to account for both sustained positive and negative BOLD signals. We also show that the increase in BOLD signal for a given increase in activity is significantly smaller the larger the baseline activity, as is experimentally observed. Furthermore, the decline of the positive BOLD signal arising from deeper cortical laminae in response to an increase in neural firing is shown to arise as a consequence of the larger baseline activity in deeper laminae. Finally, we provide quantitative relations integrating BOLD responses, energetics, and impulse firing, which among other predictions give the same results as existing theories when the baseline activity is zero. NEW & NOTEWORTHY We use a recently established relation between energetics and neural activity to give a quantitative account of BOLD dependence on neural activity. The incorporation of a nonzero baseline neural activity accounts for positive and negative BOLD signals, shows that changes in neural activity give BOLD changes that are smaller the larger the baseline, and provides a basis for the observed inverse relation between BOLD responses and the depth of cortical laminae giving rise to them.

A novel microdeletion affecting the CETP gene raises HDL-associated cholesterol levels.

We describe a novel, inherited 16q13 microdeletion that removes cholesteryl ester transfer protein (CETP) and several nearby genes. The proband was originally referred for severe childhood-onset obesity and moderate developmental delay, but his fasting lipid profile revealed relatively high levels of high density lipoprotein cholesterol (HDL-C) and relatively low levels of low density lipoprotein cholesterol (LDL-C) for age, despite his obesity. Testing of first-degree relatives identified two other microdeletion carriers. Functional assays in affected individuals showed decreased CETP mRNA expression and enzymatic activity. This microdeletion may or may not be pathogenic for obesity and developmental delay, but based on the lipid profile, the functional studies, and the phenotype of other patients with loss-of-function mutations of CETP, we believe this microdeletion to be antipathogenic for cardiovascular disease.

Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

A national benchmark for the initial assessment of men with LUTS: data from the 2010 Royal College of Physicians National Audit of Continence Care.

OBJECTIVE: To assess the degree of adherence to the current National Institute for Health and Clinical Excellence (NICE) guidelines on the management of urinary incontinence (UI) in men. DESIGN: Retrospective survey of male patients with UI in primary and acute hospital (AH) care as part of a national audit. SETTING: NHS AH and primary care (PC) trusts. SAMPLE: Twenty-five men <65 years old and 25 men ≥65 years old from each participating site. METHODS: All NHS trusts in England, Wales Northern Ireland and Channel Islands were eligible to participate. A web-based data collection form aligned to the NICE guidelines was constructed for the study. All data submitted to the audit were anonymous, and access to the web tool was password protected for confidentiality. RESULTS: Data were returned by 80 % (128/161) of acute trusts and 52 % (75/144) of PC trusts in England, and 71 % (10/14) of combined trusts from Northern Ireland, Wales and the Channel Islands including data on 559 men <65 and 1271 65+ from 141 sites within acute hospitals and 445 men <65 and 826 men 65+ in PC, a total of 3101 participants. CONCLUSION: The majority of men seen within the NHS with LUTS do not receive management according to evidence-informed NICE guidelines; in general, older men are less likely to receive care that meets guideline standards than younger men.

Are older women more likely to receive surgical treatment for stress urinary incontinence since the introduction of the mid-urethral sling? An examination of Hospital Episode Statistics data.

OBJECTIVE: To examine the trends in surgical treatment of stress urinary incontinence (SUI) in older women since the introduction of the mid-urethral sling. DESIGN: Analysis of data from Hospital Episode Statistics (HES) between 2000 and 2012. SETTING AND POPULATION: All surgical procedures for SUI in the National Health Service (NHS) in England. METHODS: Retrospective cohort analysis of Hospital Episode Statistics for England from 2000 to 2012. MAIN OUTCOME MEASURES: Number of invasive, less invasive, and urethral bulking procedures performed in women in three age groups. RESULTS: There was a 90% fall in the number of invasive surgical treatments for SUI and a four-fold increase in the number of mid-urethral slings over this time. The total number of surgical procedures for SUI increased from 8458 to 13 219. However, the rise in the number of procedures in women aged over 75 was more modest-a three-fold increase from a low start of 187-and these women now make up a smaller proportion of all women receiving a mid-urethral sling (MUS). CONCLUSIONS: Despite the development and wide availability of a less invasive, safe and effective operation for stress urinary incontinence in older women, they do not appear to have benefitted. The reasons for this require prospective investigation.

Eccentric Fatigue Modulates Stretch-shortening Cycle Effectiveness--A Possible Role in Lower Limb Overuse Injuries.

The role of fatigue in injury development is an important consideration for clinicians. In particular, the role of eccentric fatigue in stretch-shortening cycle (SSC) activities may be linked to lower limb overuse conditions. The purpose of this study was to explore the influence of ankle plantarflexor eccentric fatigue on SSC effectiveness during a hopping task in healthy volunteers. 11 healthy volunteers (23.2±6.7 years) performed a sub-maximal hopping task on a custom-built sledge system. 3D motion capture and surface EMG were utilised to measure lower limb stiffness, temporal kinematic measures and muscle timing measures at baseline and immediately following an eccentric fatigue protocol. A linear mixed model was used to test whether measures differed between conditions. Compared to baseline, eccentric fatigue induced increased stiffness during the hopping task (+ 15.3%; P<0.001). Furthermore, ankle stretch amplitude decreased (- 9.1%; P<0.001), whilst all other ankle kinematic measures remained unchanged. These changes were accompanied by a temporal shift in onset of activity in soleus and tibialis anterior muscles (- 4.6 to - 8.5%; p<0.001). These findings indicate that eccentric fatigue alters SSC effectiveness in healthy volunteers. These findings may be applied to inform pathogenetic models of overuse injury development.

An epidemiological study to investigate the relationship between Meniere's disease and migraine.

OBJECTIVES: A relationship between Meniere's disease and migraine has been postulated previously. This study investigates this relationship further and determines the most influential factors for developing Meniere's disease. DESIGN: Epidemiological study. SETTING: Two tertiary referral Neuro-Otological centres in Sheffield and Sydney. PARTICIPANTS: Adult patients referred to the Neuro-Otology clinic between 2003 and 2010. MAIN OUTCOME MEASURES: Past history and family history of Meniere's disease and migraine. Logistic regression analysis to determine the most influential factors for Meniere's disease. RESULTS: One hundred and eighty-one patients were included in the study, 102 with Meniere's disease and 79 with other balance disorders. Three significant findings were demonstrated. Firstly, a family history of Meniere's disease (33.3% versus 6.3%) or migraine (21.6% versus 9%) is more common in the Meniere's disease group than in the other balance disorders group. Secondly, a history of migrainous headaches is more common in the Meniere's disease group than in the other balance disorders group (45.1% versus 9%). Thirdly, patients with a past history or a family history of Meniere's disease or migraine have a higher likelihood of suffering from Meniere's disease. CONCLUSIONS: There is an overall relationship between Meniere's disease and migraine. A family history of Meniere's disease or migraine is more common in Meniere's disease. A history of migrainous headache is more common in Meniere's disease. Patients with a past history or family history of Meniere's disease or migraine have a higher likelihood of suffering from Meniere's disease.

Autosomal dominant PIK3R1 mutations cause SHORT syndrome.

PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Thauvin-Robinet et al. (2013) The American Journal of Human Genetics 93: 141-149 SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signalling. Chudasama et al. (2013) The American Journal of Human Genetics 93: 150-157 Mutations in PIK3R1 cause SHORT syndrome. Dyment et al. (2013) The American Journal of Human Genetics 93: 158-166.

Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype.

Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well-characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family-based whole-exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype-phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.

Are we shortchanging frail older people when it comes to the pharmacological treatment of urgency urinary incontinence?

Overactive bladder and urgency incontinence are common and distressing conditions in older people, for which the first-line pharmacological treatment is a bladder antimuscarinic agent. Of these, oxybutynin is often recommended in guidelines, but is associated with a higher incidence of adverse drug effects, and in particular has been suggested to have deleterious cognitive effects. Despite this, guidelines often suggest oxybutynin as first-line treatment, and insurance based healthcare systems often require oxybutynin to be used as a first-line therapy and fail before reimbursement for the cost of newer anticholinergics is authorised. We reviewed the literature of bladder antimuscarinics in older adults, using the headings overactive bladder, urinary frequency, urgency, urge, oxybutynin, antimuscarinic, older, older people, and frail. In general, oxybutynin had a similar efficacy to other anticholinergic drugs, but a higher incidence of adverse drug events, in particular significant yet unnoticed cognitive impairment. We conclude that oxybutynin should not be used in frail older people.

Cardiovascular risk in the young type 1 diabetes population with a low 10-year, but high lifetime risk of cardiovascular disease.

Diabetes mellitus is associated with excess cardiovascular mortality that is evident in all age groups, but is most pronounced in young people with type 1 diabetes. Cardiovascular risk estimation models generally estimate the probability of future events over a 10-year time horizon. Due to the dependency on age, children and adolescents with type 1 diabetes would be considered at low short-term risk but high life-time risk of developing a cardiovascular event. Guidelines recommend screening particularly for microvascular complications including nephropathy and retinopathy beginning around puberty. Identification of early microvascular abnormalities in children and adolescents not only predict later development of long-term microvascular complications and further end-organ damage but are associated with an increased risk for future macrovascular events. This may be because of the fact that the same glycaemic mechanisms responsible for the occurrence of microvascular disease may also apply to the development of atherosclerosis. Alternatively, interventions that reduce the development of microvascular end-organ damage may also delay the development of associated macrovascular disease. Screening for subclinical atherosclerosis, especially in the coronary and carotid vessels, has been advocated as a means of detecting early atherosclerotic disease in asymptomatic individuals with the aim of potentially reclassifying cardiovascular risk and guiding therapeutic interventions. Currently there is no randomized clinical trial evidence that additional screening using non-invasive imaging techniques alters cardiovascular disease outcomes. We do not know the best approach or combination of approaches to assess risk and reduce cardiovascular disease burden in type 1 diabetes mellitus. All screening interventions carry harms as well as benefits and until further evidence becomes available additional screening using non-invasive imaging tests for the detection of subclinical atherosclerosis cannot be currently recommended for patients with type 1 diabetes.

Development of breeding values for susceptibility to virulent footrot in sheep: A strategy to accommodate variable disease progression at time of scoring.

Genetic evaluations utilising footrot scores from industry flocks in their essence, incorporate data from a wide range of challenge environments, resulting in potentially large differences in means, variances and distribution of scores across challenges. The date that commencement of infection occurs is generally unknown, and progression of the infection varies with the prevailing environmental and management conditions, virulence of the bacterium Dichelobacter nodosus, as well as the genetic potential and (permanent) environmental ability of animals to resist footrot. In practice, animals are unlikely to be repeatedly scored to identify the best time for comparison, or monitor development of disease progression. Furthermore, field challenges are limited by the need to treat animals before their welfare is compromised. Therefore, the duration and intensity of infection varies and this affects comparisons between animals for their susceptibility. Diseases such as footrot are characterised by multiple categorical scores reflecting clinical stages that describe the progression and relative impact of the disease. This provides the opportunity for the transformation of the data to a standardised prevalence. Scoring events from multiple footrot field challenges under a standardised protocol were used to establish a series of transition matrices to describe disease progression between scores over time. These transition matrices were used to standardise challenge events to the more severe scoring events, observed later in the challenge. The accuracy of the transition technique was tested by comparing the ranking of animals and sires against the observed scores. Transitioning the data from low disease prevalence to the higher prevalence at the subsequent scoring event improved the correlations between the scoring events, at the animal level, by upwards of 0.10 across challenges. The utilisation of a transition matrix to transform low prevalence disease challenges by taking into account the natural biological rate of progression through the clinical stages of the disease provides a more accurate technique to account for variation in disease prevalence. The transition technique increases the acceptable range of disease expression targeted by producers when scoring virulent footrot challenges reducing the need for repeat scoring and allowing earlier treatment and reducing the impact of the disease on the host animal.

Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration.

BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with distinct molecular profiles. Gene expression profiling previously identified sonic hedgehog (SHH) as part of a gene signature that is differentially regulated in IBC patients. METHODS: The effects of reducing GLI1 levels on protein expression, cell proliferation, apoptosis and migration were determined by immunoblots, MTT assay, Annexin-V/PI assay and conventional and automated cell migration assays. RESULTS: Evaluation of a panel of breast cancer cell lines revealed elevated GLI1 expression, typically a marker for hedgehog-pathway activation, in a triple-negative, highly invasive IBC cell line, SUM149 and its isogenic-derived counterpart rSUM149 that has acquired resistance to ErbB1/2 targeting strategies. Downregulation of GLI1 expression in SUM149 and rSUM149 by small interfering RNA or a small molecule GLI1 inhibitor resulted in decreased proliferation and increased apoptosis. Further, GLI1 suppression in these cell lines significantly inhibited cell migration as assessed by a wound-healing assay compared with MCF-7, a non-invasive cell line with low GLI1 expression. A novel high-content migration assay allowed us to quantify multiple effects of GLI1 silencing including significant decreases in cell distance travelled and linearity of movement. CONCLUSION: Our data reveal a role for GLI1 in IBC cell proliferation, survival and migration, which supports the feasibility of targeting GLI1 as a novel therapeutic strategy for IBC patients.

Trypanosoma melophagium from the sheep ked Melophagus ovinus on the island of St Kilda.

SUMMARYThe sheep ked has been largely eradicated in the UK but persists in the feral Soay sheep of St Kilda in the Outer Hebrides. Sheep keds transmit Trypanosoma melophagium, but parasitaemias are typically cryptic and this trypanosome has not been recorded in the St Kilda sheep. Trypanosomes were detected by PCR in preserved keds and were also found in gut smears from live keds; one infected gut was used to establish the trypanosome in vitro. Examination of the morphology of bloodstream forms from culture confirmed its identity as T. melophagium. Most keds were found to harbour the trypanosome, particularly those collected from lambs. DNA was extracted from preserved keds and from trypanosomes grown in vitro. Sequence analysis of the small subunit ribosomal RNA (SSU rRNA) gene and the spliced leader transcript showed the T. melophagium sequences to be very similar to those from T. theileri. A partial sequence of the ked SSU rRNA gene was also obtained. The close genetic relationship of T. melophagium and T. theileri suggests that T. melophagium represents a lineage of T. theileri that adapted to transmission by sheep keds and hence became a specific parasite of sheep.