Angular deformities of the lower limbs are common during childhood. In most cases this represents a variation in the normal growth pattern and is an entirely benign condition. Presence of symmetrical deformities and absence of symptoms, joint stiffness, systemic disorders or syndromes indicates a benign condition with excellent long-term outcome. In contrast, deformities which are asymmetrical and associated with pain, joint stiffness, systemic disorders or syndromes may indicate a serious underlying cause and require treatment.Little is known about the relationship between sport participation and body adaptations during growth. Intense soccer participation increases the degree of genu varum in males from the age of 16. Since, according to some investigations, genu varum predisposes individuals to more injuries, efforts to reduce the development of genu varum in soccer players are warranted. In this article major topics of angular deformities of the knees in pediatric population are practically reviewed. This possibility is pertinent, but not yet investigated for the development of genu varum and playing soccer. However, several studies showed that the presence of genu varum predisposes an individual to various injuries. For example, genu varum has been associated with the deterioration of the articular cartilage in the knee's medial tibiofemoral compartment both to experimentally induced osteoarthritis and as a risk factor for osteoarthritis in a patient cohort –4.The presence of genu varum alters the forces at the knee so that the line of force shifts farther medially from the knee joint center intensifying the medial compartment load and creating a medial joint reaction force that is nearly three and a half times that of the lateral compartment . In addition to the development of tibio femoral osteoarthritis, the presence of genu varum seems also to predispose subjects to the occurrence of injuries at the patellofemoral joint. Several studies have identi?ed the presence of genu varum as a risk factor for the development of the patellofemoral pain syndrome in athletes –10.A lthough from clinical experiences an association between intense sports activities like soccer players and genu varum seems evident, today no scienti?c data regarding this association are available. Chantraine Since the knee malalignment is important in athletes, the development of normal tibiofemoral angle and common angular deformities in children and adolescents are explained in this article.. Finally the genu valgum spontaneously correct by the age of 7 years to that of the adult alignment of the lower limbs of 8 degrees of valgus in the female and 7 degrees in the male. The greater degree of valgus in females may be due to their wider pelvis.Genu varum (bow legs) and medial tibial torsion are normal in newborn and infants and maximal varus is present at 6 to 12 months of age. With normal growth, the lower limbs gradually straighten with a zero tibiofemoral angle by 18 to 24 months of age . With further normal development, knees gradually drift into valgus (knock-knee). This valgus deformity is maximal at around age 3–4 years with an average lateral tibiofemoral angle of 12 degrees Extrinsic and intrinsic factors may interfere with this normal angular alignment of the lower limbs.Bowlegs after 2 years of age are considered abnormal. It may be due to persistence of severe physiologic bowlegs (the most common etiology), a pathologic condition, or a growth disorder.History: Family history of bowlegs or other limb deformities and the presence of short stature may indicate the possibility of bone dysplasia or a generalized growth disorder. Physiologic genu varum improves with growth, whereas pathologic bowing of the legs increases with skeletal growth; therefore it seems important to ask the parents about:When they first noticed the deformity in the child.Were the legs bowed at birth and in infancy, or did the bowlegs develop later on when the child started walking?Is the deformity improving, staying the same, or increasing in severity?When did the child begin to stand and walk? Children with tibia vara (Blount's disease) are early walkers. Inquire as to the previous treatment and response to it.Etiologic factors: The physician should be aware of the dietary and vitamin intake of the patient  and also should consider any allergy to milk, history of trauma or infections and inquire the possibility of exogenous metal intoxication, specifically lead and fluoride .Examination: Short stature suggests the possibility of vitamin D refractory (hypophosphatemic) rickets  or bone dysplasia, such as achondroplasia or metaphyseal dysplasia ..In stance and supine the physician should measure the distance between the femoral condyles at the joint level with the ankles just touching each other. Ruling out the deformity of the feet especially pes or metatarsus varus or valgus which may represent torsional deformity of the limb is mandatory ; whereas in ligamentus hyperlaxity it is at the knee joint. In Blount's disease it is commonly at the proximal tibial metaphysis with an acute medial angulation immediately below the knee and in the congenital familial form of tibia vara it is at the lower tibia at the junction of the middle and the lower thirds . In the very rare distal femoral vara the site of angulation is in the distal femoral metaphysis. When the lower tibiae are the sites of varus angulation, the upper tibial segment is straight and the lower segment angulated.The site of varus angulation should be determined. In physiologic genu varum there is a gentle curve involving both the thigh and the leg with more pronounced bowing in the lower third of the femur and at the juncture of the middle and upper thirds of the tibia .Next, inspect the gait and determine the foot progression angle; in genu varum the foot progression angle may be medial or normal. When laxity and incompetence of the lateral collateral ligament of the knee are present, the fibular head and upper tibia shift laterally during gait; whereas, in physiologic bowlegs there is no such lateral thrust It is important to assess symmetry of involvement. In physiologic genu varum and congenital tibia vara it is usually bilateral and symmetric, whereas in Blount's disease it may be unilateral or bilateral, and when both tibiae are involved, the degree of affection is often asymmetric., the involved or more severely affected limb is shorter than the contralateral one; in physiologic genu varum the lower limb lengths are even.Measure both the actual and apparent limb lengths. In Blount's disease and in congenital longitudinal deficiency of the tibia .In the medially bowed leg, determine the level of the proximal fibula in relation to that of the tibia. Normally the upper border of the proximal fibular epiphysis is in line with the upper tibial growth plate – well inferior to the joint horizontal orientation line; whereas Blount's disease, congenital longitudinal deficiency of the tibia, and achondroplasia demonstrate relative overgrowth of the fibula, and the fibular epiphysis is more proximal, near the joint line Palpate the epiphysis of the long bones at the ankles, knees, and wrists. In rickets (vitamin D refractory or vitamin deficiency) they are enlarged. Inspect the thoracic cage. Is there a “rachitic rosary” of the ribs, pectus carinatum deformity, or Harrison's groove?Imaging: Take radiograms when:A child is 3 years and older and the varus deformity is not improving or is getting worse,The medial bowing is unilateral or asymmetric,The site of varus angulation is acute in the proximal tibial metaphysis immediately below the knee,, short tibia and relatively long fibula, and history of possible metal intoxication (lead or fluoride).The possibility of a pathologic condition is suggested by other clinical findings. The clinical stigmata suggesting pathologic genu varum are short stature (bone dysplasia), enlarged epiphysis and physis (rickets), history of trauma or infection (meningococcemia) Standing long films  should be made to include the hips, knees, and ankles. Proper positioning is important – knees straight and patella facing forward..The growth plates of the distal femur and proximal and distal tibia should be considered carefully. In physiologic genu varum they are normal. In rickets the physes are markedly thickened, the physeal borders of the epiphyses are frayed with a brush-like pattern of the bone trabeculae, the epiphyses are enlarged, the bone trabeculae are coarse, and the cortices of the diaphyses of the femurs and tibiae show decreased bone density Then, the epiphyses, metaphyses, and diaphyses should be inspected. In physiologic genu varum the bone seems normal without any sign of bone dysplasia. The medial bowing of the lower limb is a gentle curve, taking place at the junction of the middle and the proximal thirds of the tibiae and the distal thirds of the femurs. The horizontal joint lines of both the knee and ankle are tilted medially..List of conditions that cause pathologic tibia vara is given in Measure the metaphyseal-diaphyseal angle. In the physiologic genu varum it is less than 11 degrees, whereas in tibia vara it is greater than 11 degrees .In physiologic genu varum education and assurance of the parents is important and just follow its natural course by reassessing the child in 6 months. Orthopedic shoes are not effective in its prevention or management Metabolic deformities such as rickets could simply be corrected with medical treatment, i.e. calcium and vitamin D supplements..When severe genu varum is associated with severe medial tibial torsion and the metaphyseal-diaphyseal angle is 11 degrees or greater, a Denis Browne splint is prescribed with the feet (shoes) rotated laterally and with an 8 to 10-inch bar between the shoes. This is ordinarily worn only at night for a period not more than 3 to 6 months in order to correct excessive medial tibial torsion . It is difficult to calculate the exact age for hemiepiphysiodesis. Stapling is preferred by some authors .In the adolescent with severe genu varum with marked malalignment of the mechanical axis of the lower limbs, occasionally osteotomy of the tibia or hemiepiphysiodesis of the distal femur and/or proximal tibial physis is indicated to correct the deformity . The problem is the adolescent or the child over 8 years of age who present with moderate to severe knock-knees. The patient complains of pain in the thigh and/or calf and easy fatigability, the child walks with his knees rubbing together, feet apart and one leg swinging around the other. Frequently, parents are concerned with this form of gait. Due to malalignment and an increased Q angle of the quadriceps extensor mechanism, the patella subluxates laterally; hence, the patellofemural joint seems to be unstable. The shoes shows medial collapse of the upper parts and it is the result of abnormal weight-bearing forces on the ankle and foot . The parents seek active treatment and commonly believe that the deformity will result degenerative, crippling arthritis of the knee . In order to manage the problem properly, first we should determine the cause of abnormal genu valgum by careful history taking, physical examination, and appropriate imaging studies. The various causes of genu valgum are listed in Exaggerated genu valgum up to 7 years of age is physiologic and not pathologic History: The presence of positive family history and short stature in other members of the family will suggest the presence of bone dysplasia, such as multiple epiphyseal dysplasia, multiple metaphyseal dysplasia, multiple enchondromatosis (Ollier's disease), multiple hereditary exostosis, Ellis Van Creveld syndrome , or Morquio's disease . History of swollen and hot knees indicates rheumatoid arthritis . With increased circulation in the knee the tibia overgrows relative to the fibula. In congenital longitudinal deficiency of the fibula, genu valgum is common .Examination: For assessment of short stature and bony dysplasia the standing and sitting height of the patient should be measured . Inspect the alignment of the lower limb in stance. Measure the degree of genu valgum with a goniometer on the lateral side of the thigh-leg, the distance between the medial maleolli with the knee just touching. Genu requrvatum, if present, causes an apparent increase in the degree of deformity ..Asymmetry or unilateral involvement of the knee is suggestive of pathologic genu valgum. In walking, there is protective toeing-in to shift the foot medially so that the center of gravity falls in the center of the foot Ligamentous laxity may be the cause of knock-knees; therefore one should determine the stability of the collateral and cruciate ligaments of the knee. whereas in ligamentus hyperlaxity, congenital longitudinal deficiency of the fibula, or rheumatoid arthritis of the knee, it is at the knee and in metabolic bone disease and bone dysplasia at the distal femur or in both femur and the tibia. Tibia valga is usually associated with excessive lateral tibiofibular torsion thus the degree of tibial torsion should be assessed .The site of valgus angulation should be determined. Tibia valga, or greenstick fracture of the medial part of the proximal tibial metaphysic cause genu valgum at the proximal tibia . Exostosis and lower limb length inequality should be assessed by careful palpation of the epiphysis and metaphysis and limb length measurements, respectively .Iliotibial band contracture may cause tibia valga and its presence should be ruled out by an Ober test Imaging findings: In developmental genu valgum the epiphysis, physis, and metaphysis are normal. The horizontal axis of the knees and ankles is tilted laterally. No intrinsic bone disease is present..In pathologic genu valgum the radiographic features are usually characteristic, and diagnosis is readily made. When an osseous bridge across the lateral physis of the distal femur and proximal tibia is suspected, MRI should be performed. Bone age should be determined if a hemiepiphysiodesis is being planned . When the iliotibial band is contracted, passive stretching exercises for its stretching should be done. This may relief valgus deforming force of the knee.Special shoes are ineffective in prevention or treatment of genu valgum. If the feet are in valgus and foot strain is a complaint, foot orthotics, such as University of California Biomechanics Laboratory (UCBL) orthotics, are appropriate to support the foot. They do not correct the genu valgum but relieve foot strain, easy fatigability, and foot-calf pain The role of orthotics to control or correct genu valgum has not been proven and is controversial. Some authors do not recommend them. According to the body of literature, the only indication for a Knee Ankle Foot Orthosis (KAFO) is to support the knee ligaments and prevent them from overstretching. It is used in pathologic genu valgum..Hemiepiphysiodesis is done by stapling or fusing the medial part of the distal femoral and/or proximal tibial growth plates. Appropriate time is crucial. Despite all precautions, one may end up with overcorrection or undercorrection. Some authors prefer stapling over epiphysiodesis because it allows a certain amount of flexibility of timing –48.Osteotomy of the distal femur and proximal tibia is performed in the skeletally mature patient. Neurovascular structures, particularly the common peroneal nerve and tibial vessels, are at definite risk for injury. Gradual correction with an external fixator lessens the degree of neurovascular change In the adolescent with severe genu valgum and marked mechanical axis deviation, surgical correction is indicated. Two methods of surgical management are available:Angular deformities of the lower limbs are common during childhood and usually make serious concern for the parents. Most commonly these deformities represent normal variations of the growth and development of the child and needs no treatment except for observation and reassurance of the parents. Despite of the benign nature of physiologic or exaggerated physiologic genu varum and genu valgum, most of the pathologic causes need proper management by an orthopedic surgeon; hence, the importance of careful evaluation of the patients and determination of these pathologic causes is evident.


This is a descriptive and cross-sectional study done in 2008. The target pharmacies of this study were all the 3 teaching pharmacies affiliated with the Isfahan University of Medical Sciences. The data collecting template was prepared using the standard scientific methods according to the goals of this research The goals also nominated necessary items needed in economic profit evaluation. The data collection template was completed by reference to the teaching pharmacies financial documents and reports, used as a base for calculating the total income and the total costs in 2007-2008 financial year. The difference between these two balances showed the value of profits or loss. The profit/cost ratio was also calculated, using the proportion of the total income to the total costs. The collected data was statistically analyzed using the Excel software (Microsoft 2007). For the financial year 2007-2008, the difference between the total income and the total costs was -831.6 million Rials (excess costs to income) for the SHM pharmacy, + 25.4 billion Rials for the ISJ pharmacy and -429.5 million Rials for the AZH pharmacy. According to our findings there is a strong requirement to improve the financial performance of all the three teaching pharmacies while maintaining a high standardard of teaching and educational affairs.Teaching pharmacies are amongst the important cornerstones of a healthcare system for drug supplying, pharmacy education and pharmacy practice research. Assessment of the Iranian healthcare system costs shows that after personnel charges, drug outlay is the second expensive factor. This great financial mass requires integral audit and management in order to provide costumers satisfaction in addition to financial viability. Teaching pharmacies are required to realize financial viability as well as providing several educational and drug servicing goals, which makes microeconomic analysis important. The aim of this study was to evaluate the financial performance of the teaching pharmacies affiliated with the Isfahan University of Medical Sciences (with the  Health economics is a new branch of economic science, started in the early 1950s when health care system costs were noticed as a general basic need and therapeutic services became an industry . Health To the best of our knowledge, a limited number of studies have been performed and published that economically evaluate critical foci of the Iranian health care system including pharmacies –12. TowfNowadays, the ever increasing demand of patients for obtaining information about their physician-prescribed drugs create new expectations from community pharmacists. Pharmacist’s high potentiality for delivering clinical information and their communication skills at the time of facing patients seem to help the drugstore managers to improve their financial profitability. The increasing demand of the pharmacy clients and patients who are seeking their needed specialized information about rational use of drugs made this ring of health chain much more important than it used to be. Most of the faculties of pharmacy in Iran, own at least one or more not-for-profit teaching pharmacy for the purpose of teaching and simulating the real situation of pharmaceutical care provision. These drugstores are known by the people as the governmental pharmacies. People generally believe that these drugstores are more trustable and they offer some drugs that are not ordinary found in other pharmacies and this fact has an undeniable direct positive effect on their financial turn over and economic balance.The importance of financial performance and its direct effects on income, teaching and service provision level in educational pharmacies, made good reasons for the design and conduction of present study which evaluates the above mentioned objectives for the teaching pharmacies affiliated with Isfahan University of Medical Sciences (IUMS). The results of present study are hoped to be useful for future management goals and the pharmaceutical policymakers and authorities.abbreviated for the confidentiality of the financial data), are located in three different geographical area of the city and each is next to a teaching medical center again affiliated with IUMS and the pharmaceutical services are open to public. SHM and ISJ pharmacies are the two most important drug servicing centers for special cases of drug supply and needed drugs in Isfahan province.The research protocol and methodology  of this study as well as publication of the data was approved by the higher research committee of the School of Pharmacy and Pharmaceutical Sciences of the IUMS. This descriptive and cross-sectional study was conducted in 2008. The target pharmacies included the three teaching community pharmacies owned by the above mentioned school of pharmacy. These out-patient pharmacies named SHM, ISJ and ALZ (® (2003) software and commented according to the study aims.In order to prepare the evaluation data collection template, the goals and objectives of the study were initially reviewed by all authors carefully and the nominated necessary items needed in this financial and economic assessments were determined . Then thThe calculated financial indices of the pharmacies studied are summarized in As an introduction to this section, it should be mentioned that because of the lack of similar published studies on financial evalu-ation of teaching (out-patient) pharmacies and novelty of this issue in Iran, the results and ratios derived from them could not be discussed by comparing to other studies. Therefore, we have discussed the results with regard to the differences between the three teaching pharmacies as below.According to our findings the functional income/functional costs ratio for the SHM pharmacy was 56% . This raThe ISJ pharmacy with a substantial functional income of 29 billion Rials value  had the Economical evaluation of ALZ pharmacy in the same way showed the ratio of functional income/functional costs equal to 87% . This shComparison of the mentioned sextet ratios in SHM pharmacy, ALZ drugstore and ISJ pharmacy revealed that the ISJ pharmacy not only has the highest income but also can cover its expenses by its income. This evidence is sufficient for representing the efficiency in enterprising. Considering the forth ratio , used to compare the organization financial properties with other organizations, helps to rank the three pharmacies economic performance as following:ISJ Pharmacy >ALZ Pharmacy >SHM PharmacyThe authors believe that similar economic evaluation is necessary as an important decision making element in other similar units.In support of improving the financial performance of above mentioned teaching pharmacies , according to our literature survey, analysis of findings and discussions with relevant experts, these solutions are offered which maybe regarded as topics for further study:Study the effects of functional emoluments intensification.Designing and performing plans for a more efficient role in the drug market.Search for means to increase the non-functional revenue and its availability assessment.The use of value engineering technique to help in avoiding unnecessary expenses and probable repeats.Strategic planning for effective human resources management of these pharmaciesRecognizing wastage of drug expenditure.Using efficient supervision ways to control pharmacy disbursements.


Traumatic damage to the central nervous system (CNS) destroys the blood–brain barrier (BBB) and provokes the invasion of hematogenous cells into the neural tissue. Invading leukocytes, macrophages and lymphocytes secrete various cytokines that induce an inflammatory reaction in the injured CNS and result in local neural degeneration, formation of a cystic cavity and activation of glial cells around the lesion site. As a consequence of these processes, two types of scarring tissue are formed in the lesion site. One is a glial scar that consists in reactive astrocytes, reactive microglia and glial precursor cells. The other is a fibrotic scar formed by fibroblasts, which have invaded the lesion site from adjacent meningeal and perivascular cells. At the interface, the reactive astrocytes and the fibroblasts interact to form an organized tissue, the glia limitans. The astrocytic reaction has a protective role by reconstituting the BBB, preventing neuronal degeneration and limiting the spread of damage. While much attention has been paid to the inhibitory effects of the astrocytic component of the scars on axon regeneration, this review will cover a number of recent studies in which manipulations of the fibroblastic component of the scar by reagents, such as blockers of collagen synthesis have been found to be beneficial for axon regeneration. To what extent these changes in the fibroblasts act via subsequent downstream actions on the astrocytes remains for future investigation. After damage to the central nervous system (CNS) of adult mammals, regeneration of transected axons barely occurs. There is a growing view that severed central axons are capable of regeneration and that the failure to regenerate is due to the blocking effect of the scar formed at the lesion site. This scar consists in both glial (mainly astrocytic) and fibrotic components (Fitch and Silver Various kinds of inhibiting factors that are upregulated around the lesion site have been postulated to prevent the regrowth of severed axons beyond the lesion site. These include molecules of the chondroitin sulfate proteoglycan (CSPG) family , an inhibitor of Type IV collagen synthesis  containing neurons in the hypothalamic arcuate nucleus. Since arcuate NPY neurons exert a potent orexigenic function, many experiments have been performed to examine the effect of their destruction by electrolytic or chemical lesions and surgical deafferentation of the projection. Alonso and Privat  surgicalAdministration of gold thioglucose, a neurotoxic glucose analog, to mice increased their body weight and produced a hypothalamic lesion that extended from the ventromedial part of the hypothalamus . TRII binds to its specific ligand but TRI requires the presence of bound TRII to interact with TGF-βs . By sealing off the damage and restoring the BBB, the astrocytic reaction is protective. Both astrocytes and fibroblasts express abundant axon-repelling molecules. Suppression of TGF-β signaling has been shown to be an effective tool for preventing formation of the fibrotic scar and has been reported to promote axonal regeneration without detrimental effects on the sealing process of damaged CNS.


Foci of tick species occur at large spatial scales. They are intrinsically difficult to detect because the effect of geographical factors affecting conceptual influence of climate gradients. Here we use a large dataset of occurrences of ticks in the Afrotropical region to outline the main associations of those tick species with the climate space. Using a principal components reduction of monthly temperature and rainfall values over the Afrotropical region, we describe and compare the climate spaces of ticks in a gridded climate space. The dendrogram of distances among taxa according to occurrences in the climate niche is used to draw functional groups, or clusters of species with similar occurrences in the climate space, as different from morphologically derived  groups. We aim to further define the drivers of species richness and endemism at such a grid as well as niche similarities (climate space overlap) among species. Groups of species, as defined from morphological traits alone, are uncorrelated with functional clusters. Taxonomically related species occur separately in the climate gradients. Species belonging to the same functional group share more niche among them than with species in other functional groups. However, niche equivalency is also low for species within the same taxonomic cluster. Thus, taxa evolving from the same lineage tend to maximize the occupancy of the climate space and avoid overlaps with other species of the same taxonomic group. Richness values are drawn across the gradient of seasonal variation of temperature, higher values observed in a portion of the climate space with low thermal seasonality. Richness and endemism values are weakly correlated with mean values of temperature and rainfall. The most parsimonious explanation for the different taxonomic groups that exhibit common patterns of climate space subdivision is that they have a shared biogeographic history acting over a group of ancestrally co-distributed organisms. Factors that affect the life cycle of parasitic arthropods, like ticks, have been proposed as possible limiting factors for their ranges, and include host availability Differences in niches for tick taxa are quantified using observed occurrences of species and reflect a yet unknown conjunction of the environmental space of the species, the biotic interactions they experience and the habitats available to species and colonized by them Recent concerns over the impacts of climate trends on the distribution of ticks This paper is aimed to define the climate envelope for tick species recorded in the Afrotropical region and the relationships between groups of species, without explicit consideration of the geographical space. The study is not focused around the range of the ticks in the geographical space, but in the climate one. We describe and compare climate envelopes of ticks recorded in the Afrotropical region in a gridded climate space  and we aim to define features of species richness and endemism at such a grid. We thus explicitly sought to describe the relationships among morphologically recognized taxa according to their strict positions in the climate niche and to consider how diversity of available niches may relate to speciation and divergence from a common pool of lineages. This study is thus intended to characterize the relationships of ticks and climate, without the restrictive effects of the geographical space. We sought to disentangle the relationships among species and the climate space, as a starting point for further research in the geographical space, which should stand on the dispersion mechanisms as descriptors of the distribution of these taxa as we know today.A multivariate analysis of monthly interpolated climate  traits in the Afrotropical region produced 3 main axes, which accounted for the 89.1% of total variability. Axis 1 was loaded by and inversely related to the average annual temperature. Axis 2 was inversely correlated with the range between maximum and minimum temperatures: a large seasonal amplitude in temperature is related to negative values in this axis. Axis 3 was inversely related to total rainfall. Gradients of the first and second PCA axes draw the occurrences of the species, which are restricted to specific portions of such as axes.Hyalomma associates to portions of the climate space with high temperature and a large thermal amplitude, otherHyalomma. Systematic similarities among species in the same taxonomic group are not mirrored by the similarities of occurrences along climate gradients. Speciation processes of each morphologically-based, supraspecific group, derived into multiple branches colonizing different portions of the available climate conditions.The occurrence of Afrotropical ticks along gradients of the climate space produced a dendrogram of relationships among the species of ticks  grouped Rhipicephalus display low within-group niche equivalency values, other supraspecific taxonomic clusters having a greater niche overlap. Species within each taxonomic lineage in Rhipicephalus tend to occur on portions of the climate space more different than expected by random occurrences, therefore maximizing the occupancy of the climate space and avoiding overlaps with other species of the same taxonomic group.The The highest index of species richness is associated to the lowest seasonality (lowest variation of temperature) in temperature values . AbsolutThe tick fauna associated to the Afrotropical region has long been recognized as to represent an unpaired chance to investigate the many factors giving shape to its current relationships. This framework accounted for biases introduced by spatial resolution and corrects observed occurrence densities for each region considering the availability of climate space. Such a characterization outcomed details about the composition of “functional" groups of species and their phyloclimatic relationships, hypothesizing about the nature of the species-environment relationships. As such, it would be appropriate to construct a general area cladogram (representing a single history of place) based on congruence among the area cladograms derived from phylogenetic analyses of the multiple co-distributed taxa The Afrotropical fauna of ticks is the result of a diversification of lineages into a variety of taxa currently associated with many biomes Hyalomma has, in some extent, both a taxonomic and functional identity, most probably because its high specialization towards warmer and drier sites. Every supraspecific group, as morphologically recognized today, has species associated to different portions of the climate niche. In some cases, species within the same taxonomic group share a small portion of climate space. These findings could be interpreted as a strategy by groups of close species evolving from the same genetic pool to exploit the portions of the climate space as much separated as possible. This would minimize competition among species genetically related (same taxonomic group), being restricted by geographical barriers that could effectively operate on the spread patterns over the climate space by restricting movements in the geographical level. The most parsimonious explanation for the different taxonomic groups that exhibit common patterns of climate space subdivision is that they have a shared biogeographic history. In other words, a common set of historical vicariant events has geographically structured a group of ancestrally co-distributed organisms In the case of ticks of the Afrotropical region, groups of taxa have evolved from the primitive pool along different lines of climate pressures and they have occupied different portions of the available climate space. The observed pattern of occurrences along climate gradients suggest that supraspecific assemblages of morphologically similar taxa have a long-standing association with one another and have attained a common pattern of climatically driven subdivision as a result of being subjected to the same environmental history. Specialization is still evident, and species belonging to the same taxonomic group do not tend to occur along similar gradients of climate space. The study of the niche-segregating clusters  shows that functional groups of ticks are dissimilar to the taxonomic groups. Only the genus The mechanism by which the tick species may colonize and spread into new gradients of the climate space is largely unknown. Support for rapid niche shifts is found in diverse fields of ecology and evolution, its evidence reported in empirical studies of invasive species ecology, phylogenetic analysis and community ecology Highest richness of Afrotropical tick species has been found to be correlated with low thermal seasonality and, ranked second, warmer temperatures. Thus, the area of highest species richness is associated with zones where high species richness of birds and mammals is also concentrated The framework built in this paper may be potential drawbacks regarding the ecology of the ticks, the resolution of the climate dataset and the potential bias in reporting of tick collections. The first and the second are strongly linked. The immature stages of some species may have an endophilous behavior, i.e. connected to hosts that live in burrows or protected from hard environmental conditions Species composition is influenced by the combined effects of environmental traits, the portion of the geographical space dominated by those climate gradients and the dispersal properties of the species We determine climate niche occupancy for a set of tick records in Africa. The framework applies to comparison among any taxonomic, geographic or temporal group of occurrences, and involves the calculation of the density of occurrences and of climate gradients along axes. Those are the result of a multivariate analysis along the climate variables. We then calculated the niche overlap between species together with statistical tests of niche equivalency and the evaluation of richness and endemism of species as associated to coherent portions of the environmental space. Most of the analyses were done in R 2.7.2 www.tickbornezoonoses.org). Data from the later were used to update the taxonomic overview in the former and to produce a coherent dataset of records in Africa. The newest available records (after approximately the year 2000) was completed by a systematic search of the peer-reviewed literature between the years 2000 and 2010. The basic criteria included in both searches were the systematic generic or family names of the ticks, as found in the title or the abstract of the paper. Further reading of each reference searched for information about the specific name of the tick, and a strict reference to a site of capture. The site can be defined by its coordinates or by a name providing enough information to locate it in digital gazetteers or regional maps. Records were not included if they referred only to a generic name or if reported from a large administrative division (i.e. province) or if the information regarding the locality was ambiguous . Literature searches were concluded on 31 October 2010 and all citations meeting our search criteria were reviewed. A total of 10,628 records were included in this study. All the literature data were curated and determinations of taxa replaced with current taxonomical views if necessary, after a consultation to experts. The tick name as appearing in the final dataset is the one agreed in a recent review on the systematics of ticks Two compilations were primarily used regarding earlier surveys of ticks in the area of interest (since around the year 1950), namely the one reported out in ref. Haemaphysalis leachi and H. elliptica, see ref. Ixodes remains largely unexplored in the Afrotropical region Rhipicephalus adhered to the views summarized in ref. Some species were not included in this study because lack of agreement among experts Climate data were obtained from WorldClim r×r cells of a three dimensional volume  each cell being a unique vector of climate conditions present at one or more sites of the geographic space.We consider the first three axes of the principal components analysis of the monthly climate variables as definition of the climate space of the ticks ijkO for each cell is calculated as:The occurrences of each species in each unique cell of the grid was used to map the occurrence of the ticks in the climate space. The number of occurrences of a tick species is dependent on sampling strategy, and a dataset may not entirely reflect the actual distribution of a species. We adhered to published methods Most of the calculations were done in R 2.7.2 Niche overlap between any two species involves three steps: (1) calculation of the density of occurrences and of climate factors along the axes of the multivariate analysis before (2) measurement of niche overlap along the gradients of this multivariate analysis and (3) statistical tests of niche equivalency The comparison of We built from the methodology previously described Measures of species richness are statistical measures. There is no consensus on best estimators of species richness. In this study we sought to investigate how a range of climate factors drive taxonomic diversity in the ticks reported in the Afrotropical region. More specifically, we tested whether regions with a given gradient in the axes of climate space may harbor different diversity. We purposely remain general in scope to explore how hypotheses can be extrapolated to the taxonomic diversity of a group of ectoparasites.We computed species richness weighting the number of smoothed occurrences at each vector of the climate space with the total values of occurrences. To compute species endemism in the climate space, we estimated the number of species present at every grid squares of the three dimensional climate space. Each species is down-weighted by the number of grid squares in which it occurs, and the index is then the sum of the range-down-weighted species values for each grid. The down-weighting was calculated by dividing each grid-occurrence by the total number of grids in which that species occurs. Thus a species restricted to a single grid would be scored as ‘1’ for that grid, and ‘0’ for all other grids; a species found in two grids, would be scored as ‘0.5’ for each of the two grids, and ‘0’ for all other grids; a species found in three grids would be scored as ‘0.333’ for each of the grids, and ‘0’ for all other grids, etc.


The later waves are thought to originate from indirect, trans-synaptic activation of PTNs and are termed “I” waves. The anatomical and computational characteristics of a canonical microcircuit model of cerebral cortex composed of layer II and III and layer V excitatory pyramidal cells, inhibitory interneurons, and cortico-cortical and thalamo-cortical inputs can account for the main characteristics of the corticospinal activity evoked by TMS including its regular and rhythmic nature, the stimulus intensity-dependence and its pharmacological modulation. In this review we summarize present knowledge of the physiological basis of the effects of TMS of the human motor cortex describing possible interactions between TMS and simple canonical microcircuits of neocortex. According to the canonical model, a TMS pulse induces strong depolarization of the excitatory cells in the superficial layers of the circuit. This leads to highly synchronized recruitment of clusters of excitatory neurons, including layer V PTNs, and of inhibitory interneurons producing a high frequency (~670 Hz) repetitive discharge of the corticospinal axons. The role of the inhibitory circuits is crucial to entrain the firing of the excitatory networks to produce a high-frequency discharge and to control the number and magnitude of evoked excitatory discharge in layer V PTNs. In summary, simple canonical microcircuits of neocortex can explain activation of corticospinal neurons in human motor cortex by TMS.Although transcranial magnetic stimulation (TMS) activates a number of different neuron types in the cortex, the final output elicited in corticospinal neurones is surprisingly stereotyped. A single TMS pulse evokes a series of descending corticospinal volleys that are separated from each other by about 1.5 ms . This evoked descending corticospinal activity can be directly recorded by an epidural electrode placed over the high cervical cord. The earliest wave is thought to originate from the  Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) can activate the human brain through the intact scalp  and was therefore termed “D” wave. The later waves evoked by cortical stimulation required the integrity of the cortical gray matter, and were thought to originate from indirect, trans-synaptic activation of PTNs and were therefore termed “I” waves  direction, the descending volleys have slightly different peak latencies and/or longer duration than those induced by PA stimulation, and the order of recruitment of the descending corticospinal waves may change with late I-waves already evoked at TMS intensity close to MEP threshold  depressed by enhancement of neurotransmission through the inhibitory gamma-aminobutyric type A receptor (GABAAR) by benzodiazepines  to the test stimulus, and delivered either through the same stimulating coil for exploration of circuitry within M1, or through another stimulating coil for exploration of cortico-cortical connections to M1 [for review,     of MEPs in hand muscles is produced by conditioning the cortical magnetic stimulus with electrical stimulation of sensory peripheral nerves of the hand  repetitive discharge of the corticospinal axons. The role of the inhibitory circuits is crucial to entrain and control the firing of the excitatory networks to produce a high frequency discharge (Douglas et al., It should be considered, however, that the attempt to explain the physiological basis of TMS using the canonical cortical circuit has several major limitations because the model used in this study is extremely simplistic. It should be considered that the canonical circuit we adopted is composed of a minimum of elements and connections and thus it can capture only the essence of the function of cerebral cortex. The interaction between TMS and cerebral cortex is much more complex in that there is a great number of classes of cortical neurons and connections that can be activated by TMS but were not considered in the present paper. Moreover, this simple model cannot easily been used to explain the interaction between TMS and cortical circuits in pathological conditions characterized by structural or functional changes in cerebral cortex.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


One of the more perplexing ground water problems currently facing Bangladesh is the high concentration of arsenic in drinking water, which poses a relatively large risk to human health of this region. Traditional health practitioners (THPs) of Bangladesh primarily use medicinal plants for treatment of various ailments. The selection of any medicinal plant is a closely guarded secret and is usually kept within the family. As a result, the use of medicinal plants varies widely between THPs of different areas within the country, and is based on both medicinal plant availability and the THP’s unique knowledge derived from practice. The aim of this present study was to conduct a survey amongst the THPs to learn more about the medicinal plants used to treat one or more arsenic related infections in the Satkhira district of Bangladesh. This area is unique in its proximity to the Sunderbans forest region and contains quite different medicinal plants compared to other parts of the country because of high salinity in the soil and water.Semi-structured questionnaires were administered to twenty-four traditional health practitioners to evaluate the THPs' perceptions and practice relating to causation and treatment of one or more arsenic related infections. The THPs described the signs, symptoms, and cause of one or more arsenic related infections. Details of the preparation and use of medicinal plants for management of one or more arsenic related infections were recorded.In the present study, forty-one medicinal plant species belonging to thirty-nine genera and twenty-eight families were found to be used to treat one or more arsenic related infections in the Satkhira district.Information on indigenous use of medicinal plants has led to discovery of many medicines in use today. Scientific studies conducted on the medicinal plants may lead to discovery of more effective drugs than in use at present.


Objective: A hemisplit turndown tibialis anterior muscle flap is described for coverage of distal leg wounds with preservation of active extensor function for open wounds of the distal ankle is presented. This is a new flap not previously described and is another local option for coverage of selected distal leg wounds. Methods: A description of the operative procedure and a clinical successful example is presented. Results: The split hemitibialis anterior turndown muscle flap was successful and preserved function of the muscle and tendon. Conclusions: This is another option for coverage of difficult wounds of the lower extremity without sacrifice of function of the donor muscle. There are many options for the coverage of soft tissue defects in the distal third of the leg ranging from local flaps to microvascular free-tissue transfer.12 ulcer with exposed tibialis anterior tendon. Initially, the wound was managed conservatively with debridement and local wound care. This resulted in a 2 × 2 cm2 defect at the level of the ankle with exposure of the tendon of the anterior tibialis muscle that would not heal after several months of conservative wound care (2 full-thickness defect of the distal ankle with exposed tibialis anterior tendon. Distal pulses of the foot were intact and palpable. He underwent surgical treatment consisting of a split hemitibialis turndown muscle flap to cover the wound (A 53-year-old man sustained a severely comminuted fracture of the left ankle, from a crush injury at a construction site, which required open reduction and internal fixation with screws and plate. Subsequently, skin slough of the dorsal aspect of the ankle incision resulted in a 6 × 6 cmund care . He was he wound . The mushe wound .The split hemianterior tibialis turndown muscle flap was designed on the basis of the anatomic characteristics of its vascular supply, and the procedure is as follows.With the patient supine on the operating room table, under spinal anesthesia, the left lower extremity was prepped and draped in a sterile fashion. A pneumatic tourniquet was applied. The dorsal incision was opened and carried cephalad along the anterior tibia, providing access to the anterior tibialis muscle. The wound was debrided. The lateral portion of the tibialis anterior muscle was split longitudinally, taking about one half of the muscle bulk commencing cephalad and coursing inferiorly and distally while preserving the tibialis anterior tendon. One-half of the muscle bulk was turned inferiorly on a series of distal intermuscular pedicles, by incising the muscle from cephalad to caudad, taking as few intermuscular perforators as possible to maintain blood flow and still permit turndown of the muscle flap to reach the defect. Care was taken not to completely separate the split muscle and to maintain a muscular connection with the remaining muscle bulk to permit preservation of the intermuscular vascular anatomy. Once the split turndown muscle flap reached the defect, the tourniquet was released. Bleeding points were clamped and tied. There was evidence of arterial vascular circulation in the muscle flap and the most distal portions of it appeared to have vascular circulation. The flap was inserted and the incision was closed. Xenograft dressing was placed over the muscle flap temporarily to enable flap viability assessment. Four days later, a split-thickness autologous skin graft was applied to the split turndown tibialis anterior muscle flap, which was completely viable and resulted in complete skin graft adherence to the muscle and graft survival with dorsiflexion function of the tibialis anterior tendon maintained.Wounds or defects in the lower leg are difficult to treat as the vital structures are covered with only skin and minimal soft tissue. The repair of these wounds either requires tissue with adequate blood supply or a microvascular free-tissue transfer. Over the last 3 decades, free flaps have been the treatment of choice for these hard to cover wounds. Transpositions of local muscles on a distal pedicle are not consistently reliable and alternatives include the cross-leg flap and the use of free flaps.The choices of local flaps available for the distal third of the leg include the dorsalis pedis island,,The tibialis anterior partial muscle flap has been described to cover defects localized in the upper third and middle third of the tibial shaft, but not for wounds of the distal leg.1Several muscles have been split for coverage of difficult wounds. Robbins was the first to turn over the superficial part of the muscle as a fasciomuscle flap to cover an exposed tibia in the middle third of the leg, without causing a functional deficit.Splitting a muscle flap is not a new concept and has been described for other muscle flaps, which have been split including the latissimus dorsi and the pectoralis major muscle flap. The concept is based on the intermuscular vascular anatomy. The reach of the tibialis anterior muscle flap based on a proximal pedicle to cover the defects in the distal third of the leg is limited due to segmental short vascular pedicles. Extending the reach by the complete interruption of the musculotendinous unit leaves a considerable functional deficit and therefore is not recommended in ambulatory patients.14,The tibialis anterior muscle originates from the lateral condyle, upper half of the lateral surface of tibia, interosseous membrane, and crural fascia. The tendinous structure runs in the center of the muscle, becomes cordlike at the lower part, and inserts onto the first metatarsal and medial cuneiform bone, and it is responsible for dorsiflexion and inversion of the foot.1An ankle soft tissue defect with exposed tendon and bone was covered by splitting the tibialis anterior muscle longitudinally and turning down the split muscle flap on a distal intermuscular pedicle, while preserving its function. This turndown flap technique, to our knowledge, has not been previously described but is based on sound anatomical concepts. The split hemitibialis anterior turndown muscle flap was successful in covering an ankle wound with exposed tendon and bone and preserved active dorsiflexion of the ankle and active extension of the great toe despite using a portion of the muscle for wound coverage. The wound coverage remained stable at 6 months follow-up with active ambulation and no wound healing issues. Active dorsiflexion of the foot and active extension of the great toe were present.The split hemitibialis anterior turndown muscle flap, for distal lower leg wounds, adds another local procedure to the armamentarium of a reconstructive plastic surgeon, a simple but effective local flap procedure to manage these difficult soft tissue defects in selected patients with adequate vascular supply of the limb.


Early olfactory deprivation in rodents is accompanied by an homeostatic regulation of the synaptic connectivity in the olfactory bulb (OB). However, its consequences in the neural sensitivity and discrimination have not been elucidated. We compared the odorant sensitivity and discrimination in early sensory deprived and normal OBs in anesthetized rats. We show that the deprived OB exhibits an increased sensitivity to different odorants when compared to the normal OB. Our results indicate that early olfactory stimulation enhances discriminability of the olfactory stimuli. We found that deprived olfactory bulbs adjusts the overall excitatory and inhibitory mitral cells (MCs) responses to odorants but the receptive fields become wider than in the normal olfactory bulbs. Taken together, these results suggest that an early natural sensory stimulation sharpens the receptor fields resulting in a larger discrimination capability. These results are consistent with previous evidence that a varied experience with odorants modulates the OB's synaptic connections and increases MCs selectivity. Neuronal representations of sensory stimuli are shaped by sensory experience and the modification of these representations may underlie changes in perceptual abilities. The neuronal representations in vertebrates initiate with the activation of the olfactory receptor neurons (ORN) by odorants. The ORNs, expressing the same receptor molecule In this study we examined the properties of the MC activity changes induced by early sensory deprivation in terms of neural sensitivity. Sensitivity is defined as the fraction of neurons that show positive responses (excitatory and inhibitory) to Our results show that despite the remarkable anatomical changes in the early deprived OB, MCs ongoing and odorant triggered activity is comparable in both the normal and deprived olfactory bulb. Specifically, in the absence of olfactory stimulation, the MCs firing rate is similar in deprived and normal OBs, consistent with the homeostatic hypothesis Surgical and experimental techniques described in detail in Unitary activity was recorded with a Olfactory stimuli were presented with a custom made olfactometer by a PC controlled solenoid valves. Pressurized air, from commercially purified tanks, previously humidified was streamed to an empty tube or a tube with an odorant diluted in mineral oil  for the MCs that did not exhibited odorant responses were different in the deprived and normal OB. As expected, the mean ratios were not significantly different in both conditions see . These rTaken together, these results indicate that early sensory deprivation likely induces an homeostatic adjustment of the level of excitatory and inhibitory sensory induced activation in the OB. Notwithstanding, there is an increase sensitivity to different odorants in the deprived OB.Odorants activate a distributed combination of glomeruli representing a spatial code We define a set of binary numbers which represents the probability of having The main objective of this work was to compare the properties of the MCs discharge from deprived and normal OBs in anesthetized rodents and estimate, from the theoretical standpoint, the discriminability and storage capacity of deprived and normal OBs. Our results show that the deprived OB maintains the basal level of activity in the absence of odorant stimulation, in agreement with homeostatic mechanisms that keep the system within a sensitive range to external stimulation. Homeostatic mechanisms for activity dependent excitability and synaptic strength regulation have been previously described in invertebrates as a result of action potential blockade In the presence of olfactory stimulation we found an increase in the incidence of excitatory and inhibitory responses in MCs from deprived OB when compared to the normal OB, indicating regulation of the activity levels during odorant stimulation. In summary, these results demonstrate an overall increase in the sensitivity of the deprived OB to olfactory stimuli. Despite the regulation of the overall OB activity levels during baseline and odorant stimulation, the deprived OB MCs activation patters are consistent with a reduced discrimination ability. In other words, the number of neurons involved in stimulus coding is larger in the deprived OB when compared to the normal OB. This reduction in the sensitivity of MCs is due to an increase in the excitatory as well as the inhibitory responses.The adjustment of the overall OB activity levels during baseline and odorant stimulation is apparently inconsistent with a reduction in the inhibitory input onto MCs Other studies about the effect of early sensory deprivation on the olfactory pathway have shown an increase in the epithelial response to odorants The consequences of the differences in the sensitivity of deprived and normal MCs can be explained in terms of stimuli discrimination, where the normal OB has a clear advantage in this sense. In a system with low activation levels, like the normal OB, the percentage of overlap is significantly reduced as shown in As described in the last section, the OB needs to balance between the ability to discriminate different odorants and the potential to store different odorants, i.e. storage capacity. We show that there is a negative relation between discrimination and storage capacity, the higher the system discrimination the lower the system storage capacity . A systeThe olfactory system detects, discriminate and identifies hundreds of different odorants which could be a single molecule type or a combination of several compounds. Our study aimed to compare the functional responses of MCs in normal and deprived OBs. The low number of odorants and the use of anesthetized animals are limitations of this study. We used a low number of odorants because the time necessary to test a higher number of odorants would substantially reduce the number of sites recorded for each animal, and increase the number of animals required. Furthermore, the use of anesthetized animals in this study minimized the firing rate variability due to the animals active modulation of the respiratory cycle. It is well known that the respiratory cycle is highly modulated in awake rodents by several factors such as novelty, previous learning, stimulus meaning such as appetite or aversive, etc. In our recordings, there was a constant respiratory rate reducing the variation of the firing rate due to the respiratory rate see .In summary, we compared the ongoing and odorant induced MCs activity in the normal and deprived OBs from the same animal. We have shown that the deprived OB retains a basal level of activity suggesting an homeostatic mechanism to keep the system in a sensitive range to external stimulation. Furthermore, the deprived MCs increase their excitatory and inhibitory responses when compared to the normal MCs during odor stimulation. We show an overall increase in the sensitivity of the deprived OB to olfactory stimuli versus normal OB. This means, that the number of neurons involved in stimulus coding is larger in the deprived OB when compared to the normal OB. Finally, we show from the theoretical standpoint, that in a system with low activation levels , the percentage of overlap is significantly reduced, increasing the discrimination between activity patterns induced by different odorants.


There are a large number of commercially available milk formulae labelled as "hypoallergenic". However, only a minority of these comply with the criteria established in the guidelines of Subcommittee on Nutrition and Allergic Disease of the American Academy of Pediatrics.As far as the treatment of cow's milk allergy is concerned, the extensive hydrolysed protein formulae and aminoacid-based formulae are the only two preparations that meet the standards required for hypoallergenicity, defined as absence of reactions in 90% allergic patients with 95% confidence. However, even in these cases there is great variability in the content of the extensive hydrolysed formulas on the market and, for some of them, the clinical data in support of the claim of hypoallergenicity are missing. In addition, other products known as "partially hydrolysed formulae" have previously been advertised as being safe for cow’s milk allergic patients but turned out to be inadequate and responsible for anaphylactic reactions in many cases. These data underline the fact that it is mandatory to define the criteria in terms of peptidic content and preclinical profile of any formula put on the market as hypoallergenic formula for treatment of cow's milk allergy.In the case of prevention of cow’s milk allergy, the data currently available are incomplete since no study has yet been published that meets all the criteria recommended by the American Academy of Pediatrics. Nonetheless, the studies conducted to date seem to indicate a greater efficacy of extensive hydrolysed protein formulae over partially hydrolysed formulae, although the latter may present nutritional advantages and lower cost.In conclusion, further efforts are required in the characterisation of the commercially available milk formulae used for treatment and prevention of cow’s milk allergy. In the absence of well-documented studies proving the prophylactic value of partially hydrolysed formulae, children at high risk of atopy should be fed with a prophylactic hypoallergenic diet based on extensive hydrolysed formulas.


A prominent feature of many intracellular compartments is a large membrane surface area relative to their luminal volume, i.e., the small relative volume. In this study we present a theoretical analysis of discoid membrane compartments with a small relative volume and then compare the theoretical results to quantitative morphological assessment of fusiform vesicles in urinary bladder umbrella cells. Specifically, we employ three established extensions of the standard approach to lipid membrane shape calculation and determine the shapes that could be expected according to three scenarios of membrane shaping: membrane adhesion in the central discoid part, curvature driven lateral segregation of membrane constituents, and existence of stiffer membrane regions, e.g., support by protein scaffolds. The main characteristics of each scenario are analyzed. The results indicate that even though all three scenarios can lead to similar shapes, there are values of model parameters that yield qualitatively distinctive shapes. Consequently, a distinctive shape of an intracellular compartment may reveal its membrane shaping mechanism and the membrane structure. The observed shapes of fusiform vesicles fall into two qualitatively different classes, yet they are all consistent with the theoretical results and the current understanding of their structure and function. Many intracellular compartments, such as the Golgi apparatus and the endoplasmic reticulum, exhibit flattened shapes with a large membrane surface area relative to the luminal volume, i.e., they have a small relative volume. Since the small relative volume may well be intertwined with the function of these organelles, understanding the mechanisms of their shape generation is of great interest. Different organelles often show similar morphological features despite expressing very different sets of proteins. A large part of the morphological analyses of organelles has thus focused on the mechanisms of shaping of the lipid membrane, which is their universal structural backbone Theoretical studies of membrane shapes have proved fruitful, yet they were primarily focused to lipid membrane compartments of relatively large relative volumes, e.g., lipid vesicles and red blood cells A remarkable example of intracellular compartments with a small relative volume are the fusiform vesicles (FVs) of urinary bladder umbrella cells, which constitute the blood-urine barrier tissue . In the In this study we present a systematic theoretical analysis of discoid membrane shapes with small relative volumes, and then we quantify the morphology of FVs and compare it to the theoretical results. Specifically, we build on three existing extensions of the standard approach to lipid membrane shape calculation and determine the shapes that could be expected according to three proposed scenarios of membrane shaping, i.e., membrane adhesion, curvature driven lateral segregation of membrane constituents and emergence of stiffer membrane regions with a defined spontaneous curvature. We find that both classes of observed FV shapes are consistent with the theoretical results and the current understanding of FV structure.Animals were treated in accordance with European guidelines and Slovenian legislation. The experimental protocol was approved by the Veterinary Administration at the Ministry of Agriculture, Forestry and Food of Republic of Slovenia (permit number: 34401–5/2009/4).http://imagej.nih.gov/ij/). On each FV we measured the maximum length of the vesicle profile, thickness of the vesicle lumen in the central part of the vesicles, the lengths of thickened and unthickened membranes.Three albino ICR mice (CD-1) were fed standard laboratory chow and water was available ad libitum. At the age of five weeks, they were killed with COIn this section, we present the standard theoretical framework of lipid membrane shapes and discuss the challenges related to assessing shapes with small relative volumes. In the next three sections we will then employ three established extensions of the standard theory which will serve to describe the discoid shapes according to three scenarios that have been proposed for organelle membrane shaping .area difference elasticity (ADE) model The shapes of closed lipid membrane compartments in equilibrium are the shapes that correspond to the minimum of the elastic energy of the membrane at given values of external parameters, e.g., the compartment volume. According to the standard model of elasticity of the lipid bilayer, the Membrane elastic energy is scale invariant, i.e., it does not depend on the actual size of a compartment but rather on its relative shape The Gaussian bending term is not explicitly present in the Euler-Lagrange equations, rather it is a part of the boundary conditions that arise from the variation of the functional The homogeneous membrane ADE model was a basis for a number of successful studies of membrane shapes with a very good agreement between theoretically calculated shapes and experimentally observed shapes of giant lipid vesicles and red blood cells, which have relative volumes  contact . At relaAdhesion between flat membrane regions has been proposed as one of the possible stabilizing mechanisms for the flattened compartment geometry in the Golgi Minimization of the total energy, The coexistence of a highly curved membrane in the rim and a relatively flat membrane in the central discoid part can be stabilized by a nonhomogeneous distribution of membrane constituents. For example, segregation of conical molecules into the rim and cylindrical molecules into the central membrane regions leads to a local spontaneous membrane curvature that matches the actual membrane curvature and thus relaxes the bending stresses in the membrane . In the Here, we will focus on the dependence of the local membrane spontaneous curvature on the intrinsic shape of membrane constituents, which can vary considerably among different lipid species The coupling between the membrane composition and its spontaneous curvature can be described as A seminal study of the curvature driven segregation Note that although no additional parameters are needed to describe the membrane shapes within the weak lateral segregation scenario, the calculation of the shapes with large The third scenario addressed in the present analysis involves membranes that are composed of distinct regions with markedly different mechanical properties and well-defined boundaries. For example, large proteins accumulating in certain regions of the membrane may act as a protein scaffold and impose their intrinsic curvature to the membrane Within this scenario, the discoid membrane compartments can be described by two connected ADE regions, one being stiffer with a defined spontaneous curvature, and the other being normal with a vanishing spontaneous curvature. The minimization of the total elastic energy of the membrane then leads to two coupled sets of the standard ADE Euler-Lagrange equations with separate sets of ADE parameters. It turns out, that the shape is not affected by the absolute stiffness of the two regions but rather by the relative stiffness of the stiffer one Clearly, the parameter space in this case is rather large, and therefore the present analysis will focus to the effects of the three most relevant parameters: the relative stiffness of the stiffer membrane region, its relative size and its spontaneous curvature. All other parameters will be held in their plausible range, e.g., the value of the Gaussian bending constant will be The analysis presented does not take into account two properties that generally play a role in the mechanics of protein scaffolding and multicomponent membranes. First, a possible shear rigidity of the protein scaffold has been neglected. It can be shown theoretically that the shear rigidity does not influence the equilibrium membrane shape in the limit of small deformations of a nearly flat scaffold  and slightly raised unthickened membrane (hinge) regions. The cytoplasm of umbrella cells contained numerous flattened FVs . We anal2 nm . Vesicle2 nm .c, In order to obtain an insight into the variety of possible shapes at small relative volumes, we will focus to the discoid shapes calculated at the relative volume shape c, . Typicald and e) and lateral segregation  on the standard ADE shape (shape c).We start by examining the effects of adhesion and curvature driven lateral segregation, as these two models are straightforward extensions of the standard homogeneous ADE model. d and e) is an increase in the membrane contact surface area. While the surface area of membrane in contact within the standard ADE model in absence of intermembrane adhesion is approximately 32% of the total membrane surface area, it reaches approximately 49% in the limit of strong adhesion. Correspondingly, an increasing adhesion makes the shape of the rim more and more round. The maximal contact surface area could increase further with a decreased relative volume. The main effect of adhesion (f and g). Weak lateral segregation effectively increases the bilayer couple effect in the membrane, i.e., increases the effective difference in lateral tensions between the membrane leaflets, described by the dimensionless parameter f in g).The effect of weak lateral segregation of membrane constituents is presented in the bottom part of see f in . A furthAccording to the third proposed scenario, the discoid shapes are stabilized by regions of stiffer membrane with a defined spontaneous curvature. The results will focus to the three parameters: the relative stiffness, the relative size and the spontaneous curvature of the stiffer membrane region. Some of the typical calculated shapes are presented in h through m) and 5A. If the stiff region is small, the membranes in the central part are in contact, just as with the homogeneous membrane. As the stiff region grows in size, the central discoid part first separates when the stiffer region occupies 46% of the total membrane, comes into contact again at 68%, only to detach once more at 85%. Finally, as the stiff membrane region grows towards 100% of the total membrane, the membrane comes back in contact and the shape approaches the standard homogeneous ADE shape. The point of contact is always in the discoid center. The impact of a very stiff membrane region in the central discoid part is presented in n through p). As the size of the stiffer region increases, the central discoid sides first separate at the discoid center (shape n) and then come into contact again away from the center (shape p). In other words, the curved rim forces the central discoid part to undulate. Interestingly, The effects of a stiffer membrane region with a large spontaneous curvature supporting the discoid rim are presented in Finally, The aim of this work was to theoretically analyze three scenarios for membrane shaping in discoid intracellular compartments at small relative volumes c in The first conclusion of the theoretical analysis is that all three scenarios of membrane shaping can lead to qualitatively similar shapes with a flattened central part and a drop-like cross-section at the rim, a shape comparable to the shape theoretically associated with simple homogeneous membrane (shape e in e) corresponds to an adhesion strength of approximately 10000 kT per On the other hand, at certain values of model parameters the three scenarios can also yield different shapes. In these cases, the shape of the compartment can in fact indicate its underlying shaping mechanism. For example, with an increasing adhesion between the membranes in the central part, the rim becomes more and more round , and in the limit of strong adhesion, the lumen of the compartment would become spherical with all the excess membrane adhered and wrapped up. In addition, one can expect small energy differences between different shapes at small relative volumes The shape of FVs in umbrella cells can be best studied by transmission electron microscopy. We aimed to prepare mouse urothelium in a way that preserved the ultrastructure closest to its native state. Therefore we applied high pressure freezing for tissue fixation, which immobilized cellular structures within a few milliseconds s and t in r in The shapes of FVs with a small relative volume Click here for additional data file.


Tunnels are access paths connecting the interior of molecular systems with the surrounding environment. The presence of tunnels in proteins influences their reactivity, as they determine the nature and intensity of the interaction that these proteins can take part in. A few examples of systems whose function relies on tunnels include transmembrane proteins involved in small molecule transport and signal transduction, peptide exit channels through which ribosomes release newly synthesized proteins during transcription Knowledge of the location and characteristics of protein tunnels can find immediate applications in rational drug design, protein engineering, enzymology etc.Identification and characterization of tunnels has been the focus of several studies, and various algorithms and software tools have been developed for these purposes -4. TheseIn the presented study we perform a benchmarking study of the most known approaches and software tools for finding tunnels in proteins . We focused on proteins from the cytochrome P450 family, which are very important from the biological point of view. We provide a critical discussion of the strong and weak points of the analyzed approaches and software tools.


In non-human primates a scheme for the organization of the auditory cortex is frequently used to localize auditory processes. The scheme allows a common basis for comparison of functional organization across non-human primate species. However, although a body of functional and structural data in non-human primates supports an accepted scheme of nearly a dozen neighboring functional areas, can this scheme be directly applied to humans? Attempts to expand the scheme of auditory cortical fields in humans have been severely hampered by a recent controversy about the organization of tonotopic maps in humans, centered on two different models with radically different organization. We point out observations that reconcile the previous models and suggest a distinct model in which the human cortical organization is much more like that of other primates. This unified framework allows a more robust and detailed comparison of auditory cortex organization across primate species including humans. One of the oldest and best characterized organizational features in the auditory system is its cochleotopic or tonotopic organization. Tonotopy is the ordered representation of sound frequency in auditory areas. It has been shown at all levels of the auditory pathway including the cochlea, the auditory brainstem nuclei, and the auditory cortex in at least mammals and birds. In the cortex of non-human primates, multiple areas can be defined neurophysiologically by gradients of neuronal sound frequency preference and by reversals of the frequency gradient between neighboring auditory cortical areas  areas along the length of Heschl's gyrus   and fMRI did not provide the resolution and power for detailed tonotopic maps in the auditory cortex. However, a number of PET and fMRI studies consistently demonstrated significantly activated clusters or voxels responding to high frequency tones in the vicinity of the medial HG and to low frequency tones in the lateral HG  T1 mapping  and gradient quantification.The goal of this work is a robust scheme for the definition of functional areas in humans that might in future properly justify the application of primate nomenclature to human studies and allow the development of better-defined primate models for human auditory cognition. Here we suggested a unified primate model of core and belt fields which provides testable hypotheses for future functional and anatomical comparative studies in primates.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Post traumatic osteonecrosis of distal pole of scaphoid is very rare. We present a case of 34 years old male, drill operator by occupation with nontraumatic osteonecrosis of distal pole of the scaphoid. The patient was managed conservatively and was kept under regular follow-up every three months. The patient was also asked to change his profession. Two years later, the patient had no pain and had mild restriction of wrist movements (less than 15 degrees in either direction). The radiographs revealed normal density of the scaphoid suggesting revascularization. Osteonecrosis is one of the common complications of a scaphoid fracture. Its incidence has been reported to be ~10 – 15%,1246We present here a case of nontraumatic osteonecrosis of the distal pole of the scaphoid in a 34-year-old drill operator.A 34-year-old male patient, a drill operator by occupation, presented to us with complaints of pain in the right wrist. The radiographs were not suggestive of any fracture or pathology and the patient was managed with analgesics for four weeks. The patient, however, complained of persistent pain. Four weeks later, the patient revisited us with complaints of persistent pain, along with restriction of activity. The patient was reinvestigated radiologically including radiographs  and magnTwo years later, the patient had no pain and had mild restriction of wrist movements (less than 15 degrees in either direction). The radiographs revealed normal density of the scaphoid suggesting revascularization .Although osteonecrosis of the whole scaphoid can be seen in the absence of trauma (Preiser’s disease), osteonecrosis of the distal pole of scaphoid in the absence of trauma has not been reported to date. Osteonecrosis of the distal pole in our case may have occurred as a result of repeated microtrauma, leading to damage of all the dorsal vessels entering the bone distal to the waist. Cumulative micro trauma has been incriminated as a cause of osteonecrosis of other carpal bones such as lunate (Kienbock’s disease).7et al.213Vibration exposure is another recognized cause of osteonecrosis of carpal bones.71A fracture running proximal to the insertion of the dorsal ridge vessels, or one which damages these vessels predisposes the vascularity of the proximal fragment. The site of entry of the dorsal vessels is variable — they enter distal to the waist in 14%, at the waist in 79%, and proximal in 7%.45Avascular necrosis of the scaphoid has been reported in patients with collagen vascular disease.Osteonecrosis of the distal pole in our case probably occurred as a result of repeated microtrauma leading to a damage of all the dorsal vessels entering the bone proximal to the waist. A change of profession and conservative management has given good results in our case.


Dynamic drop test for studying the temporal lowering of hydrophobicity on the surface of silicone rubber with direct current voltage application was carried out. In this study, we evaluated the influence of the temporal lowering of hydrophobicity under various conductivities and dropping rates for water droplets. As a result, it was found that the dropping rate and the conductivity of water droplets greatly influenced the hydrophobicity loss time on the surface of silicone rubber. The development of insulating materials used in electric-powered apparatuses plays an essential role in a stable power supply. Polymer materials, for example, have attracted attention in recent years. The use of polymer materials for housings of insulators and arresters has increased. The widely accepted polymer materials for housings are silicone rubber [SiR] and ethylene vinyl acetate. These polymer materials have some excellent properties such as being lightweight, hydrophobicity, and antiweatherability . AdditioIncidentally, electric-powered apparatuses are utilized not only by alternating current [AC] voltage applications, but also by direct current [DC] voltage applications. The polymer material is made from organic matters; therefore, the aged deterioration due to electric discharges and acidic products is worrying. Studies on evaluation methods of insulation deterioration of polymer materials are continuously made by the International Council on Large Electric Systems [CIGRE]. A dynamic drop test [DDT] which can easily evaluate the characteristics of temporal lowering of hydrophobicity on the surface of the polymer material was proposed through a continuous research effort . Here, iIn this study, we carried out DDT for evaluating the temporal lowering of hydrophobicity on the surface of silicone rubber with DC voltage application. Our results have contributed to the evaluation of polymer materials' reliability with DC voltage application.The temporal decrease of hydrophobicity on the surface of the polymer material for the DDT is evaluated by dropping water in small amounts under DC voltage application in DDT. Table We evaluated the influence of the temporal lowering of hydrophobicity under various conductivities and dropping rates. The changes of hydrophobicity and discharges generated at the surface of the test sample were observed by a CCD camera and shown in Figure Figure Figure Figure Thus, due to the influence of the high electric field, the increase of dropping rate was confirmed after impressed voltage was applied. Such increase of droplets is remarkable with the increase of the initial dropping rate of electrolyte. The increase of droplets promoted the lowering of hydrophobicity, and the hydrophobicity loss time became shorter. The surface of the test sample has a greater opportunity to attach NaCl and keeps electrification on the surface of SiR with the increase of the dropping rate.We carried out DDT in investigating the temporal lowering phenomena of hydrophobicity of the SiR surface with DC voltage application. Here, the influence of the temporal lowering of hydrophobicity under various conductivities and dropping rates was evaluated. With the progress of the lowering of hydrophobicity, small discharges on the surface of SiR could be seen. Additionally, in the final stage, the hydrophobicity lowered, and an obvious water channel was confirmed. Such hydrophobicity loss was influenced by the conductivity and dropping rate of the electrolyte.The authors declare that they have no competing interests.TS and TA conceived the experiments. YS performed the experiments and analyzed the data together with NO and TM. TS and TA provided valuable advice. TS and TA co-wrote the paper. All authors discussed the results and commented on the manuscript.


Hepatocellular carcinomas (HCCs) have different etiology and heterogenic genomic alterations lead to high complexity. The molecular features of HCC have largely been studied by gene expression and proteome profiling focusing on the correlations between the expression of specific markers and clinical data. Integration of the increasing amounts of data in databases has facilitated the link of genomic and proteomic profiles of HCC to disease state and clinical outcome. Despite the current knowledge, specific molecular markers remain to be identified and new strategies are required to establish novel-targeted therapies. In the last years, mathematical models reconstructing gene and protein networks based on experimental data of HCC have been developed providing powerful tools to predict candidate interactions and potential targets for therapy. Furthermore, the combination of dynamic and logical mathematical models with quantitative data allows detailed mechanistic insights into system properties. To address effects at the organ level, mathematical models reconstructing the three-dimensional organization of liver lobules were developed. In the future, integration of different modeling approaches capturing the effects at the cellular up to the organ level is required to address the complex properties of HCC and to enable the discovery of new targets for HCC prevention or treatment. Hepatocellular carcinoma (HCC) represents one of the most frequent cancers with the highest incidence in developing countries. Due to its aggressiveness it is third in causing cancer-related deaths worldwide , vascular invasion  .A functional genomic study was performed applying siRNA to identify tumor suppressor genes in a mosaic mouse model  is a database for genomic changes of several cancer types, including 99 HCC samples and their normal liver tissues. TCGA includes gene and miRNA expression data and the epigenetic DNA methylation status.The integrated Clinical Omics Database (iCOD) collects all available information of 140 cases of HCC, ranging from gene expression profiles to relevant clinical data   that contains links of gene expression to specific liver diseases   model of liver lobule was developed (Hoehme et al., Taken together, these studies show that even for complex situation such as HCC, systems properties can be addressed by combining experimental data with mathematical modeling.HCC represents a particularly complex disease and the integration of all features of HCC including the tumor stage, the etiology, the mutational status, the response to therapy, and tumor recurrence are required to better understand its development and to design a most efficient treatment. There is an urgent need for molecular markers specific for HCC to facilitate early diagnosis in order to improve the prognosis after treatment. Systems-wide studies begin to show evidence for HCC classifiers and for the impact of alterations in hub genes for these classifiers. Additionally, first steps have been taken to provide a deeper understanding of dynamic properties of signaling networks in the liver. A summary of the reviewed results is given in Table Future developments require the integration of data at different scales, connecting the genomic information to the signaling regulation and finally to tumor behavior. To this aim, model integration linking intracellular events to responses at the organ level is essential. The major challenge is to develop mathematical formalisms allowing connecting events occurring at different time scales. In conclusion, the combination of clinical and experimental data with mathematical modeling promises to provide means to handle the complexity that is characteristic for HCC and to facilitate the development of personalized targeted therapy.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The following article appeared on page 372 of the July 2012 issue of the Annals. Unfortunately the images that accompanied the tip were incorrect. We reproduce the image below with the correct images displayed. The Editor apologises for any confusion caused.The development of pancreatic necrosis is a significant complication of acute pancreatitis and can result in progressive multiple organ failure and death. Recently, in an attempt to reduce the high morbidity and mortality from open necrosectomy, minimal access techniques have been developed.2 pressure (8mmHg) permits visualisation of the retroperitoneum, and standard laparoscopic graspers and a suction device can be placed through additional port sites in the unit to allow removal of necrotic tissue  can be used to gain retroperitoneal access  and alloc tissue . Post-opThe technique of minimally invasive necrosectomy has been well described previously


Use of thrombolytic therapy in pulmonary embolism is restricted in cases of massive embolism. It achieves faster lysis of the thrombus than the conventional heparin therapy thus reducing the morbidity and mortality associated with PE. The compartment syndrome is a well-documented, potentially lethal complication of thrombolytic therapy and known to occur in the limbs involved for vascular lines or venepunctures. The compartment syndrome in a conscious and well-oriented patient is mainly diagnosed on clinical ground with its classical signs and symptoms like disproportionate pain, tense swollen limb and pain on passive stretch. However these findings may not be appropriately assessed in an unconscious patient and therefore the clinicians should have high index of suspicion in a patient with an acutely swollen tense limb. In such scenarios a prompt orthopaedic opinion should be considered. In this report, we present a case of acute compartment syndrome of the right forearm in a 78 years old male patient following repeated attempts to secure an arterial line for initiating the thrombolytic therapy for the management of massive pulmonary embolism. The patient underwent urgent surgical decompression of the forearm compartments and thus managed to save his limb. Acute massive pulmonary embolism (PE) is an uncommon clinical entity but carries an exceptionally high mortality. A rapid diagnosis of massive PE is very crucial to initiate the potentially life-saving therapy. The use of thrombolysis in conjunction with standard anticoagulation in the acute phase has been shown to reduce the mortality rate in this group of patient . AccordiDue to its fatal haemorrhagic complications, the thrombolytic therapy has been strictly recommended for the patients with proven massive PE. The rate of significant bleeding has been reported to be around 22–45%. The bleeding most commonly occurs at the vascular catheter site, viscera, and intracranium. Although management for minor bleeding has been supportive, serious bleeding does warrant withdrawal of the thrombolytic therapy. Isolated cases of compartment syndrome after thrombolytic therapy have been reported in the literature [A 78-year-old male presented to the hospital with the history of fever and breathlessness. After initial assessment and investigations, the diagnosis of chest infection was made, and the patient was admitted to short stay unit for further management. The patient was a known case of myasthenia gravis and had history of asbestosis in the past. Whilst being on ward, the patient suddenly collapsed and required resuscitation. The anaesthetist was called to intubate the patient and was then transferred to the Intensive care Unit (ICU) for further management. After initial stabilisation, the patient was investigated to find the cause of sudden collapse. The ECG showed the right bundle branch block. The patient had raised Troponin T level, and the echocardiogram revealed well-preserved left ventricular function with reduced right ventricular function and bright mass in pulmonary artery, thus confirming the diagnosis of massive pulmonary embolism.The patient was thrombolysed using 100 mg of tissue plasminogen activator (tPA) over two hrs and Heparin 1000 units per mL at 1 mL/hr given in separate lines. The nor-adrenaline was used to maintain mean arterial pressure of around 85. The patient had femoral arterial line after numerous failed attempts to have a right radial artery line. The patient responded very well to the thrombolytic treatment leading to stable haemodynamic condition. Eight hours following the initiation of thrombolytic therapy, the right forearm of the patient was noted to be very swollen and tight. The orthopaedic team was called immediately to assess the forearm in view of compartment syndrome. As patient being intubated, it was difficult to diagnose a compartment syndrome on just clinical ground, and hence a universally accepted, calibrated handheld device  was used to measure the compartment pressure in the involved forearm compartments . The pre The fasciotomy of the forearm was performed by extensile Henry's approach along with decompression of carpel tunnel and abductor compartment of the hand . The mus At the end of 3-month followup, the patient had full range of movements in elbow, terminal restriction of movement in wrist and hand. He had functional muscle power in his intrinsic muscles of the hand. Apart from mild tingling in the hand, there was no sensory deficit.Acute compartment syndrome occurs as a result increased interstitial pressure in closed osseous fascial compartment thus compromising the circulation and function of the tissues within that compartment. The initial insult either in the form of trauma, internal bleeding, or ischaemia leads to swelling within the closed compartment and compromising the tissue perfusion. This sequence of event causing tissue ischaemia if not reversed in time by decompression of compartment can lead to necrosis of the tissue . In our The diagnosis of compartment syndrome is usually made on clinical suspicion when patient complains of a disproportionate pain in the involved limb and elicits the severe pain on passive stretch of the muscle within the involved compartment. It is very difficult to make this judgement in a patient with a head injury, unconscious or on artificial ventilation like our case. In such scenario, measurement of intracompartmental pressure with the calibrated device along with clinical suspicion helps to make the diagnosis of compartment syndrome . The StrMcCarthy et al.  in theirIt has been well documented in literature about the complications of bleeding with thrombolytic therapy administered to patients with myocardial infarction and stroke but not much data about the patients with massive pulmonary embolism. The complication rate for bleeding due to thrombolytic therapy seems to be higher in elderly population –12. In mMcQueen et al.  emphasizIt is imperative for medical staff working on ICU setup to be aware of the possibility of compartment syndrome in a patient on thrombolytic therapy. One has to be very careful in taking vascular access in such group of patient to avoid extravasation of blood leading to increased intracompartmental pressure. Prompt referral should be made to the orthopaedic team to assess the tense swollen limb in a patient treated with thrombolysis for massive pulmonary embolism.


Both in vivo  and in vSpike patterns associated with cells assemblies can be identified by clustering the spectrum of zero-lag cross-correlation between all pairs of neurons in a network . Other mHere we investigate how the identification of cell assemblies is dependent on the methodology chosen, and to what extent the statistical properties of the cell assemblies make them suitable for representation of system states in the striatum during reinforcement learning.