Bioimpedance analysis is a noninvasive, low cost and a commonly used approach for body composition measurements and assessment of clinical condition. There are a variety of methods applied for interpretation of measured bioimpedance data and a wide range of utilizations of bioimpedance in body composition estimation and evaluation of clinical status. This paper reviews the main concepts of bioimpedance measurement techniques including the frequency based, the allocation based, bioimpedance vector analysis and the real time bioimpedance analysis systems. Commonly used prediction equations for body composition assessment and influence of anthropometric measurements, gender, ethnic groups, postures, measurements protocols and electrode artifacts in estimated values are also discussed. In addition, this paper also contributes to the deliberations of bioimpedance analysis assessment of abnormal loss in lean body mass and unbalanced shift in body fluids and to the summary of diagnostic usage in different kinds of conditions such as cardiac, pulmonary, renal, and neural and infection diseases. The essential fundamentals of bioimpedance measurement in the human body and a variety of methods are used to interpret the obtained information. In addition there is a wide spectrum of utilization of bioimpedance in healthcare facilities such as disease prognosis and monitoring of body vital status. Thus, with such a broad utilization, we feel that this warrants a review of the most fundamental aspects and healthcare applications of bioimpedance analysis.Studies on the electrical properties of biological tissues have been going on since the late 18th century  exploredi.e., active and passive response. Active response (bioelectricity) occurs when biological tissue provokes electricity from ionic activities inside cells, as in electrocardiograph (ECG) signals from the heart and electroencephalograph (EEG) signals from the brain. Passive response occurs when biological tissues are simulated through an external electrical current source [The electrical properties of biological tissues are currently categorized based on the source of the electricity, t source . Bioimpet source .et al. [Due to the noninvasiveness, the low cost and the portability of bioimpedance analysis systems, numerous researchers have conducted studies on bioimpedance analysis and its applications in body composition estimation and evaluation of clinical conditions. Recently, Mialich et al.  reviewedet al.  has revi2.c) that is caused by the capacitance of the cell membrane [Impedance (Z), from an electrical point of view, is the obstruction to the flow of an alternating current and, hence, is dependent on the frequency of the applied current, defined in impedance magnitude (|Z|) and phase angle (φ) as shown in membrane :(1)Z=R+c) of an object as shown in Resistance of an object is determined by a shape, that is described as length (L) and surface area (A), and material type, that is described by resistivity (ρ), as shown in 0 ≈ 8.854 × 10−12 F·m−1) and the relative dielectric permittivity constant (εr) that is defined based on the material between the plates , as shown in Capacitance (C) is defined as the ability of the non-conducting object to save electrical charges, that is equal to the ratio between differentiation in voltage across object (dV/dt) and current that is passed through the object (I(t)), as shown in b) through the basic means of resistance measurement. From b) can be obtained by substituting the surface area (A) with the numerator and denominator of the length (L), as in Body composition estimation using bioimpedance measurements is based on determination of body volume (VBody) and fat free mass (FFM), as shown in The human body as a volume is composed generally of fat mass (FM) which is considered as a non-conductor of electric charge and is equal to the difference between body weight  that include protein and total body water that consists of extracellular fluid (ECF) and intracellular fluid (ICF) . Figure 2/R) [2/R50 that was introduced by Kyle et al. [et al. [Most of the known prediction methods rely on the relation between water volume and the ratio between square length to resistance (L2/R) , howevere et al. ,14 and H [et al. .Measurement of bioimpedance is obtained from the whole body and body segments separately, using single frequency, multiple frequencies and bioimpedance spectroscopy analysis. In addition to several alternative assessments method such as bioimpedance vector analysis and real time bioimpedance analysis.2.1.Analysis of bioimpedance information obtained at 50 KHz electric current is known as single-frequency bioimpedance analysis (SF-BIA). SF-BIA is the most used and is one of the earliest proposed methods for the estimation of body compartments, It is based on the inverse proportion between assessed impedance and TBW, that represents the conductive path of the electric current .SF-BIA predicts the volume of TBW that is composed of fluctuating percentages of extra cellular fluid (ECF) which is almost equal to 75% of TBW, and ICF that represent the rest . Studies2.2.et al. [et al. [et al. [et al. [Analysis of bioimpedance that is obtained at more than two frequencies is known as multiple-frequency bioimpedance analysis (MF-BIA). MF-BIA is based on the finding that the ECF and TBW can be assessed by exposing it to low and high frequency electric currents, respectively. Thomasset  has propet al.  stated t [et al.  state th [et al.  report t [et al.  reported [et al. .2.3.0) and resistance at infinity frequency (Rinf) that is then used to predict ECF and TBW, respectively. The use of 100 and 1 kHz, respectively, was earlier proposed by Thomasset [Analysis of bioimpedance data obtained using a broad band of frequencies is known as bioimpedance spectroscopy (BIS). The BIS method is based on the determination of resistance at zero frequency , in The determination of Cole module parameters (Rb) and substituting the surface area (A) by body volume (Vb). Ayllon et al. [0, Rinf, α, Fc) that is obtained by using only resistance achieves slightly better results and there is less standard error based on the Non-Linear Least Squares technique as compared to the capacitive and impedance complex components. Ward et al. [b is the body volume and Kb is a dimensionless shape factor calculated from the length and perimeters of the upper and lower limbs, and the trunk, taken into consideration the body shape composed of the five cylinders.; Van Loan et al. [b) from statistical anatomical measurements in adults to be equal to 4.3.In n et al.  reports d et al.  concluden et al.  calculat2.4.et al. [et al. [et al. [Measurement of total body bioimpedance is the most commonly used method for estimating whole body compartments. Many of the whole body bioimpedance instruments apply three approaches for impedance measurement: hand to foot method ,17, footet al.  through et al. . Hand to [et al.  by perfo [et al.  validate2.5.et al. [Segmental bioimpedance analysis achieves better estimation of skeletal muscle mass (SMM) than whole body bioimpedance analysis, with a reported standard error of 6.1% in reference to MRI measurements among 30 male subjects . Baumgaret al.  stated tSegmental bioimpedance analysis detects the fluctuation in ECF due to differences in posture and is more precise than the ankle foot method , and givet al. stated that the trunk represents 50% of the body mass [et al. pointed out that total bioimpedance measurement assesses mainly the upper and lower limb compartments, and shows some limitation to predict water compartments of the trunk [Segmental or perpendicular bioimpedance analysis defines the measurement method of body segments that is mostly treated as five cylinders as in ody mass . Kyle ethe trunk .et al. [et al. [et al. [et al. [Measurement of segmental bioimpedance can be achieved through four types of protocols. The first approach, as suggested by Scheltinga et al. , uses du [et al. , through [et al. , who sug [et al. ,59,60, iet al. [2 = 0.99; furthermore Seward et al. [Limitations of whole body bioimpedance measurement in evaluating body segment compartments have given rise to the demand for segment localized bioimpedance analysis applications. Scharfetter et al. , reported et al. , introduet al. [Studies report that the segmental bioimpedance analysis method shows some limitations in the estimation of FFM ,63, withet al.  conclude2.6.et al. [c graph) from bioimpedance measurements. Using 8,022 normal subjects  Piccoli et al. [Bioimpedance analysis, as an independent method for the assessment of the human health status from absolute bioimpedance measurements, has triggered a new path of data analysis and interpretation. The bioimpedance vector analysis method (BIVA) is a novel approach established essentially by Piccoli et al. ,65 to esi et al.  formulatet al. [Evaluation study of the BIVA method by Cox-Reijven et al. , on 70 det al. .In  the BIVAThe BIVA method is also considered as a valid tool for the estimation of dry weight in 24 haemodialysis patients' with reference to the Bilbrey Index based on different allocation of values before and after obtrusion .et al. reported that the BIVA method is affected by differences in biological factors and measurement artifacts [Kyle rtifacts . Ward anrtifacts .et al. [2/4π and (c) is the circumference in meter of the arm, waist and calf, respectively; L = 1.1 (Ht), where Ht is body height in meters.A specific BIVA method has been proposed by Marini et al.  to neutret al. ,74, wheret al. [et al. [Another alternative method for analysis is real time processing of bioimpedance data which is currently introduced as a key feature for body health monitoring applications. A logarithmic analysis carried out between 0.01 and 10 Hz with five frequencies needs 276 s to be completed, this includes the calculation time . Sanchez [et al.  introduc [et al. .Use of multi-sine excitation signals in bioimpedance measurements that is proposed in ,79 helpe3.Body composition assessment is considered a key factor for the evaluation of general health status of humans. Several methods use different assumptions to estimate body composition based on the number of compartments. This review considers that the human body is composed of two main compartments, FM and body lean mass or FFM. FFM is composed of bone minerals and body cell mass (BCM) that includes skeletal muscle mass (SMM). BCM contains proteins and TBW that represents 73% of lean mass in normal hydrated subjects. TBW is composed of ICF and ECF as illustrated in 3.1.FM and FFM estimations are considered one of the main objectives of body composition assessment techniques. Variations in FM among the reference population are due to several factors, but are believed to follow aging factors in addition to gradual changes in lifestyle .Anthropometric and skin fold thickness measurements are traditional, simple and inexpensive methods for body fat estimation to assess the size of specific subcutaneous fat depots  comparedBioimpedance analysis has been shown in recent studies to be more precise for determining lean or fat mass in humans . In compet al. [2 in reference to DXA method:50) and  is resistance and reactance at 50 KHz, and (Wt) is body weight. The developed equation achieved a correlation coefficient (R) that is equal to 0.986, standard error of the estimate (SEE) is equal to 1.72 kg and technical error is 1.74 kg.Kyle et al.  developeIn ,85, FFM et al. [Sun et al. , used a R2 = 0.90 and 0.83 and root mean square errors of 3.9 and 2.9 kg for males and females, respectively.The mean FFM prediction equations achieved a correlation coefficient et al. [Deurenberg et al. , used deR2 = 0.93 and standard estimation error (SEE) = 2.63 kg.The FFM prediction equations achieved a correlation coefficient et al. [et al. [Pichard et al. , assesse [et al. , and conHeitmann  compared2 = 0.89) and lower standard estimation error (SEE = 3.32 kg) than the multiple regression equations for skin fold  or body mass index .The multiple regression Heitmann  assessedet al. [ecf and Rtbw represents resistance of extracellular fluids and total body water extracted using the Cole module [Recently, Pichler et al.  assessede module . In conce module .3.2.+ and Cl−, and for ICF are K+ and PO−4 [Body fluid is the total volume of fluids inside a human body that represents the majority of the FFM volume percentage. TBW includes the fluids inside the cellular mass that is known as ICF; and the fluid located outside the cell body which is composed of plasma and interstitial fluid which is known as ECF. ECF and ICF fluids that are incorporated under TBW, contain several ion types with different concentrations, however the main ions in ECF are Naand PO−4 .Body fluids estimation using bioimpedance measurements are based on the inversely proportional between body resistance and the total amount of body water . There aet al. [Sun et al.  develope2) and mean square error equal to 0.84 and 3.8 L in men, and 0.79 and 2.6 L in women.The developed equation achieved a correlation coefficient  and standard estimation error equal to 0.89 and 1.7 L.After measurements performed using bioimpedance and bromide dilution methods on 40 subjects  aged 21–81 years, of which 22 were healthy subjects, 12 were affected by chronic heart failure and 6 by chronic renal failure, the best estimation results at 1 KHz achieved a correlation coefficient  and standard error of estimate (SEE) equal to 0.95 and 1.73 L using Z100KHz, and 0.95 and 1.74 L using Z50KHz:The prediction equation of TBW achieved a correlation coefficient (R2) and standard error of estimate (SEE) equal to 0.87 and 0.98 L using Z1KHz, and 0.86 and 1.02 L using Z5KHz.The prediction equation of ECF achieved a correlation coefficient  is volume fraction of non-conducting tissue. Based on Hanai's mixture method [a) can be calculated using the following Prediction of body fluids using the BIS method in three steps involves firstly determination using the values of Re theory :(27)ρa=e method , tissue ecf) and TBW volume (Vb). The volume fraction of non-conducting tissues at low frequencies calculated as in At low frequencies the current will pass through extracellular fluids only without intracellular fluid due to the high capacitance of cell membranes . In thata) at low frequency represents the extracellular fluid resistivity (ρAecf), thus the resistance of ECF (Recf) can be recalculated in aecf) from Based on the mixture theory , apparenecf to be equal to 40.3 Ω ·cm for men and 42.3 Ω ·cm for women, which is close to that achieved by saline, and is about 40 Ω ·cm t for the ECF composed of plasma and interstitial water [Hanai , calculaal water .ecf) caused by changes in estimated ECF resistance (Recf), that is achieved by replacing body volume (Vb), that is equal to the ratio between body weight (Wt) in Kg and body density (b)D in Kg/L from To reform the equation to evaluate the variance in ECF volume (Vb), extracellular fluid resistivity (ρaecf) and body density (bD) are constant values that can be included in one factor defined as extracellular fluid factor (Ke) as in ecf) as in Body factor  and taking the module of non-conducting tissue factor (c) in ecf) using the same equation as Moissl et al. , suggestFrom , (a) andet al. [inf using the same assumption of mixture theory [Jaffrin et al.  suggestee theory , and assa_tbw) from actual total body water resistivity (ρtbw), the parameters in (c) from To determine the apparent resistivity of total body water (ρb) from tbw) and total body water volume (Vtbw) is recalculated by using By replacing the actual resistivity by apparent resistivity for total body water in et al. [tbw to be equal to 104.3 Ω ·cm in men and 100.5 Ω ·cm. A validation study conducted in 28 dialysed patients [tbw was equal to 108.1 Ω·cm in men and 100.2 Ω·cm, which predicted 91% of mean water loss when compared with 39% for Cole method [tbw and hydration rate values.Considering that total body water is equal to the accumulation of ECF and ICF, Jaffrin et al.  calculatpatients , conclude method , but oveet al. [icf) using a new assumption for TBW resistivity (ρtbw), as in For ICF prediction using a BIS method, Matthie et al.  introductbw/Recf) is opposite and proportional to (Vtbw/Vecf):In the second version of mixture theory, total body water volume is considered to be equal to the summation of ECF and ICF, for ECF estimation, the relation in et al. [ρicf to be equal to 273.9 Ω·cm and ρecf = 40.5 Ω·cm in men and 264.9 Ω·cm and 39.0 Ω·cm, respectively in women. De Lorenzo et al. [icf):Moissl et al.  calculato et al.  suggest et al. [Ri is less accurate than for Re in parallel module because it sums up the errors on Re and Rinf, is not.Jaffrin and Morel  claim thet al. , who staet al. [icf), taking into consideration that the non-conducting tissue factor (c) is as given in Moissl et al.  introducicf) and intracellular fluid volume (Vicf) are added as in tbw) and total body water volume (Vtbw) is equal to the summation of ECF and ICF volumes as in tbw) using different assumption of (Ktbw) and (ρtbw) from Jaffrin et al. [et al. [40K isotope [Then the recalculated intracellular fluid factor  with a correlation coefficient referenced to the total body potassium counting method is equal to 0.91, 0.82 and 0.89, and a standard estimation error equal of 5.6 kg, 6.3 kg and 1.3 kg for FFM, BCM and ECF, respectively.Ward et al.  presente4.2.Variations in body composition between male and female were proven in several studies . In bodyet al. [FFM or lean mass studies show that males have greater FFM than females with different ranges. Kyle et al.  state thet al.  on 1649 et al. [et al. [TBW averaged 73.2% of fat free mass in the healthy population; however several studies show that males have less TBW than females . Sun et et al. , stated  [et al.  state thDue to the different body composition between males and females, gender considerations have a strong impact in estimating body compartments.4.3.Aging is defined as a multi-factor changing in the physical and biological activities of the human body that leads to differences in body composition among age groups. When the human body becomes older it leads to a gradual increase in fat mass and spontaneous decrease in lean mass. Fat free mass to fat mass ratio increases gradually in response to increase of age, and a noticeable increment in average weight is seen among the elder population compared with adults associated with increment in fat mass . In someet al. [Several studies were conducted using the BIA method on children ,105 adulet al.  reported4.4.Body composition varies among different races and ethnic groups due to the environment, nutrition factors, culture and anthropometric measurements that include body conformation . There iet al. [et al. [et al. assessed the segmental lean mass among Koreans [et al. assessed the fat free mass among Germans and compared it to the American and Swiss population [et al. studied the clinical applications of BIVA on Slovaks [et al. had performed a comparative study among two different Indian races [et al. obtained specific BIVA reference values for the Italian healthy elderly population in order to construct the specific tolerance ellipses to be used for reference purposes for assessing body composition in gerontological practice and for epidemiological purposes [The majority of bioimpedance measurement studies have been done on Caucasian subjects , Kotler et al.  and Sun  [et al.  have inc Koreans , Schulz pulation . Sivákov Slovaks . Nigam ean races , whereaspurposes . Validat4.5.Simplicity and the economic acceptance of bioimpedance analysis method for body composition estimation have increased the need to unify the protocols and procedures of bioimpedance measurements in order to retrieve robust data.For the foot to ankle measurement method, bioimpedance measurements performed in a supine position with abduction of the upper limbs to 30 degrees and lower limbs to 45 degrees for 5 to 10 min. studies show that when the posture changes from a standing to a supine body position, the ECV decreased in the arms by 2.51% and legs by 3.02%, but increased in the trunk by 3.2% . Fastinget al. concluded that the error in total body water prediction range from 1 to 1.5 L figured out after laying at rest for one hour [Electrodes should be placed on the pre-cleaned metacarpal and metatarsal phalangeal joints with a distance in between of at least 5 cm without skin lesions at the location of the electrodes. In some studies skin temperature should be counted ,120. Subone hour .4.6.In bioimpedance analysis, the geometrical structure of electrode has a strong impact on elementary data retrieved during the measurement process. In bioimpedance analysis electrodes are defined as isoelectric materials with a negligible voltage drop along the connectors. The minimum numbers of electrodes required to perform the bioimpedance measurements are two, one for current injection with the assumption of zero potential difference and the other for collecting the voltage drop with a negligible current flow and is more affected by position.The tetrapolar electrode approach become widely used for whole bioimpedance measurements because of the uniformity of current distribution compared to monopolar electrodes , and the2 are the most commonly used shapes [Ag-AgCl electrodes are now used in most bioimpedance measurements because it has a well-defined DC potential with electrolyte gel to minimize the gap impedance between skin and electrodes. Circular and rectangular electrode shapes with a contact area greater than 4 cmd shapes .et al. investigated the impact of electrode discrepancy on BIS measurements and concluded that mismatched potential electrode causes 4% overestimated measurements in resistance at zero and infinite frequency because of an imbalanced electrical field distribution [et al. stated that capacitance between different body segments and earth, and capacitance between the signal ground of the device and earth cause a significant false dispersion in the measured impedance spectra at frequencies >500 kHz [Buendía ribution . Shiffmaribution  addresse>500 kHz .Errors in bioimpedance measurements are caused by many factors such as motion, miss-positioning, connector length and fabrication errors. Moreover, the diversity of the commercially available bioimpedance analyzers cause a wide range of fluctuations in measurements between the devices. Thus the calibration of the components inside a bioimpedance analyzer such as signal generator, sensing apparatus, scales of weight and height and electrical interference should be conducted to ensure the reliability of the bioimpedance analyzers .5.Bioimpedance analysis in healthcare practice contributes to the estimation of body compartments to assess the regular change in nutrition status in in-patients and to monitor nutritional risk in out-patients . Most ofObservation of body compartment fluctuations like fat free mass, fat mass and total body water from normal limits are considered as key factors to be used in bioimpedance analysis in healthcare applications. Abnormal loss in lean body mass and unbalanced shifts in body fluids are the most measured parameters to be used to assess the healthiness of the human body. Analysis of bioimpedance parameters has bern used in several studies to estimate and analyze the changes in disorders of different kind of diseases.et al. [et al. [Norman et al.  stated t [et al.  stated t6.Increasing demands for accurate, cost effective and non-invasive systems for clinical status monitoring and diagnosis of diseases in healthcare, has accelerated the research endeavors to provide new methods and technologies to evaluate the health condition of human body. Body composition assessment tools has been considered a promising approach for the quantitative measurement of tissues characteristic over time, in addition to direct relativity between fluctuations in body composition equivalences and survival rate, clinical condition, illness and quality of life. Bioimpedance analysis is a growing method for body compartments estimation in nutrition studies, sport medicine and evaluation of hydration rate, fat mass and fat free mass between healthy and diseased populations. Fat mass, fat free mass including skeletal muscle mass, bone minerals, and total body water, which is composed of intercellular fluid and extracellular fluid, are compartments that can be predicted and analyzed using suitable bioimpedance measurements techniques, procedures and population, age, ethnic groups or disease-dedicated bioimpedance analysis equations. Further studies are needed to evaluate the correlations between variations in bioimpedance parameters, especially in ECF and ICF, and the deviation from health to disease.


It is now well documented that over 400 subglacial lakes exist across the bed of the Antarctic Ice Sheet. They comprise a variety of sizes and volumes (from the approx. 250 km long Lake Vostok to bodies of water less than 1 km in length), relate to a number of discrete topographic settings  and exhibit a range of dynamic behaviours . Here we critique recent advances in our understanding of subglacial lakes, in particular since the last inventory in 2012. We show that within 3 years our knowledge of the hydrological processes at the ice-sheet base has advanced considerably. We describe evidence for further ‘active’ subglacial lakes, based on satellite observation of ice-surface changes, and discuss why detection of many ‘active’ lakes is not resolved in traditional radio-echo sounding methods. We go on to review evidence for large-scale subglacial water flow in Antarctica, including the discovery of ancient channels developed by former hydrological processes. We end by predicting areas where future discoveries may be possible, including the detection, measurement and significance of groundwater (i.e. water held beneath the ice-bed interface). SubglacSubsequent to the discovery of subglacial lakes over 40 years ago, the consensus among glaciologists at the time was that water flowed very slowly at the Antarctic Ice Sheet bed and, therefore, had minimal glacial dynamical impact. As a consequence, little research on subglacial lakes was conducted in the 1980s, except for an unpublished chapter in a PhD thesis . This laInterest in subglacial lakes was renewed in the early 1990s, when high-precision ERS-1 satellite radar altimetry revealed that the 1970s RES data from Lake Vostok coincided with a notably flat ice surface . This brIn the 20 years that followed, our appreciation of Antarctic subglacial lakes developed considerably and allowed a wider appreciation of hydrological processes beneath the ice. We now know that over 400 lakes exist at the ice-sheet bed. The last full inventory of subglacial lakes provided information on 379 features ; this waSome subglacial lakes are prone to sudden discharges of water , which can flow hundreds of kilometres and also connect with other lakes . Such waThe last review on the state of knowledge of subglacial lakes and their impact on ice-sheet hydrology was undertaken by Wright & Siegert . An exce2.Satellite altimetry techniques have been used on numerous occasions to identify the presence of ‘active’ subglacial lakes, their connectivity and their impact on ice dynamics ,17,25,26et al. [2 surface depression. Between 2009 and 2012, the lake re-filled slowly, causing the ice-sheet surface to slowly rise again [3) yet reported from Antarctica [One of the most remarkable ‘active’ subglacial lakes identified by Smith et al.  is Lake et al. , and ASTet al. . The datse again ,30. The et al. [et al. [Since the publication of Smith et al. , severalet al. ,31,32,33 [et al.  and the et al. [To investigate the nature of the subglacial environment directly beneath and around a zone of known ice-surface elevation change, Siegert et al.  undertooet al. , as wellet al. [The first thing to note about the resulting dataset is that no obvious RES reflection from a deep-water subglacial lake was identified . Normallet al. .et al. [The second observation is that Institute E2 does coincide, at least in part, with a small minimum in the subglacial hydrological potential, meaning that basal water is expected to accumulate at some level. The location of this potential minimum is downstream of a subglacial hill. The implication is that Institute E2 is an ephemeral, probably shallow, lake that exists because water pools on the lee side of a subglacial hill; the potential minimum being a result of the ice thickness gradient rather than the basal topography. One possible explanation, given the spatially restricted nature of the hydrological minimum, is that its dimensions are far smaller than those proposed by Smith et al. .et al. [et al. [et al. [Clearly, the differences between Institute E2 and Lake Vostok are substantial and they possibly represent end-members of the spectrum of Antarctic subglacial lakes. To see whether other ‘active’ subglacial lakes conform to observations at Institute E2, Wright et al.  undertoo [et al.  had noti [et al. , no dire3.et al. [The dynamic behaviour of ‘active’ lakes demonstrates that there are hydrological pathways and connections beneath the ice sheet. Wright et al.  showed tet al. . The natet al. [et al. [et al. [−2). Using the correct (greater) geothermal heat flux will produce higher meltrates than previously calculated, which may be capable of supporting persistent R-channels.Wingham et al.  first ev [et al.  provide  [et al. ). The qu [et al. . Carter  [et al.  suggest  [et al.  suggest et al. [Le Brocq et al.  provide et al. ).4.Geomorphological evidence for channels associated with former subglacial flow of water and its connectivity is well documented from the areas of former Northern Hemisphere glaciation (e.g. ), from t3) palaeo-subglacial lake in the upper Wilkes Basin in the Middle Miocene [et al. [−1), meaning the channels have clear surface expressions  and smaller scale canyon-like structures . Combin [et al.  were abl [et al.  interpre [et al. , which a [et al.  postulatet al. [et al. [While channels at the ice-sheet bed have only been identified across a few locations, it is entirely possible that other regions of the ice-sheet base contain both relic and ‘active’ subglacial drainage features. By combining satellite and airborne geophysical datasets, using techniques established by Rose et al.  and Jord [et al. , the imp5.et al. [Research undertaken in the last 4 years has expanded our knowledge of subglacial hydrology considerably and has also allowed a number of new research questions to be framed. Wright & Siegert  and Wriget al. ,14 list et al.  also deset al. [The notion of ‘active’ subglacial lakes has provoked speculation that subglacial lake water at the centre of the ice sheet is able to flow to the margin. While direct evidence for such flow will obviously be difficult to acquire, Wright et al.  have shoet al.  and, whiAnother unknown is the size and nature of the basal water bodies that are responsible for ice-surface elevation changes. Research to date points to much smaller water bodies than originally depicted, but more work is needed to fully appreciate the hydrological processes responsible for the surface observations.et al. [The traditional view of Antarctic subglacial hydrology is to consider the ice-sheet bed as being impermeable. This is almost certainly not the case and there is every possibility that groundwater exists across large portions of the continent. Indeed ice-sheet modelling has pointed to groundwater as being critical to maintaining the flow of ice streams in the Siple Coast . Furtheret al.  postulatet al. . The rea


Manual therapy has long been a component of physical rehabilitation programs, especially to treat those in pain. The mechanisms of manual therapy, however, are not fully understood, and it has been suggested that its pain modulatory effects are of neurophysiological origin and may be mediated by the descending modulatory circuit. Therefore, the purpose of this review is to examine the neurophysiological response to different types of manual therapy, in order to better understand the neurophysiological mechanisms behind each therapy's analgesic effects. It is concluded that different forms of manual therapy elicit analgesic effects via different mechanisms, and nearly all therapies appear to be at least partially mediated by descending modulation. Additionally, future avenues of mechanistic research pertaining to manual therapy are discussed. Manual therapy has been a component of physical rehabilitation programs since as early as 400 BC . Since iβ fibers that inhibit nociceptive input from Aδ and C afferent fibers [Melzack and Wall  were thet fibers , 10. Howt fibers –19. Whatt fibers  and plact fibers –27 is alβ-endorphins are EO peptides that have not only been shown to have a comparable analgesic effect to morphine [morphine , but aremorphine . Diffusemorphine  and Le Bmorphine  found thmorphine , 33, andmorphine . It has morphine .Previous reviews have noted potential descending modulatory mechanisms, an endogenous opioid response, in both physical therapy  and physIn order to investigate the neurotransmitters associated with a descending inhibitory response to manual therapy, PubMed was searched using the following query:  AND  NOT (“labor” OR “cardiac” OR “uterus” OR “milk”) in November 2015. All relevant studies and reviews that were written in English were included, with the exception of those that were retracted. Animal studies were included, as they may provide further insight into mechanisms that may not be ethical to directly measure in humans; for example, utilizing brain biopsies to observe receptor activity. The general methods and important findings pertaining to descending pain modulatory systems were described.Through the millennia, numerous types of manipulation therapies have been developed and advocated, and have been purported to cure everything from scarlet fever and diphtheria to hearing loss . Howeverβ-endorphin and N-palmitoylethanolamide (PEA), an endogenous analog of arachidonylethanolamide (AEA), or anandamide, an endocannabinoid, were observed 30 minutes after treatment; at 24 hours, similar biomarker changes from baseline were found. Subjects with chronic low back pain presented greater biomarker alterations following OMT than the control (asymptomatic) group. However, because no true control or sham group was utilized, it is not possible to distinguish whether these changes in biomarkers were due to the placebo effect or something greater, as endocannabinoids are implicated in placebo-induced analgesia [Degenhardt et al.  recruitenalgesia , though In a blinded, randomized control trial, McPartland et al.  investigβ-endorphin levels in the experimental group (n = 9) who, following a 20-minute relaxation period, underwent a procedure intended to mobilize the upper cervical spine through “joint play maneuvers” [β-endorphin levels were taken at −20, −15, +5, +15, and +30 minutes prior to and following the intervention, and effects were determined via an analysis of variance. Neither the sham group (n = 9), which underwent the same joint play manipulation but without the thrusting maneuver , nor the control group (n = 9) experienced such an increase in plasma β-endorphin concentration. However, two subsequent studies demonstrated findings contradicting those of Vernon et al. [β-endorphin concentrations in experimental groups with respect to sham and control groups following spinal manipulation. Sanders et al. [β-endorphin levels across all time points. Christian et al. [β-endorphin assays. Relevant methodological differences between the investigations of Christian et al. [n = 10) and symptomatic (n = 10) groups that received the experimental spinal manipulative therapy (SMT) protocol and asymptomatic (n = 10) and symptomatic (n = 10) groups that received the sham SMT procedure. Experimental and sham SMT procedures employed by Christian et al. [n = 6) from the aforementioned two include the region of the spine considered , the application of light touch to the affected area in the sham group as opposed to joint play of any kind, and the population sampled. Unlike Christian et al. [A number of studies have investigated the pain modulation mechanisms of spinal manipulation, which, as the name implies, is specific only to spinal articulation. The first to do so were Vernon et al. , who founeuvers” , during n et al. : Christin et al.  and Sandn et al.  both fais et al.  drew blos et al. , an analn et al.  drew thrn et al.  describen et al.  and Vernn et al.  include n et al. : asympton et al.  and Vernn et al.  were iden et al.  and Sandn et al. , no contn et al. . Methodon et al.  study  and thoracic manipulations (n = 10) to a control group (n = 10) in a single-blind, randomized study of graduate student subjects who responded to university-placed advertisements. Cervical manipulations consisted of a high-velocity, mid-range, and leftward rotary thrust about the C4 and C5 vertebrae of the supine subject. Thoracic manipulations consisted of a high-velocity, end-range force applied in the anteroposterior plane to T3-4/T4-5 articulations. Blood was collected from the cephalic vein of each subject before, immediately after, and two hours following the intervention. Both cervical and thoracic groups saw decreases in neurotensin and oxytocin, as well as increases in orexin A plasma concentrations following respective interventions.Recently, Plaza-Manzano et al.  comparedMultiple reviews have also investigated the pain modulating mechanisms of spinal manipulation , 45 and γ-aminobutyric acid (GABAA) receptors in the spinal cord. Knee manipulations employed consisted of the movement of the tibia on the fixed femur. For a duration of three minutes, the joint was flexed and extended across its full range of motion while the tibia was made to translate in the anteroposterior plane. One minute was allowed for rest between each of the three manipulation sessions. Using a model of capsaicin-induced hyperalgesia and the systematic introduction of GABAA, opioid, α2-adrenergic, 5-HT1/2, 5-HT1A, 5-HT2A, and 5-HT3 receptor inhibitors, the authors determined that the analgesic effects of knee joint manipulation were not impacted by the spinal blockade of opioid or GABAA receptors but were impacted by the blockade of 5-HT1A and α2-adrenergic receptors. It was therefore posited that descending inhibition following knee joint manipulation may be modulated by serotonergic and noradrenergic mechanisms. No attempt has been made to replicate these findings in humans.Skyba et al.  investigThere is evidence to support that, in male, Swiss mice, ankle mobilization-induced analgesia is mediated by EO, endocannabinoidergic, and adenosinergic pathways –50. All Importantly, Martins et al.  noted thFurther research by Martins et al.  investigPaungmali and colleagues have studied Mulligan's Mobilization with Movement (MWM) in lateral epicondylalgia , 56. Tweproven to be clinically effective,” at least in the reduction of pain.Neural mobilization (NM) is a type of therapy that purports to relieve adverse neural tension, using methods such as nerve gliding and neural stretching. A systematic review put forth by Ellis and Hing  highlighn = 5) and Western blot assays of the PAG, the authors examined the brains of the rats for μ-, δ-, and κ-opioid receptor expression potentially resulting from the neurodynamic intervention. The NM protocol adopted by the investigators is as follows: rats in the experimental group were anesthetized and placed on their left sides such that the side affected by the CCI (the right) could be manipulated freely; rats in the sham group were just anaesthetized. With the right knee remaining fully extended throughout the session, the investigators flexed the right hip to 70–80° (absolute) until the hamstrings produced a light resistance. At this point, the right ankle was dorsiflexed 30–45° relative to its resting position until a similar resistance (presumably from the gastrocnemius) was detected by the manipulator. Following the establishment of minimal resistance in the manipulated joints, oscillations of the right ankle, wherein the joint was dorsiflexed to 30–45° repeatedly from resting, were initiated. The oscillations were carried out every other day for two minutes, each at 20 oscillations/min with 25-second pauses between them. A total of 10 sessions were completed. Apart from the experimental group (CCI + NM), four other groups were considered. These included “naïve” control, CCI only, sham, and sham + NM groups. Researchers did not find changes in δ- or μ-opioid receptor expression following the intervention; however, κ-opioid receptor expression underwent a significant, 17% increase. These data indicate that the analgesic effects reported by those treated with neural mobilization may be mediated by EOs that act on κ-opioid receptors, such as dynorphin A and subtypes thereof.Under the hypothesis that the EO system mediates the reversion of neuropathic pain following neurodynamic treatment and an earlier study suggesting that glial cells and neural growth factor may be involved in the analgesia associated with neural mobilization , Santos β fibers, which inhibit nociceptive input from Aδ and C afferent fibers [Massage therapy is often sought for both pleasure and therapy. It has been proposed to work through the gate control theory of pain , initialt fibers , 10. Deet fibers . Therefo12 and subcostal strokes, giving rise to “sharp, cutting” sensations in the subjects. Following this, 10 minutes was spent treating more local areas of pain specific to each subject using the same stroke length and pressure as applied to the initially treated region. Following the termination of massage treatment and an unspecified storage time on ice , blood samples were centrifuged and processed using an assay designed specifically to detect human β-endorphin (New England Nuclear β-endorphin 125I radioimmunoassay). Blood work reportedly indicated a statistical increase in plasma β-endorphin levels following connective tissue massage, similar to the time course observed in acupuncture and to the magnitude observed during exercise. These results are indicative of a CPM response, which modulates pain through descending inhibition.Connective tissue massage is intended to both decrease pain and increase range of motion . In the  or a saline substitute. No indication of exactly how many of the five rats received naloxone versus saline was provided by the authors. Assessments of antinociception consisted of tail-flick latency tests in which the distal portion of the rats' tails was subjected to a current-containing, tungsten wire heated to 75 ± 5°C. These assessments were performed 10 minutes prior, 10 minutes into, and 20 minutes following the acupressure procedure. Trentini et al. [ saline versus those injected with naloxone, indicating possible EO-mediated nociception resulting from acupressure at the acupoint. These results are internally substantiated by the authors' establishment of a statistically greater tail-flick latency in experimental trials as opposed to sham and control trials, which remained at or below baseline for the duration of the assessment.Using naloxone in male and female Sprague-Dawley rats, Trentini et al.  suggestei et al.  found stβ-endorphin levels were not observed in follow-up research in humans [β-endorphin levels remain unclear. It is also worth noting that both groups of investigators discussed here applied experimental, sham, and control treatments on the same groups of subjects. It was specified by Fassoulaki et al. [Despite the findings of Trentini et al. , changesn humans  followinn humans , Fassouln humans  only invi et al.  that eaci et al.  providedβ-endorphin or β-lipotropin levels following a 30-minute back massage. The possibility of oxytocinergic mechanisms in massage-like stroking in rats was investigated by Agren et al. [d = 0.89) in plasma oxytocin was observed five minutes after massage, which returned to baseline after 30 minutes. Bello et al. [β-endorphin in the massage group relative to the control group. Importantly, a larger sample size was incorporated here, relative to the other studies , so the findings of Morhenn et al. [Regular massage, consisting of effleurage and other common techniques, has been well studied, but its effects are still not completely understood. Day et al.  were then et al. , who tesn et al. . Particio et al.  also obso et al. . Similaro et al. , who comn et al.  may be mSince then, two studies have found that massage increases urine concentration of dopamine and serotonin , 74, sugThe longitudinal effects of massage on select catecholamines and neuropeptides have also been investigated. Hart et al.  treated Corticotropin releasing factor (CRF) acts on the locus coeruleus and is associated with analgesic responses, possibly due to the role of the locus coeruleus in modulating ascending and descending pain pathways . Therefo or both hands and lower arms. The control group received the same amount of attention but was not touched. Plasma oxytocin levels experienced no statistical changes over the course of therapy in either group; however, a 47.6% decrease in oxytocin in the massage group over the treatment period was observed [In a randomized-controlled trial in women with breast cancer, subjects received ten twenty-minute effleurage massage treatments over three to four weeks. These treatments were applied to either both feet and lower legsobserved .Recently, Tsuji et al.  carried  and one versus two times per week, for five weeks, on a number of neuroendocrine measures, including arginine vasopressin and oxytocin. In the acute trial, a larger decrease in arginine vasopressin was found relative to the touch group, but no statistical differences were observed for oxytocin [ d effect sizes are presented relative to the touch (control) group. Following the final intervention, the once per week group experienced negligible effects for oxytocin (−0.14). The twice per week group, following the final intervention, noted increased levels of oxytocin (0.50). Preceding the final intervention, negligible increases in oxytocin were noted (0.05) for the once per week massage group. A large effect was observed in the twice per week group for oxytocin (0.92) following the final intervention [Further longitudinal and acute work has been done by Rapaport et al.  and Rapaoxytocin . In the rvention .From the aforementioned studies, it appears clear that oxytocin plays a role in the analgesic response following conventional massage therapy, but the role of other neuropeptides is unclear.Being that the analgesic effects of both human touch  and placNearly all types of manual therapy have been shown to elicit a neurophysiological response that is associated with the descending pain modulation circuit; however, it appears that different types of manual therapy work through different mechanisms . For exaFor some therapies, such as manipulation, a minimal amount of force may be required for an analgesic effect , but wheDespite the large popularity and long history of manual therapy, its mechanisms are not truly understood. Understanding these mechanisms may help researchers and clinicians to choose which therapy is most appropriate for each patient or subpopulation and may also lead to more effective therapies in the future.


Liver diseases are a worldwide medical problem because the liver is the principal detoxifying organ and maintains metabolic homeostasis. The liver metabolizes various compounds that produce reactive oxygen radicals (ROS). Prooxidants are ROS which can cause tissue liver damage and whose levels may be increased by certain drugs, infection, external exposures, tissue injury, and so forth. Oxidative stress can result from an increase in prooxidant formation or a decrease or deficiency in antioxidants. Molecular redox switches and oxygen sensing by the thiol redox proteome and by NAD/NADP and phosphorylation/dephosphorylation systems are bias involved in signaling, control, and balance redox of a the liver system.β (TGF-β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α).Because of their reactivity, ROS readily interact with all cellular macromolecules. ROS cleave the phosphodiester bonds holding bases in RNA and DNA together, breaking the chain structure of RNA and DNA. Polyunsaturated fatty acids are also a major target for oxidation by ROS, in a process called lipid peroxidation that disrupts normal membrane structure leading to necrosis. In addition, ROS, especially the hydroxyl radical, oxidize the SH group of cysteine residues of proteins to the disulfides or to the sulfoxide or the sulfonic acid; since enzymatic activity depends on cysteine, enzymes are inactivated by ROS. Also oxidative stress contributes to fibrogenesis by increasing harmful cytokines such as transforming grown factor-2O2-dependent oxidation of thiol residues. These transcription factors subsequently activate many genes, some of which code for cellular antioxidants. Thus, low levels of ROS can cover up for high levels of ROS. Endogenous  or exogenous antioxidants (mainly from diet) inhibit either formation of ROS or remove/scavenge the generated radicals. Due to the central role of oxidative stress on liver disease, this special issue was devoted to its implication in hepatic health and disease.However, ROS are not always the bad guy; important transcription factors such as Nrf2, NF-kB, and AP-1 are activated by Hα-Adrenergic Signaling”) found that the sympathetic nervous system allows oxidative stress to damage the liver, thus suggesting that targeting the hepatic α-adrenergic signaling may provide a therapeutic approach to fight liver disease. Obesity associated with excessive alcohol consumption produces fatty liver; in this regard. Professor M.-C. Gutiérrez-Ruiz et al. from Mexico  found that the combination of ethanol and cholesterol in vitro produced a potent damage in steatotic hepatocyte. From Italy, Professor A. Galli et al.  provided us with a very original review about the evolving concept of oxidative stress in the cellular hepatocyte compartments, highlighting the essential mechanisms of damage caused by free radicals.From Mexico, Dr. J. Camacho et al.  reviewed the link of ion channels and oxidative stress in hepatic injury of various etiologies; the main conclusion is that such association may be useful to develop new treatments for the principal liver diseases. The group of Dr. H.-S. Lee et al. from Taiwan . In the review made by Professor R. Hernández-Muñoz et al. from Mexico , the utility of liver enzymes as markers of oxidative stress is challenged. Dr. Li et al., from Taiwan , studied the effect of ulinastatin on liver IRI and graft survival in mice and found that this compound affords significant protection to donor livers from cold IRI, probably by inhibition of proinflammatory cytokine release and modulating apoptosis.The protective effect of dietary curcumin against alcohol induced liver disease and atherosclerosis was reported by the group of Professor M. R. Lakshman et al. from Washington (in “Protective Role of Dietary Curcumin in the Prevention of the Oxidative Stress Induced by Chronic Alcohol with respect to Hepatic Injury and Anti-atherogenic Markers”). Since ischemia/reperfusion (IR) injury is still an unsolved problem in the clinical practice, efforts are being made to prevent it; in this regard, Dr. P. C. Pérez et al. from Mexico demonstrated that spironolactone reduced liver damage produced by IR by increasing IL-6 production and catalase activity (“Spironolactone Effect in Hepatic Ischemia/Reperfusion Injury in Wistar Rats”). Oligonol, a low molecular weight polyphenol derived from lychee fruit, was reported by Dr. J.-O. Moon et al., from Korea, to ameliorate CClThese authors highlight both the importance of free radicals in the development, establishment and perpetuation of liver disease, and the potential therapeutic effect of compounds that directly or indirectly interfere with the prooxidant process.Hopefully, this publication will provide a benchmark for future investigations evaluating a far greater body of basic and clinical evidence regarding the role of oxidative stress in liver health and disease as well the beneficial effect of antioxidant therapy to prevent or reverse hepatic injury.Pablo MurielPablo MurielKarina R. GordilloKarina R. Gordillo


Chronic exposure to cadmium (Cd), even at low concentrations, has an adverse impact on the skeletal system. Histologically, primary and secondary osteons as basic structural elements of compact bone can also be affected by several toxicants leading to changes in bone vascularization and mechanical properties of the bone. The current study was designed to investigate the effect of subchronic peroral exposure to Cd on femoral bone structure including histomorphometry of the osteons in adult male rats.2/L, for 90 days. Ten one-month-old males without Cd intoxication served as a control group. After 90 days of daily peroral exposure, body weight, femoral weight, femoral length, cortical bone thickness and histological structure of the femora were analysed.In our study, 20 one-month-old male Wistar rats were randomly divided into two experimental groups. In the first group, young males received a drinking water containing 30 mg of CdClP < 0.05) in Cd-intoxicated rats. These rats also displayed different microstructure in the middle part of the compact bone where vascular canals expanded into central area of substantia compacta and supplied primary and secondary osteons. Additionally, a few resorption lacunae which are connected with an early stage of osteoporosis were identified in these individuals. Histomorphometrical evaluations showed that all variables  of the primary osteons’ vascular canals, Haversian canals and secondary osteons were significantly decreased (P < 0.05) in the Cd group rats. This fact points to alterations in bone vascularization.We found that subchronic peroral application of Cd had no significant effect on body weight, femoral length and cortical bone thickness in adult rats. On the other hand, femoral weight was significantly increased (Subchronic peroral exposure to Cd significantly influences femoral weight and histological structure of compact bone in adult male rats. It induces an early stage of osteoporosis and causes reduced bone vascularization. Histomorphometrical changes of primary and secondary osteons allow for the conclusion that the bone mechanical properties could be weakened in the Cd group rats. The current study significantly expands the knowledge on damaging action of Cd on the bone. Cadmium (Cd) is considered as one of the most toxic heavy metals . Adverseet al. [Bone is one of the target organs for Cd toxicity ,4. Varioet al.  have repet al. .The damaging action of Cd on the rat skeleton during chronic exposure and its possible mechanisms have been extensively studied and reported by other researches; however, a detailed histological analysis of compact bone including histomorphometrical evaluations of primary and secondary osteons after subchronic peroral administration of Cd in rats had not been done prior to our experiment. In general, individual osteon morphology reflects changes in formation and resorption of bone, thus histomorphometrical analyses may give important information about the reorganization process in the bone also in stress situation, e.g. intoxication with various xenobiotics. Therefore, the aim of the present study was to analyse changes in macroscopical structure of femoral bones, and also in qualitative and quantitative histological characteristics of compact bone in rats subchronically exposed to Cd in their drinking water. In the case of potential alterations, the hypothesis of toxic effects of Cd on femoral bone structure, mechanical properties and vascularization of investigated bones will be described.ad libitum. We used cages Tecniplast 2154 F  which comply with the Government Regulation No. 23/2009. The cage disposed dimensions 480 × 265 × 210 mm, with a floor area 940 cm2. We used wood chips as bedding material with paper rolls which enriched the living-space of animals. The clinically healthy experimental animals were randomly divided into two groups, of ten animals each. In the first group (Cd group), young males were dosed with a daily Cd intake of 30 mg CdCl2/L in drinking water for 90 days. The second group  without Cd intoxication served as a control. The water consumption was daily monitored during the whole experiment. Since Cd absorption from the gastrointestinal tract in rats is lower than in humans [2/L in drinking water; chosen on the basis of studied literature and our previous experiments with tested dose–response effects) was high enough to reach a toxicity level but also safe enough to prevent animal mortality  [Our experiment was conducted on 20 one-month-old male Wistar rats obtained from the accredited experimental laboratory (number SK PC 50004) of the Slovak University of Agriculture in Nitra. Generally, the laboratory rat is the preferred animal for most researchers. Its skeleton has been studied extensively in various experimental protocols leading to bone loss, including hormonal interventions, immobilization, and dietary manipulations. Although there are several limitations to its similarity to the human condition, these can be overcome through detailed knowledge of its specific traits or with certain techniques . We usedn humans . The conal dose) ,20-22. Tal dose) .All procedures were approved by the Animal Experimental Committee of the Slovak Republic.et al. [et al. [At the end of 90 days, all rats were euthanized, weighed and their femurs were used for macroscopical and microscopical analyses. The right femurs were weighed on analytical scales with an accuracy of 0.01 g and the femoral length was measured with a sliding instrument. For histological analyses, the right femurs were sectioned at the midshaft of the diaphysis and the segments were fixed in HistoChoice fixative . The segments were then dehydrated in increasing grades (40 to 100%) of ethanol and embedded in Biodur epoxy resin  according to the method described by Martiniaková et al. . Transveet al. . The quaet al.  and Ricq [et al. , who claT-test was used for establishing statistical significance (P < 0.05) between Cd and control groups of rats.Statistical analysis was performed using SPSS 8.0 software. All data were expressed as mean ± standard deviation (SD). The unpaired Student’s P < 0.05) in Cd-intoxicated rats  of the thin sections. This type of bone tissue contained cellular lamellae and osteocytes without occurrence of primary and/or secondary osteons. Areas of primary vascular radial bone tissue  were also identified in anterior, posterior and lateral views. Some primary and secondary osteons were exceptionally found in anterior and posterior views near endosteal surfaces. The occurrence of the osteons (primary and secondary) was also identified in middle parts of s Figure .Figure 1The rats exposed to Cd displayed a similar microarchitecture to that of the control rats, except for the middle part of the compact bone in the medial and lateral views. In these views, primary vascular radial bone tissue occurred because vascular canals expanded from endosteal border into central area of the bone and supplanted primary and secondary osteons. Therefore, a smaller number of the osteons was observed in Cd-intoxicated rats. In these rats, we identified a few resorption lacunae near endosteal surfaces  which are connected with an early stage of osteoporosis Figure .Figure 2P < 0.05) in rats from the Cd group as compared to those of the control one.For the quantitative histological characteristics, 841 vascular canals of primary osteons, 435 Haversian canals and 435 secondary osteons were measured in total. The results are summarized in Table et al. [2+ with Cd2+ in many enzymes and transcription factors may induce aberrant gene expression, resulting in the stimulation of cell proliferation. Rat experiments indicate that oral ingestion of Cd through drinking water leads to an accumulation of Cd into the bone as it has also been observed in our study (Cd concentrations in the control and Cd groups were 0.92 ± 0.21 mg/kg dry weight (dw), 1.33 ± 0.18 mg/kg dw, respectively). In accordance with our results, Cd-induced increase in a weight of liver, kidney and spleen has also been mentioned in rats subcutaneously exposed to 2.0 mg CdCl2/kg (three days/week or daily) for 28 or 21 days, respectively [et al. [Cadmium is an environmental pollutant that causes serious toxicity in humans and animals . As a reet al. , the repectively ,28. In cWe have found no significant differences for body weight and femoral length between the both groups of rats. Similarly, no demonstrable changes in the body weight ,33 and fet al. [et al. [In general, the thickness of cortical bone is an important parameter in the evaluation of cortical bone quality and strength. According to Garn et al. , cortica [et al. , corticaet al. [Our findings from the qualitative histological analysis of compact bone in rats from the control group correspond with those reported by other researches -38. The et al.  for thirsubstantia compacta  in rats from the Cd group, where primary vascular radial bone tissue was found. Formation of this type of bone tissue may be explained as an adaptive response of the bone to Cd toxicity in order to protect bone tissue against death of cells and subsequent necrosis. It is known that Cd induces apoptosis in osteoblast-like cells [et al. [On the other hand, prolonged intake of moderate dose of Cd induced changes in the middle part of ke cells -43, osteke cells ,45 and hke cells . Disappe [et al.  for ovarin vitro [Additionally, we identified a few resorption lacunae near endosteal surfaces in Cd-exposed rats which signalize an early stage of osteoporosis or a presence of an inflammatory process. However, the inflammatory process is characterized by newly built bone formation on periosteal surface   which hain vitro . It alsoin vitro  which arin vitro ,56.et al. [et al. [et al. [et al. [et al. [The vascular  canal constriction identified in rats from the Cd group could be associated with structural changes of blood vessels due to toxic effect of Cd. Each Haversian canal contains blood vessels and nerves supported by loose connective tissue . Blood vet al. , mechaniet al. -63 showeet al. . On the et al. . The impet al. . Accordi [et al.  and Stra [et al. , angioge [et al.  found th [et al. . The res [et al.  demonstret al. [All variables of the secondary osteons had also lower values in Cd-intoxicated rats. Generally, it is known that heavy metals (including Cd) are adsorbed and stored within bones . In boneet al.  showed tet al. ,76. On tet al. , the metet al. . Furtheret al. ,79.Our study demonstrates that subchronic exposure to Cd had a significant impact on femoral weight and compact bone microstructure in adult male rats. The histomorphometrical changes were identified on levels of primary osteons’ vascular canals, Haversian canals and secondary osteons. Due to increasing trend of Cd environmental contamination and human exposition, our findings are of high importance and could also have practical implications in humans. Our results with the moderate dose of Cd in rats, reflecting possible Cd exposure in humans in specific conditions, give a real indication that the same changes in bone microstructure may also occur in exposed humans. The environmental Cd contamination, as well as improper living habits, such as cigarette smoking, can lead to damages and diseases of bones. Identifying environmental factors (such as Cd) and possible mechanisms that contribute to bone loss, decreased bone vascularization and weakening of mechanical bone properties is the first step to prevention of skeletal damages in humans.2/L in drinking water for 90 days has the significant impact on femoral weight and both the qualitative and quantitative histological characteristics of compact bone in adult male rats. It induces an early stage of osteoporosis, alterations in bone vascularization and potentially diminished bone mechanical properties. Our study can be involved in creation a comprehensive novel insight into bone toxicology in experimental animals.The current study revealed that subchronic peroral administration of 30 mg CdCl


Extracorporeal shock wave therapy has been reported as an effective treatment for lower limb ulceration. The aim of this systematic review was to investigate the effectiveness of extracorporeal shock wave therapy for the treatment of lower limb ulceration.d) from means and standard deviations.Five electronic databases  and reference lists from relevant studies were searched in December 2013. All study designs, with the exception of case-reports, were eligible for inclusion in this review. Assessment of each study’s methodological quality was performed using the Quality Index tool. The effectiveness of studies was measured by calculating effect sizes . Improvements in wound healing were identified in these studies following extracorporeal shock wave therapy. The majority of wounds assessed were associated with diabetes and the effectiveness of ESWT as an addition to standard care has only been assessed in one randomised controlled trial.Considering the limited evidence identified, further research is needed to support the use of extracorporeal shock wave therapy in the treatment of lower limb ulceration.The online version of this article (doi:10.1186/s13047-014-0059-0) contains supplementary material, which is available to authorized users. Lower limb ulceration is reported as a common problem world-wide, and is considered a major social and economic burden . Lower lThe use of extracorporeal shock waves in medicine was first reported over 30 years ago as a treatment for kidney stones , and is Despite the reported success of ESWT for the treatment of lower limb ulceration, the quality of evidence investigating the effectiveness of this intervention has not been reviewed in detail. Therefore, the aim of this review was to investigate the effectiveness of ESWT for the treatment of lower limb ulceration.All studies included in this review were obtained from English-language peer reviewed scientific journals investigating the effectiveness of ESWT for lower limb ulceration. All study designs, with the exception of case-reports, were eligible for inclusion in this review. Letters to the editor, opinion pieces and editorials were also excluded.Studies were included if the use of ESWT for the treatment of lower limb ulceration was assessed. The category of ulcers included in this review were those of neurovascular origin . Studies where the participant’s ulcer was associated with pressure sores, burns or surgical complications were excluded.In December 2013 an electronic database search was conducted using Medical Subject Headings (MeSH), followed by a keyword search strategy. Auto-alerts were developed to provide updates on recent publications until the review was finalised (March 2014). The following databases were searched: Ovid MEDLINE (1966 to date), CINAHL (1982 to date), Web of Knowledge, Scopus and Ovid AMED (from inception). The database search strategy is presented in Table Upon completion of the search (March 2014), a hand search was performed of references from the studies identified in the electronic search, and Google Scholar was searched in an attempt to identify any further material. Two reviewers (PAB and TPW) then independently reviewed titles and abstracts according to the pre-determined inclusion criteria. Discrepancies between reviewers regarding eligibility were discussed until consensus was reached. Progression to full text review was then permitted.p values) were extracted from studies by two investigators (PAB and TPW), with specific attention to the following variables; study design, participant numbers, mean age, sex, ulcer classification, change in healing and ulcer size and ESWT protocol used. The data pertaining to each study was then assigned a numerical value to ensure the two investigators (PAB and TPW) were blinded to author and publication details during quality assessment. Where disagreements occurred during the quality assessment process, a third assessor (YDP) made the final decision on quality assessment scores. Where studies provided sufficient statistical data, effect size (Cohen’s d) was calculated from means and standard deviations. Effect sizes were categorized as follows: negligible effect (≥ − 0.15 and <0.15); small effect (≥0.15 and <0.40); medium effect (≥0.40 and <0.75); large effect (≥0.75 and <1.10); very large effect (≥1.10 and <1.45) and, huge effect (≥1.45) [A predefined data extraction form was used in the extraction process  ,20.r = 0.88) and good inter-rater reliability (r = 0.75). The Quality Index tool consists of 27 items, and allows for assessment of internal and external validity, reporting and power.Assessment of each study’s methodological quality was performed using the Quality Index tool developed by Downs and Black . This toa priori decision was made to remove two items where they did not apply to the respective studies identified. Firstly, Item 25 was removed for non-randomised controlled studies, as it has been shown that case mix adjustment cannot reduce the extent of bias in non-randomised trials [For this systematic review, an d trials . SecondlWe chose to present the quality assessment results as percentage scores, which is typical of previous studies using the Quality Index tool ,23-24. FA total of 555 results were identified through our electronic search .Table et al.  found thet al. [Saggini et al.  treated et al. [p = 0.001. Furthermore, greater than 50% improvement of the ulcer was observed in 89% of participants in the ESWT group and 72% of participants in the HBO group (p < 0.001). In their second study comparing ESWT and HBO, Wang et al. [p = 0.003); ≥ 50% improved ulcers in 32% and 15% (p = 0.071), and unchanged ulcers in 11% and 60% (p < 0.001) respectively.Wang et al.  found thg et al.  found: cet al. [p = 0.001). Furthermore, arterial insufficiency ulcers did not completely heal in 33% of cases, the second worst healing rate of all ulcer types. The primary outcome assessed in their study was the safety and feasibility of using ESWT on wounds, the authors concluding that ESWT is a safe and effective treatment.Schaden et al.  found thThe aim of this systematic review was to investigate the effectiveness of ESWT for the treatment of lower limb ulcers. We evaluated five studies in this review, and identified a trend to suggest that ESWT may be effective in improving wound healing and decreasing wound size. Furthermore, ESWT may also be a safe treatment option with few complications associated with its use, however; we found average study quality for the studies identified. External validity across studies was rated most poorly, due to deficient definitions of the source population and methods of patient selection, and poor identification of confounding factors. It is difficult therefore, to generalise the findings of the studies to the populations from which the study participants were derived. Furthermore, it is unknown whether participants were representative of the population from which they were recruited. As such, all five studies performed poorly on the external validity questions, scoring a mean of only 27% for questions 11 to 13 on the quality Index tool.et al. [et al. [All studies also rated poorly on the internal validity component of the Quality Index (questions 14 to 26). For example, Moretti  [et al. , the autet al. [et al. [et al. [et al. [et al. [et al. [et al. [The internal validity of the studies identified may also have been threatened due to a loss of participants during the study. While Moretti et al.  and Sagg [et al.  suggeste [et al.  describe [et al.  describe [et al. ,29, grou [et al.  made an  [et al.  were notet al. [2. Although Moretti et al. [et al. [et al. [et al. [et al. [The classification of ulceration varied across the five studies identified in this review. Moretti et al.  defined i et al.  made an  [et al.  included [et al.  defined  [et al. ,29 inclu [et al. ,29, and  [et al. , there wet al. [et al. [et al. [et al. [The ESWT protocol varied between studies resulting in study heterogeneity, making comparison difficult. Specifically, there were differences in the duration, frequency and strength of ESWT application identified between studies. Furthermore, these differences were also noticeable within studies. For example, a repeat course of treatment was performed in cases with incomplete healing from the first course of treatment in the study by Wang et al. . Moreove [et al.  and Scha [et al.  was depe [et al. , particiThis systematic review has identified a number of important implications for future research. Firstly, to reduce bias it is essential that when evaluating the effectiveness of ESWT for the treatment of lower limb ulceration, that rigorous randomised controlled trial (RCT) methods are used ,31. SecoThe existing evidence that supports the use of ESWT for treatment of lower limb ulceration therefore needs to be viewed in light of some limitations. Firstly, there were only two studies (one of which was an RCT) that investigated the effect of ESWT versus standard treatment, and there were small participant numbers in the studies identified. Secondly, this review identified significant methodological heterogeneity between studies. For example; one of the studies in this review included smokers and also assessed ulceration associated with multiple comorbidities , whereasThis systematic review identified five studies that reported on the effectiveness of ESWT for the treatment of lower limb ulcers. There is limited evidence to support ESWT as a treatment for lower limb ulceration. Considering this, further research is needed to support the use of ESWT in the treatment of lower limb ulceration.


In recent years there have been monumental and exciting advances in the treatment of retinal disease which made a special issue on advances in retinal therapeutics relevant and interesting. Indeed, in this issue there are 11 papers reporting either original basic or clinical research findings or reviewing the literature and reporting recent developments.The papers in this issue are on a wide range of topics. J. He et al. present original basic research in elucidating the effects of VEGF receptor 1 blockade on diabetic retinopathy while M. L. Perepechaeva et al. present original basic research identifying a potential novel target for the treatment of age-related macular degeneration in a rodent animal model of the disease. O. Chrapek et al. present original clinical research identifying occult CNVM and lesion size less than 5 disc diameters as baseline characteristics predicting inactivity after 3 injections of an intravitreous anti-VEGF agent (ranibizumab) for neovascular age-related macular degeneration (nARMD). S. M. Prea et al. review endogenous inhibitors of nARMD as well as the principles of gene therapy that could use such inhibitors to treat nARMD clinically. There are 2 papers discussing advances in retinal laser treatment—one by Y. G. Park et al. discussing developments on laser photocoagulation for diabetic macular edema and another by K. Inagaki et al. discussing micropulse laser for persistent macular edema from branch retinal vein occlusion in eyes which includes eyes with good visual acuity at baseline. Two additional papers address vitreoretinal surgery topics: one by Dr. C. Pournaras et al. that reports on the outcomes of repair of recurrent retinal detachment, including presenting visual outcomes which are not uncommonly omitted in prior publications and the other paper by A. García-Layana et al. that reviews the current treatment of vitreomacular traction and macular hole. The paper by M. Harrell and P. E. Carvounis is an up-to-date evidence-based review of the treatments of toxoplasma retinochoroiditis which takes into account evidence published within the last 2 years when the previous evidence-based review was published. Finally, the paper by M. Cabrera et al. reviews the 3 sustained-release corticosteroids available for the treatment of retinal disease.The 54 authors and coauthors should be commended for the quality of their manuscripts; the science as well as the writing is of high caliber. It is our belief that the readership of the Journal of Ophthalmology will enjoy reading the papers in this special issue as much as we did.Petros E. CarvounisPetros E. CarvounisThomas A. AlbiniThomas A. AlbiniAndrew J. BarkmeierAndrew J. BarkmeierMiltiadis TsilimbarisMiltiadis Tsilimbaris


Sit's name was originally spelled incorrectly, and Dr. Ng's degree was listed incorrectly. The article has since been corrected online.In the article “Acupuncture and Related Therapies for Symptom Management in Palliative Cancer Care: Systematic Review and Meta-Analysis”,


Root canal irrigants play a significant role in elimination of the microorganisms, tissue remnants, and removal of the debris and smear layer. No single solution is able to fulfill all these actions completely; therefore, a combination of irrigants may be required. The aim of this investigation was to review the agonistic and antagonistic interactions between chlorhexidine (CHX) and other irrigants and medicaments. An English-limited Medline search was performed for articles published from 2002 to 2014. The searched keywords included: chlorhexidine AND sodium hypochlorite/ethylenediaminetetraacetic acid/calcium hydroxide/mineral trioxide aggregate. Subsequently, a hand search was carried out on the references of result articles to find more matching papers. Findings showed that the combination of CHX and sodium hypochlorite (NaOCl) causes color changes and the formation of a neutral and insoluble precipitate; CHX forms a salt with ethylenediaminetetraacetic acid (EDTA). In addition, it has been demonstrated that the alkalinity of calcium hydroxide (CH) remained unchanged after mixing with CHX. Furthermore, mixing CHX with CH may enhance its antimicrobial activity; also mixing mineral trioxide aggregate (MTA) powder with CHX increases its antimicrobial activity but this may negatively affect its mechanical properties. Chlorhexidine (CHX) is a synthetic cationic bisguanide consisting of two symmetric 4-cholorophenyl rings and two biguanide groups, connected by a central hexamethylene chain . It is uThis increases the permeability of the cell wall, which allows the CHX molecule to penetrate into bacteria. CHX is a base and is stable in the salt form. The most common oral preparation, CHX gluconate, is water-soluble and at physiologic pH level it readily dissociates and releases the positively charged CHX component . At low Different endodontic agents used as intracanal medicaments or irrigants may interact with CHX. For instance, interaction of sodium hypochlorite (NaOCl) mixed with chlorhexidine (CHX) produces a brown precipitate containing para-chloroaniline (PCA) which is not only toxic but also interferes with canal sealing . RegardiExposure to CHX decreases the push-out bond strength of mineral trioxide aggregate (MTA) to dentin . HoweverChelating agents such as ethylenediaminetetraacetic acid (EDTA) can interact with CHX, as it is shown that subsequent use of CHX, NaOCl and EDTA can cause a color change in dentine .The aim of the present critical review is to determine the interaction between CHX and different endodontic agents according to the results of previous studies published from 2002 to 2014.Retrieval of literatureAn English-limited Medline search was performed through the articles published from 2002 to 2014. The searched keywords included “chlorhexidine AND sodium hypochlorite (NaOCl)”, “chlorhexidine AND ethylenediaminetetraacetic acid (EDTA)”, “chlorhexidine AND calcium hydroxide (CH)”, and “chlorhexidine AND mineral trioxide aggregate (MTA)". Then, a hand search was done in the references of collected articles to find more matching papers.A total of 1095 articles were found which in order of their related keywords are “567-chlorhexidine AND NaOCl”, “255-chlorhexidine AND EDTA”, “252-chlorhexidine AND CH” and “21-chlorhexidine AND MTA".Combination of irrigants and medicaments with CHXDespite having important useful properties, CHX possesses some drawbacks as well. One of its important drawbacks is lacking tissue solubility, which is one of the most important properties of a standard irrigation solution . Therefoa) irrigation with NaOCl to dissolve the organic components, b) irrigation with EDTA to assist in the elimination of the smear layer and finally, c) irrigation with CHX to increase the anti-microbial spectrum of activity and impart substantivity.A suggested clinical protocol by Zehnder  for dentEnterococcus faecalis  and Candida albicans  are the main causes of treatment failure, CH is ineffective against these two species [Studies have demonstrated that in retreatment cases where microbial species like  species . TherefoInteraction between CHX and NaOClThe combined use of NaOCl and CHX has been advocated to enhance their antimicrobial properties. In other words, a final rinse with CHX offers the advantage of substantivity (due to its affinity to dentine hydroxyl apatite) which prolongs the antimicrobial activity of CHX . HoweverA study used electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-QTOF-MS) analyses to investigate the byproducts formed after combination of CHX and NaOCl . Findinget al. [et al. [It seem that the oxidizing activity of NaOCl causes chlorination of the guanidino nitrogens of the CHX . Basraniet al.  detectedet al. , 18, 19.et al. . Some coet al. . Basrani [et al.  tested c [et al. .et al. [et al. [Studies have been undertaken to elucidate the chemical composition of the flocculate produced by the association of NaOCl with CHX -21. Marcet al.  combined [et al. , showed et al. [et al. [et al. [et al. [Krishnamurthy and Sudhakaran  detectedet al.  showed tet al. . Findinget al. . Using S [et al.  assessed [et al.  compared [et al.  showed t [et al. .In summary, the combination of NaOCl and CHX causes color changes and the formation of a neutral and insoluble precipitate, which may interfere with the seal of the root filling. Therefore, drying the canal with paper points before the final CHX rinse is suggested.Interaction between CHX and chelatorsin vitro study on bovine dentin slices using atomic absorption spectrophotometry, Gonzalez-Lopez et al. [In an z et al.  assessedz et al. .et al. [et al. [et al. [et al. [et al. [Akisue et al.  showed t [et al.  and Rasi [et al.  demonstr [et al.  showed t [et al.  showed t [et al. .In summary, CHX forms a salt with EDTA rather than undergoing a chemical reaction.Interaction between CHX and CHThe optimal antimicrobial activity of CHX is achieved within a pH range of 5.5 to 7.0 . TherefoE. faecalis harbored within the dentinal tubules [et al. [E. faecalis from the dentinal tubules; a 1% gel CHX worked slightly better than the other preparations. These findings were corroborated by Gomes et al. [. faecalis, followed by liquid CHX and CH and then CH used alone. Using agar diffusion test, Haenni et al. [et al. [E. faecalis inside human dentinal tubules, followed by a CH mixed with 2% CHX, whilst CH alone was totally ineffective, even after 30 days. The 2% gel CHX was also significantly more effective than the CH and 2% CHX mixture against C. albicans at seven days, although there was no significant difference at 15 and 30 days. CH alone was completely ineffective against C. albicans. In another study on primary teeth, 1% CHX gluconate gel with and without CH, was more effective against E. faecalis than CH alone within a 48-h period      [When used as an intracanal medicament, CHX was more effective than CH in eliminating  tubules , 30. In  [et al. , all of s et al.  in bovins et al.  in humani et al.  could noi et al. . This mai et al. . Ercan e [et al.  showed tiod      .E. faecalis than CH used alone, or a mixture of the two. This was also confirmed by Lin et al. [et al. [et al. [et al. [C. albicans than saturated CH, while CH combined with CHX was more effective than CH used alone.Schafer and Bossmann  reportedn et al. . In a st [et al.  using bo [et al.  reported [et al.  reportedIn summary, combined use of CHX and CH in the root canal may generate excessive reactive oxygen species, which may potentially kill various root canal pathogens. In addition, it has been demonstrated that the alkalinity of CH when mixed with CHX remained unchanged. Furthermore, mixing CHX with CH may enhance its antimicrobial activity.Interaction between CHX and MTAMTA is marketed in gray and white colored preparations: both contain 75% Portland cement, 20% bismuth oxide and 5% gypsum by weight. MTA is a hydrophilic powder which requires moisture for setting. Traditionally, MTA powder is mixed with supplied sterile water in a 3:1 powder/liquid ratio. Different liquids have been suggested for mixing with the MTA powder such as lidocaine anesthetic solution, NaOCl and CHX .et al. [et al. [et al. [Stowe et al.  determin [et al. . Hernand [et al.  comparedet al. [et al. [in vitro. Kogan et al. [et al. [et al. [Cell cycle analysis showed that exposure to MTA/CHX decreased the percentage of fibroblasts and macrophages in S phase (DNA synthesis) as compared with exposure to MTA/water. On the other hand, Sumer et al.  examined [et al.  found thn et al.  found th [et al.  found th [et al.  evaluateOverall, it can be concluded that mixing MTA powder with CHX increases its antimicrobial activity but may have a negative effect on its mechanical properties.


Bioconversion of lignocellulosic biomass to bioethanol has shown environmental, economic and energetic advantages in comparison to bioethanol produced from sugar or starch. However, the pretreatment process for increasing the enzymatic accessibility and improving the digestibility of cellulose is hindered by many physical-chemical, structural and compositional factors, which make these materials difficult to be used as feedstocks for ethanol production. A wide range of pretreatment methods has been developed to alter or remove structural and compositional impediments to (enzymatic) hydrolysis over the last few decades; however, only a few of them can be used at commercial scale due to economic feasibility. This paper will give an overview of extrusion pretreatment for bioethanol production with a special focus on twin-screw extruders. An economic assessment of this pretreatment is also discussed to determine its feasibility for future industrial cellulosic ethanol plant designs. Biomassstimated . Lignocestimated .Lignocellulosic biomass can be converted into fermentable sugars for fermentative ethanol production. However, this bioconversion is further complicated due to recalcitrance caused by the association of cellulose, hemicelluloses and lignin in the biomass . CelluloA large number of pretreatment methods have been proposed generally on a wide variety of lignocellulosic biomasses for bioethanol production since different feedstocks have different physical-chemical characteristics. These pretreatment methods are usually divided into physical, chemical, physical-chemical and biological, such as steam explosion , dilute Extrusion is defined as an operation of creating objects of a fixed, cross-sectional profile by forcing them through a die of the desired cross-section. The material will experience an expansion when it exits the die. The extrusion process has been expanded as one of the physical continuous pretreatment methods towards bioethanol production due to its significant improvements of sugar recovery from different biomass feedstocks. Extrusion pretreatment has some advantages over other pretreatments: (1) low cost and provides better process monitoring and control of all variables ; (2) no A screw extruder is based around screw elements, including (1) forward screw elements, which principally transport bulk material with different pitches and lengths with the least degree of mixing and shearing effect; (2) kneading screw elements, which primarily exert a significant mixing and shearing effect with different stagger angles in combination with a weak forward conveying effect; and (3) reverse screw elements, designed with a reverse flight to push the material backward, which carries out extensive mixing and shearing effects . The arret al. [Different types of extruders, such as single-screw extruders and twin-screw extruders, have been widely examined for different lignocellulosic biomass, resulting in subsequently high enzymatic hydrolysis rates. The extrusion pretreatment process can be used as a physical pretreatment for the bioconversion of biomass to ethanol production; it also can be conducted in a large number of systems with or without the addition of chemical solutions. Karunanithy and Muthukumarappan ,30 reporet al.  evaluateLignocellulosic biomass can be treated with chemical solutions such as acid and alkali during the extrusion process ,34,35; hi.e., kneading disks [The screw extruder is a well known technology in the production, compounding, and processing of plastics; it also can be used in food processing industries, such as pet food, cereals and bread. The single screw extrusion process consists of an Archimedean screw in a fixed barrel. It can be classified as a smooth barrel, grooved and/or pin barrel screw extruder. Both are employed when melting and pressure build up are required. However, the mixing ability of single screw extruders is limited to distributive mixing and dispersive mixing  . These cng disks .i.e., co-rotating or counter-rotating for which the screws rotate in either similar or opposite directions, respectively. Twin-screw extruders can be further subdivided into fully, partial or non-intermeshing based on the relative position of the screws [Twin-screw extruders consist of two parallel screws with the same length placed in a stationary barrel section. Twin-Screw extruders can be classified according to their direction of screw rotation, e screws . In conte screws . Therefoe screws .et al. [et al. [et al. [et al. [Screw design strongly influences work done on the material and amount of shear force generated during extrusion processes such as compression ratio, screw speed and barrel temperature. Karunanithy and Muthukumarappan  conducteet al.  investiget al.  evaluate [et al.  investig [et al. . Karunan [et al.  optimize [et al.  also eva [et al.  investig [et al.  conducteFibrillation of Douglas-fir was performed using water with mechanical kneading forces instead of chemicals for biomass pretreatment in a batch type kneader with twin screw elements. Douglas-fir was milled in a ball milling for 20 min and then kneaded at 40 °C at 90 rpm in a batch-type kneader by adding water for 30 min. The results showed the surface area of cellulose was increased and the glucose yield from the fibrillated products by enzymatic hydrolysis was 54.2%, much lower than the extrusion process with chemicals .2SO4). Consequently, 38.2% of dry sawdust solids were converted to soluble liquids and 44.4% of cellulose was converted to soluble monomer sugars and oligosaccharides [Extruders can be used as an acid hydrolysis reactor. Acid pretreatment is effective for converting cellulose and hemicelluloses into monomeric sugars. For example, an extruder type reactor was used for dilute acid hydrolysis for municipal solid wastes and the optimal glucose yields reached 60% at temperatures of 230 °C, pressures of 30–32 atm, pH values of 0.50 and reaction times of 8–15 s . A twin charides . Later tcharides . The twicharides .2S). Similarly, Zhang et al. [et al. [et al. [et al. [Alkali pretreatment can be performed at a lower temperature and pressure compared to other chemical pretreatment methods. The process in the extruder also does not cause as much sugar degradation . Carr ang et al.  also evag et al.  also carg et al.  evaluate [et al.  conducte [et al.  performe [et al.  employed [et al. .et al. [et al. [et al. [Biomass extrusion can be utilized as a stand-alone pretreatment method, or in combination or sequence with other pretreatment techniques. Lee et al.  evaluateet al. . Zheng e [et al.  evaluate [et al.  investig [et al. . The ext [et al. .et al. [Many pretreatment technologies of lignocellulosic biomass have been studied to improve ethanol yield . Thermo-et al.  carried et al. [et al. [Yoo et al.  analyzedet al. . In the  [et al.  report t [et al. .et al., 2010 [et al., 2011 [The underlying assumptions of each economical model have to be carefully evaluated when comparing different pretreatment techniques, as can be illustrated by the different assumptions for the capital costs of a diluted acid process of 376 MM by Kazi l., 2010  and 191 l., 2011  made in l., 2011 . The Purl., 2011 .The main purpose of pretreatment is to remove hemicelluloses and lignin, to increase the accessible surface area for enzymes and to descrystallize cellulose. The advantages of extrusion pretreatment technologies have been listed and discussed above. However, due to the varying types of biomass, efficient and economical methods need to be developed in a feedstock-specific manner; here, a few reports of quantitative economical analyses of data of different pretreatment technologies were discussed. In this review, the feasibility and economical analysis of extrusion pretreatment offers an initial glimpse into future investigations in pretreatment technology. None of the cellulosic ethanol from extrusion pretreatment technology has been commercialized to date, and uncertainties and limitations are unavoidable in the economic analysis and comparison of conversion technologies. Therefore, identifying the economic impact of different pretreatments related to productivity, capital cost, and operating cost, as well as defined assumptions, is important when conducting an economic analysis of bioethanol to aid reliable and creditable cost predictions. Further, improvements in pretreatment, enzymatic hydrolysis, and fermentation should be studied in order to reduce production costs.