Abstract:
An apparatus for the delivery of hypoxic air to a user comprising a biofeedback means where at least one physiologically measurable parameter of the user is substantially constantly measured by a monitoring means and the measured data transmitted to a control means, where the control means comprises: i) means for comparing the measured data of the at least one physiological parameter with a pre-set target value for the parameter; and ii) adjustment means to vary the oxygen concentration in the hypoxic air delivered to the user in response to the transmitted data.

Description:
FIELD OF THE INVENTION  
       [0001]     This invention relates to improved method and apparatus for the treatment of mammals using pre-acclimatisation to a simulated altitude environment by the process of hypoxic air breathing. More specifically, the present invention relates to improved apparatus for the administration of Intermittent Hypoxic Training (IHT), which involves subjecting a mammalian user to repeated exposures of normobaric hypoxic air breathing, alternated with ambient air breathing and to a method employing the improved apparatus.  
       BACKGROUND OF THE INVENTION  
       [0002]     Pre-acclimatisation to simulated altitude conditions (reduced oxygen breathing) is known to produce a cluster of beneficial alterations to mammalian physiology. Short-term respiration with reduced oxygen air initiates a number of compensatory mechanisms in the mammalian body. A course of repeated short-term hypoxia exposures has been shown to stimulate erythropoietin and haemoglobin production, stimulate respiratory muscles and ventilation, produce hypotensive and vasodilative effects, reduce free-radical formation in the body and also increase the body&#39;s antioxidant enzymatic capacity.  
         [0003]     These physiological responses are utilised very effectively in the training and treatment of athletic users, for improved general health and wellbeing and for the treatment of various degenerative disorders found in mammals in general.  
         [0004]     The most commonly used treatment protocol for Intermittent Hypoxic Training (IHT) comprises subjecting the user to repeated exposures of hypoxic air breathing, alternated with breathing ambient or normoxic air. During a normal training course, the oxygen concentration in the hypoxic air supplied to the user is decreased gradually from 15-12% of oxygen by volume down to 8-12% of oxygen by volume in order to provide the user with a step-wise reduction so as to avoid any undesired symptoms that may arise as a result of over-training.  
         [0005]     In a normal treatment program, IHT is delivered to the user 2-7 times per week for a period of 2-4 weeks and the duration of one session is usually in the range of between 40-120 minutes.  
         [0006]     Typically, the user&#39;s physiological response is monitored over the course of treatment by a pulse oximeter, which is a device that measures arterial oxygen saturation (SpO 2 ) and heart rate (HR). Optionally, other physiological parameters may also be monitored, for instance blood pressure, heart activity by way of an electrocardiogram, etc. Careful monitoring of a user&#39;s physiological parameters allows the undesirable effects of over-dosing to be avoided.  
         [0007]     A number of systems and devices for delivery of Intermittent Hypoxic Training (IHT) have been proposed in the past including disclosures in Soviet Union Patents, SU1264949, SU1313444, SU1335294, SU950406 and SU1801440; Russian Patents RU2158610, RU2004261, RU2019199, RU2201769 and RU2115366 and U.S. Pat. Nos. 5,101,819, 5,850,833 and 6,009,870.  
         [0008]     All of the above prior devices focus on oxygen concentrations in hypoxic air as delivered to respiratory system of the user. A problem associated with each of these earlier devices is that they follow the standard pre-set approach and do not take into consideration each individual user&#39;s response thereby resulting in an inability to tailor or maximise delivery of and hence the benefits of IHT to each individual user&#39;s needs.  
         [0009]     The earlier IHT devices described in the above mentioned patents can be schematically summarised as shown in  FIG. 1 . The “Hypoxic Air Generator” produces hypoxic air, the oxygen composition in the hypoxic air is selected and set and controlled by “O 2  control” and delivered to the “User” or the “User&#39;s Respiratory System”.  
         [0010]     It has been widely accepted by workers in this field, for example, as reported by Levine B D and Stray-Gundersen J, “Living high-training low: Effect of moderate-altitude acclimatization with low-altitude training on performance,” J. Appl. Physiol. (1997) July; 83(1):102-123; Stray-Gundersen J and Levine B D “Living high and training low can improve sea level performance in endurance athletes,”. Br. J. Sports Med., (1999) June; 33(3): 150-1; Levine B. D. in “Intermittent hypoxic training: fact and fancy,” High Alt. Med. Biol. (2002) Summer; 3(2): 177-93; and Serebrovskaya T. V., “Intermittent hypoxia research in the former Soviet Union and the Commonwealth of independent States: History and review of the concept and selected applications,” High Alt. Med. Biol., (2002) Summer; 3(2): 205-21, that the optimal regime for a particular individual can readily be determined using parameters such as the timing, duration and dosage of IHT exposure. While timing and duration of the session at pre-set O 2  levels was easy to determine and control, the selection of an optimal dosage has hitherto remained the most difficult task to achieve.  
         [0011]     It is an object of the present invention to provide an improved apparatus for and method of delivery of IHT to a mammal, wherein the method overcomes or alleviates the disadvantages of the prior art.  
       SUMMARY OF THE INVENTION  
       [0012]     The present invention is directed to an apparatus for and method of IHT delivery in which the delivery of hypoxic air to the user&#39;s respiratory system is made to be directly dependent upon the individual user&#39;s physiological response. At least one of each individual user&#39;s physiological parameters, for example, his/her SpO 2 , is used to determine the oxygen concentration in the hypoxic air delivered to that particular user. This automated biofeedback allows the oxygen concentration in the hypoxic air to be continuously adjusted according to a substantially constant pre-set SpO 2  target value. Thus, a SpO 2 -driven exposure of a user to variable oxygen concentration allows the system to deliver an individually tailored exposure to each user regardless of his/her current physiological state, age, sex and other conditions.  
         [0013]     According to the present invention, there is provided an apparatus for the delivery of hypoxic air to a user comprising a biofeedback means wherein at least one physiologically measurable parameter of the user is substantially constantly measured by a monitoring means and the measured data transmitted to a control means, wherein the control means comprises: 
        i) means for comparing the measured data of the at least one physiological parameter with a pre-set target value for the parameter; and     ii) adjustment means to vary the oxygen concentration in the hypoxic air delivered to the user in response to the transmitted data.        
 
         [0016]     Preferably, the physiologically measurable parameter is selected from the group of arterial oxygen saturation (SaO 2 ), heart rate (HR), blood pressure, ECG, cardiac output, exhaled CO 2 , exhaled nitric oxide, breathing frequency, ventilation or any combination of any one or more of these parameters.  
         [0017]     More preferably, the control means further comprises data input means for entering the pre-set target value for the user; data recording means for recording the target value for the user measured by the monitoring means; data transmitting means for transmitting the recorded measured data to a data comparing means, wherein the target value of step i) is compared with the measured value of step ii); and output means for transmitting a control signal to the adjustment means in response to the compared data of step iii), wherein if the measured value is below the target value, the adjustment means increases the oxygen concentration in the hypoxic air supplied to the user or if the measured value is above the target value, the adjustment means decreases the oxygen concentration in the hypoxic air supplied to the user.  
         [0018]     The physiologically measured parameter of choice is the pulse oximeter measured arterial oxygen saturation (SpO 2 ) but may be any parameter that is suitable for the present invention.  
         [0019]     The adjustment means preferably comprises at least one variable orifice mixer, where the greater the size of the orifice the lower the oxygen concentration in the produced hypoxic air delivered to the user. The adjustment means is most preferably electronically operable.  
         [0020]     The apparatus of the invention preferably further comprises a hypoxic air generator for producing hypoxic air which is connected to the control means, where the generator responds to an output instruction received from the control means. Preferably, the hypoxic air generator comprises at least one of an air separation device or a pressure swing adsorption device to vary the oxygen concentration of the hypoxic air produced thereby.  
         [0021]     If the device used is the air separation device, this may comprise a semi-permeable membrane supported therein and a pump for pumping intake air across the membrane, wherein the membrane separates the mixture into an oxygen-reduced gas mixture which is supplied to the user and an oxygen-rich gas mixture which is vented externally of the user or which is recyclable through the air separation device. Alternatively, the air separation device comprises a pressure swing adsorption device and a pump for pumping intake air across the pressure swing adsorption device. The pressure adsorption device preferably comprises molecular sieve material, more preferably a zeolite, which absorbs nitrogen from the mixture being compressed by the pump, leaving the oxygen-rich gas mixture, which is vented externally to the user or which may be transmitted to the user as required. More preferably, when the adsorption device is depressurised, a nitrogen concentrate gas is transmitted as the oxygen-reduced gas mixture to the user.  
         [0022]     The control means of the invention further preferably comprises a flow control valve which is located inside the control means, which valve controls the flow rate of hypoxic air and thereby the oxygen concentration delivered to the user. The control valve is more preferably variable with respect to the concentration of oxygen delivered.  
         [0023]     The intake air is preferably passed through at least one other piece of equipment selected from the group of an air pump, an air dryer and a moisture trap or any combination of one or more of said equipment before being fed through the semi-permeable membrane or the pressure swing adsorption device to produce hypoxic air.  
         [0024]     In a preferred embodiment of the invention, the hypoxic air emitted from the membrane is fed into a 3/2 port switch, whereby the hypoxic air delivered to the user can be selected from hypoxic air or hyperoxic air.  
         [0025]     The apparatus of the invention further comprising a respiratory circuit comprising a reservoir or breathing bag connected to the source of hypoxic air; a blow-off valve to prevent the bag from over-inflating; a demand valve for connecting the user to the external environment thereof whereby the respiratory circuit is interrupted; and a delivery means to deliver the hypoxic air to the user.  
         [0026]     In an alternative use of the apparatus of the present invention, the first variable orifice mixer can be a fixed orifice mixer in order to keep the concentration of the oxygen in the hypoxic air emitted from the membrane substantially constant.  
         [0027]     In yet a further preferred embodiment, there is a feeder pump connected to the source of hypoxic air to create a negative pressure towards the supply or storage of hypoxic air as well as to ambient air from the external environment, such that the hypoxic air and the ambient air form a mixture suitable for use in the invention as required. More preferably, the flow rate of the air mixture emitted from the feeder pump is greater than the flow rate of the hypoxic air emitted from the hypoxic air generator, if the hypoxic air is supplied under some pressure. There is preferably a second variable orifice valve located between the 3/2 port switch and the feeder pump to facilitate the mixing of the ambient air with the hypoxic air, thereby providing further means to control the oxygen concentration of the hypoxic air delivered to the user.  
         [0028]     The monitoring means is more preferably selected from the group of a pulse oximeter, a blood pressure monitor, an electrocardiograph, a spirometer, an oxygen analyser, a capnometer, a nitric oxide meter and the like or any combination or series of any one or more of said means.  
         [0029]     Generally, the oxygen concentration in the hypoxic air is varied in the range of between 15% and 8% by volume.  
         [0030]     The scope of the present invention also extends to a method for the delivery of Intermittent Hypoxic Training (IHT), comprising the delivery of hypoxic air to a user utilising the apparatus of the invention, wherein at least one physiologically measurable parameter of the user is substantially constantly monitored and is used as a biofeedback means to vary the oxygen concentration in the hypoxic air delivered to the user as required, while keeping the chosen parameter substantially constant. The oxygen concentration in the hypoxic air is preferably varied between 15% and 8% by volume.  
         [0031]     The IHT is conducted over a sufficient number of training sessions to substantially improve the fitness of the user thereof and is individually designed or tailored for each individual&#39;s personal requirements. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0032]      FIG. 1  is a schematic representation if IHT devices in the prior art.  
         [0033]      FIGS. 2A  and B are graphs of the results of tests of two different subjects receiving the same level of hypoxic air composed of 12% of oxygen by volume for the same time period, where the top curve represents SpO 2  and the bottom curve represents HR.  
         [0034]      FIG. 3  is a graph of the results of tests conducted on subject “Bart” receiving hypoxic air composed of 11% of oxygen by volume, where the top curve represents SpO 2  and the bottom curve represents HR.  
         [0035]      FIG. 4  is a graph of the results of tests conducted on subject “Matt” receiving hypoxic air composed of 11% of oxygen by volume, where the top curve represents SpO 2  and the bottom curve represents HR.  
         [0036]      FIG. 5  is a schematic diagram of the device for the delivery of hypoxic air utilized in the method of this invention.  
         [0037]      FIG. 6  is a schematic diagram of the apparatus of the invention showing the Variable Orifice Mixer.  
         [0038]      FIG. 7  is a schematic diagram of the apparatus of the invention showing the incorporation of the semipermeable air separator mechanism.  
         [0039]      FIG. 8  is a schematic diagram showing the PSA air separator mechanism of the invention.  
         [0040]      FIG. 9  is a schematic diagram showing pre-treatment of air fed into the Hypoxic Air Generator.  
         [0041]      FIG. 10  is a schematic diagram showing the fixed orifice control valve. 
     
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0042]     It has been discovered that different users exposed to the same oxygen level in a pre-determined inspired hypoxic gas mixture (FiO 2 ) respond very differently. Further, it has surprisingly been found that the same user responds demonstrably differently on different days to the same concentration of oxygen in the delivered hypoxic air (FiO 2 ) as measured in the SpO 2  and/or HR parameters of the user, respectively.  
         [0043]     Using a typical IHT device as shown in  FIG. 1 ,  FIGS. 2A and 2B  illustrate the results of hypoxic tests conducted on two non-athletic users exposed to the same level of hypoxia for 9 to 10 minutes. Both subjects received hypoxic air composed of 12% of oxygen by volume with the balance being made up of nitrogen (FiO 2 =0.12) at sea level.  FIG. 2A  shows results for subject “Robin,” a 36-year-old non-athletic female with mild CFS.  FIG. 2B  shows results for “Rosy,” a 42-year-old non-athletic female. In subject “Robin”, the SpO 2  decreased down to 78% within 8 minutes, whereas subject “Rosy” was not able to desaturate below 85% under the same time and level of exposure.  
         [0044]     In a further example, a typical training session for athletic subject “Bart,” a 28-year-old world class male athlete, is shown on  FIG. 3 . During a 5-minute hypoxic air exposure to FiO 2 =0.11, alternated with ambient air breathing, his arterial oxygen saturation repeatedly dropped below 73%. The same composition of hypoxic air (FiO 2 =0.11) was used by an athletic subject “Matt,” a 29-year-old male triathlete, and caused a maximum desaturation of only 80% over a time period, as shown in  FIG. 4 .  
         [0045]     It can therefore be seen from the devices and methods of the prior art that the supply of a known composition of hypoxic air to the user, does not ensure a predictable result or benefit for the user. As each course of treatment is individually prescribed, depending upon each user&#39;s requirements and desired outcomes, it would be extremely beneficial for the user if the treatment protocol could instantaneously be tailored to the user&#39;s individual current physiological requirements.  
         [0046]     It has been demonstrated that the efficiency of IHT sessions can be increased considerably if the control and adjustment of the oxygen concentration in hypoxic air, which is delivered to the user&#39;s respiratory system, is made to be directly dependent upon the individual user&#39;s physiological response.  
         [0047]     The invention will now be described, further explained and illustrated with reference to the following non-limiting example. Typically, the apparatus used in the treatment program of the present invention is described with particular reference to FIGS.  5  to  8  below as follows:  
         [0048]     A schematic diagram of a preferred apparatus utilised in the method of the present invention is provided in  FIG. 5 , which shows a Hypoxic Air Generator  1 , which produces hypoxic air, the oxygen composition of which is controlled by a control mechanism, referred to as O 2  Control unit  2 . The hypoxic air produced is then delivered to a User&#39;s Respiratory System  3 . An arterial oxygen saturation (SpO 2 ) monitoring device  4  (pulse oximeter) monitors the user&#39;s individual response to the oxygen in the hypoxic gas mixture which the user has inspired (FiO 2 ) and if the user&#39;s SpO 2  is below or above the pre-determined and pre-set target SpO 2  value, a control signal is sent to the O 2  Control unit  2  by means of an O 2  Control device  5  that increases or decreases the oxygen content in the hypoxic air (FiO 2 ) delivered to the User&#39;s Respiratory System  3 .  
         [0049]     In one preferred embodiment of the present invention as illustrated in  FIG. 6 , the Hypoxic Air Generator  1  comprises an air separation device  6  to control the amounts of oxygen and nitrogen constituting a pre-mixed gas mixture, which serves as the source of hypoxic air. In this way, the oxygen concentration can be fixed or varied as required. This hypoxic air is then delivered to the User&#39;s Respiratory System  3  via a Variable Orifice Mixer  7  that can further alter the composition of the hypoxic air by mixing the air produced by the Hypoxic Air Generator  1  with ambient air in order to generate a hypoxic air mixture having a higher oxygen concentration, which can then be delivered to the User&#39;s Respiratory System  3 . The SpO 2  monitoring device  4  analyses the current value of the user&#39;s SpO 2 . The SpO 2  monitoring device  4  further comprises means to enter and record the pre-determined and pre-set target value. If the user&#39;s current SpO 2  differs from the pre-set target value, a control signal is sent to the O 2  Control device  5 , which, in a more preferred embodiment is a Variable Orifice Mixer  7  and most preferably, a Venturi Mixer  8 , in order to adjust the oxygen concentration in the hypoxic air delivered to the user. The oxygen concentration in the gas mixture produced by the Hypoxic Air Generator  1  is adjusted so that if the SpO 2  value is higher than the target value, the oxygen concentration in the hypoxic air is decreased and if the SpO 2  is lower than the pre-set target value, then the oxygen concentration is increased.  
         [0050]     The air separation device  6  for adjusting the oxygen concentration in the hypoxic air more preferably comprises a semipermeable membrane system  9  as shown in  FIG. 7 . In this form of the device, the O 2  Control unit  2  further preferably comprises a Flow Control Valve  10  that is able to adjust the flow of hypoxic air produced by the semipermeable membrane system  9 , whereby the oxygen concentration in the hypoxic air is directly proportional to the flow of the delivered hypoxic air. In response to a control signal delivered by the SpO 2  monitoring device  4 , the oxygen concentration in the hypoxic air, which is delivered to the user, can be varied by varying one or more of the orifices of the Flow Control Valve  10 .  
         [0051]     Yet another preferred embodiment of the apparatus of the invention is illustrated in  FIG. 8 . In this embodiment, the Hypoxic Air Generator  1  utilises a Pressure Swing Adsorption (PSA) mechanism  11  to produce the hypoxic air. In this form of the apparatus, the SpO 2  monitoring device  4  sends a control signal to the Flow Control Valve  10  attached to the inlet of this device, which allows for adjustment of the oxygen concentration in the hypoxic air generated by the PSA mechanism  11 .  
         [0052]     Preferably, the air that is fed into the Hypoxic Air Generator  1  is compressed by an air pump  12 , dried by an air drier  13  and dehumidified by a moisture trap  14  and then pumped through the semipermeable membrane system  9  as shown in  FIG. 9 . The latter is designed so as to allow the compressed air to be divided into two streams namely, hyperoxic or hypoxic air. The hyperoxic air is either vented to the atmosphere or it can be used during the phase of IHT when the user receives ambient air in the form of hyperoxic air.  
         [0053]     In this embodiment, the composition of the hypoxic air is controlled by a Variable Orifice Flow Controller  15 , or alternatively, a proportional valve, which is preferably controlled by an electronic controller  17 , which is connected to the O 2  Control unit  2 . Preferably, the Variable Orifice Flow Controller  15  is motorised for greater efficiency and ease of use. The larger the orifice of the Variable Orifice Flow Controller  15 , the lower the oxygen concentration in the produced hypoxic air will be.  
         [0054]     In this way, the hypoxic air produced via a normally open 3/2 port switch  18  may be delivered to the User&#39;s Respiratory System  3 . The apparatus of the invention further preferably comprises a User&#39;s Respiratory Circuit  19  having the following elements:  
         [0055]     a reservoir/breathing bag  20  connected to the source of hypoxic air;  
         [0056]     a Blow-off Valve  21  to blow off ambient air and prevent the breathing bag  20  from over-inflating;  
         [0057]     a Demand Valve  22  that connects the User or the User&#39;s Respiratory System  3  to the ambient air, in the case of a mismatch between the delivery of and demand for the hypoxic air or if the system is malfunctioning;  
         [0058]     means to deliver hypoxic air to the User&#39;s Respiratory System  3 , preferably comprising an oxygen mask  23  with a Non-rebreathing Valve  24  connected to the mask  23 ; and  
         [0059]     supplies of both hypoxic air and ambient air, respectively.  
         [0060]     The 3/2 port switch  18  is preferably incorporated for the purposes of switching the User&#39;s Respiratory System  3  from the delivery of hypoxic air to the delivery of ambient or a hyperoxic gas mixture.  
         [0061]     The User&#39;s Respiratory System  3  is also connected to the O 2  Control unit  2  that monitors both the oxygen concentration in the hypoxic air delivered to the user as well as the user&#39;s physiological parameters, such as the SpO 2 , HR, blood pressure, etc as described above.  
         [0062]     The Control device  5  sends a control signal to the Variable Orifice Flow Controller  15  that controls the oxygen concentration in the produced hypoxic air.  
         [0063]     If the pre-set target value of SP 02  is below the recommended value pre-determined for the user, then the O 2  Control unit  2  sends a signal to open the Variable Orifice Flow Controller  15  to increase the oxygen content in the hypoxic air delivered to the User&#39;s Respiratory System  3 . Alternatively, if the SpO 2  value is above the desired value, the Variable Orifice Flow Controller  15  can be closed a fraction in order to deliver a lower oxygen concentration in the hypoxic air.  
         [0064]     Yet another preferred embodiment of the apparatus of the present invention is illustrated in  FIG. 10 .  
         [0065]     In this form of the apparatus, there is a Fixed Orifice Control Valve  25  to enable the oxygen concentration in the hypoxic air produced to be maintained at a substantially constant level, which level is determined by the accuracy of the source of hypoxic air.  
         [0066]     Preferably, the apparatus is additionally equipped with a Feeder Pump  26  to further assist with the control of the air composition and the breathing process of the user.  
         [0067]     The oxygen composition in this apparatus is controlled by a Variable Orifice Flow Controller  15 , or a proportional valve as an alternative controller, which may be motorised as before, but in this embodiment the controller  15  is connected between the vacuum port of the feeder pump  26  and the source of hypoxic air. The hypoxic air enters the feeder pump  26  through the vacuum port.  
         [0068]     By varying the cross-sectional diameter of the controller  15  or in the alternative, a Multiple Orifice Valve  28 , the O 2  Control unit  2  is able to alter the proportion in which the supplied hypoxic air is mixed with the ambient air and ultimately, therefore, the oxygen composition of the hypoxic air produced by the system.  
         [0069]     The scope of the present invention also extends to a method of administering IHT to a mammalian user, which employs or incorporates the apparatus of the present invention in its IHT training regimen.  
         [0000]     Results after Employing the Method and Apparatus of the Invention  
         [0070]     The method utilizing the apparatus of the present invention was tested on Subject “Rosy”. Her IHT training schedule as prescribed by her IHT practitioner is provided in Table 1, which records the number of the training session and the target SpO 2  set for that session.  
                             TABLE 1                           Rosy&#39;s IHT Training Schedule                    Target SpO 2             Session   (+/−2%                       1   88           2   88           3   86           4   86           5   83           6   83           7 onwards   80                      
 
 Results 
 
         [0071]     Before starting on and on the completion of the program, various physiological parameters for “Rosy” were measured. These results are shown in Table 2 below.  
                                 TABLE 2                           Results of testing the IHT method of       the invention on subject “Rosy”                Parameter   Initial   Final                       Heart Rate (beats/min)   68   62           Blood Pressure (mm Hg)   145/90   130/80           Exercise till Exhaustion   50W at 150 (beats/min)   doubled           Time   for 12 minutes                      
 
         [0072]     Similar results on other users in Rosy&#39;s age group have previously only been seen after two or three courses of IHT, each course comprising 15 daily training sessions, when using the conventional protocol. These results therefore illustrate that the method of the present invention demonstrates higher efficacy, faster beneficial results and therefore a reduced number of courses and lower overall cost for the user. Those skilled in the art will appreciate that while the invention described herein for simplicity&#39;s sake has referred to a human user, it has a general applicability to mammals in general. As a consequence, in another form of the invention, the method of treatment can be applied to an animal. It is to be understood that the invention includes all such variations and modifications. The invention also includes all the steps, features, concentrations, time periods, variations in hypoxic air generators, including air separation devices, semipermeable membranes, pressure adsorption devices, mixers, control valves, breathing regimens, respiratory circuits, breathing masks etc. referred to or indicated in the specification individually or collectively and any and all combinations of any two or more of said steps, devices or features. Where the terms “comprise”, “comprises”, “comprised” or “comprising” are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but nor to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.