The present invention relates to a method comprising subjecting a test site of a responsive system to a primary challenge; subjecting the same test site to a secondary challenge, wherein the secondary challenge is designed to enhance and/or prolong a response of the responsive system to the primary challenge, without confounding the response nor altering the mechanism by which the primary challenge elicits a response from the responsive system; and assessing the response subsequent to the secondary challenge. The methods claimed herein also preferably comprise the additional step(s) of subjecting test site(s) to one or more pre-challenge intervention(s) and/or post-challenge intervention(s) and/or concurrent-challenge intervention(s). The methods of the present invention are also useful in a study design, also claimed herein, wherein the study comprises the steps of the method outlined above in addition to comprising the steps of creating one or more controls selected from the group consisting of negative controls, primary controls, secondary controls, positive controls, and mixtures thereof. The use of the novel methods described herein often significantly shorten the duration of and/or number of subjects needed for studies aimed at understanding the etiology of a disease and/or the ability of a intervention or challenge to prevent, cure, heal, and/or reduce and/or induce damage or injury to a responsive system.

The present invention relates to test methods that can be used for clinical and non-clinical fundamental research and/or other studies to determine the consequences of a challenge to a responsive system, such as to determine the efficacy of an action, substance and/or product to prevent, induce, reduce or heal disease or injury to a responsive system. By using germane challenges to the specific responsive systems, the present invention of using a secondary challenge to enhance and/or prolong the effects of a primary challenge is amenable for use with challenges to multi-cellular and unicellular organisms such as animals, plant, fungi, bacteria, and the like, to organs of multi-cellular organisms such as epidermis, liver, heart and the like, and to tissues or individual cells or cell cultures such as isolated cells from multi-cellular organisms such as sperm, eggs, white blood cells, neurons, and the like or cultures of such cells. One embodiment of the present invention enhances and/or prolongs the effects of a primary challenge to human epidermis by using a different secondary challenge.
Studies on the effects of a challenge (insult) to provoke a human physiological response are needed to understand the etiology of disease and to develop both preventative measures and efficacious treatments. For example, studying the effects of stool on the etiology of diaper rash is needed to develop and/or determine efficacy of products, medications and/or processes that effectively prevent and/or treat diaper rash, which continues to routinely occur among many diapered children. Despite the many studies done to date, the etiology of diaper rash and the mechanisms of various diaper rash preventative and curative agents is incompletely understood. In general, this can be said for most dermatological diseases, as well as many common diseases of other tissues, organs and organisms.
Clinical and non-clinical scientific studies of biological responses, such as of diaper rash and many other dermatological responses, are hindered when current methods and/or devices cannot detect weak responses and/or distinguish among multiple causes for an observed response (i.e., disentangle or interpret a confounded response). Such studies are further hindered when the response being studied, such as diaper rash, occurs with relatively low and unpredictable frequency among the general population.
A common procedure to enhance a weak or inconsistent response is to damage or prime the responsive system prior to challenging it, but the enhanced response is often confounded. For example, the scarification test (Frosch and Kligman, 1976, Contact-Dermatitis 2: 314-242) has long been used to study irritant responses by first physically scarring skin with a needle prior to challenging that damaged skin with substances suspected to have mild irritancy or a weak response. Studies of allergenic and sensitization responses of human skin have long applied this approach by first priming the responsive system with repeated challenges, often over several weeks, to study effects of a second challenge of the same or different type (e.g., Kaidbey and Kligman, 1980, Contact Dermatitis 6:161-169).
There are two concerns with first damaging or priming a responsive system to study responses of that system. First, the damage or modification to the responsive system can cause the responsive system to respond to a challenge by a different mechanism than would the same naxc3xafve (undamaged and/or unmodified) responsive system. Second, the degree or severity of the response to a second challenge by a responsive system that has already been damaged or modified can be completely erroneous compared to a naxc3xafve responsive system. For example, a second challenge to already damaged skin could result in a severe response when the response by naxc3xafve skin would have been nil. Moreover, when the subjects are infants there is heightened justifiable concern anytime a severe response is observed and researchers would rather avoid inducing severe responses by any available means.
A common procedure to minimize confounding of a response, particularly when trying to study mechanisms of disease progression and/or the effects of interventions on the disease or on a injury, is to control the challenge, such as by using direct patching methods in dermatology studies. Such methods, however, are often inadequate when the response occurs at low frequency in the study population and/or the tools used to assess the response are relatively insensitive. To overcome these problems, a direct patching method is often used to study dermatological responses. However, these methods, when they work, typically require lengthy and/or repeated exposures that can be excessive and/or irrelevant to the normal course of events. In addition, many researchers and/or subjects find current patching methods sufficiently inconvenient and costly in time and resources that development of abbreviated methods is desirable.
The present invention is a novel approach to study physiological responses, particularly where enhancing and/or prolonging a response to a challenge without changing the inherent nature of the response is desirable. The methods are useful when the response of interest needs to be studied under both highly controlled and poorly-controlled challenge scenarios. In addition, the present invention reduces the challenge duration needed to provoke an enhanced and/or prolonged response. A specific embodiment of the present invention accomplishes this by enhancing and/or prolonging the effects of the primary challenge (stool) to human epidermis by using a different secondary challenge (tape-stripping) to elicit enhanced and durable erythemic and increased transepidermal water loss (TEWL) responses. In addition, the response to the initial challenge typically corresponds closely to what normally occurs with subjects during their normal lives because the exposure duration is relevant to the common experience of the subjects. Moreover, the primary challenge is applied to healthy, non-damaged skin so that the response is not confounded with the skin""s responses to any other pre-damage challenge.
The present invention relates to a test method to enhance and/or prolong the response of a primary challenge to a responsive system, so that the primary challenge can be better studied, by using a different secondary challenge that does not alter the mechanism by which the primary challenge affects the responsive system nor does it confound the response of the primary challenge. Further, the present invention typically: 1) reduces the exposure duration needed for the primary challenge to induce a response to one that is more relevant to normal exposure scenario(s) for the responsive system or subject, 2) reduces the number of subjects needed to observe statistically significant and/or clinically relevant effects, 3) is more convenient for the researchers, and 4) is minimally stressful to the responsive system or subjects. In addition, the primary and/or secondary challenge may be preceded by one or more interventions in studies designed to understand the etiology of the disease and/or determine the efficacy of a preventative measure. In addition, the secondary challenge may be preceded by and/or followed by one or more interventions in studies designed to determine the efficacy of a curative measure.
As used herein, xe2x80x9cstudyxe2x80x9d refers to either clinical or non-clinical research with specified testable hypotheses. As used herein, xe2x80x9csubjectxe2x80x9d refers to a human, lower animal species, or other specified organism participating in a study. As used herein, xe2x80x9cresponsive systemxe2x80x9d refers to any organism, organ, tissue, mass of cells, or individual cell(s) for which a change in activity, appearance, function, structure, or other condition can be provoked or induced. As used herein, xe2x80x9cchallengexe2x80x9d refers to the entity and/or process of provoking, moderating or otherwise influencing a physiological (including biochemical) activity by exposure under defined conditions to one or more physical, chemical or biological conditions or actions. As used herein, xe2x80x9ctest sitexe2x80x9d refers to any physical location on the responsive system, entity or organism that is monitored during the course of a study. As used herein, xe2x80x9cprimary challengexe2x80x9d refers to the first challenge applied to one or more test sites, that elicits one or more response(s) (which may or may not be detectable until after the secondary challenge). The primary challenge is the main challenge of interest in the study. There may be more than one component to primary challenge (e.g., there may be a chemical challenge and a physical challenge or there may be two successive identical or different chemical challenges) wherein all components of the primary challenge precede the secondary challenge. As used herein, xe2x80x9csecondary challengexe2x80x9d refers to a challenge applied after the primary challenge to one or more test sites designed or intended to enhance and/or prolong the response of the primary challenge. Importantly, a secondary challenge does not confound the response of the primary challenge nor does it alter the mechanism by which the primary challenge elicits a response. As used herein, xe2x80x9cconfoundxe2x80x9d means to confuse the meaning or interpretation of an observation even in the presence of controls. As used herein, xe2x80x9cenhancesxe2x80x9d refers to increasing the magnitude or intensity of an entity or event, such as increasing the color intensity or area affected during a dermatological response to a challenge. As used herein, xe2x80x9cprolongsxe2x80x9d refers to increasing the duration of an event. As used herein, xe2x80x9crecovery periodxe2x80x9d refers to a defined period of time during which the responsive system has opportunity to overcome the effects of a challenge. As used herein, xe2x80x9cinterventionxe2x80x9d refers to any process, act, condition, substance and/or entity attempting to affect the outcome of a challenge, such as to prevent, reverse, and/or attenuate the response of a responsive system to a primary challenge. As used herein, xe2x80x9cpre-challenge interventionxe2x80x9d refers to any process of exposing a test site and/or control site to one or more physical, chemical or biological conditions prior to exposure to at least one primary challenge. Thus, where there are a series of primary challenges, a pre-challenge intervention can occur anytime so long as it precedes one or more of the primary challenges. As used herein, xe2x80x9cpost-challenge interventionxe2x80x9d refers to any process of exposing a test site and/or control site to one or more physical, chemical or biological conditions subsequent to exposure to any primary challenges. The xe2x80x9cpost-challenge interventionxe2x80x9d can precede one or more secondary challenges, occur between/among one or more secondary challenges, or can follow one or more secondary challenges. As used herein, xe2x80x9cconcurrent-challenge interventionxe2x80x9d refers to any process of exposing a test site and/or control site to one or more physical, chemical or biological conditions during one, or more, of the primary challenger(s). As used herein, xe2x80x9cresponsexe2x80x9d refers to any detectable condition or change in condition of a responsive system. For example, a change in visual rash severity or TEWL before and after a challenge is a measure of response to that challenge. The method of detection includes but is not limited to methods utilizing human skills only and/or chemical, physical, mechanical, and/or electrical methods and equipment. As used herein, xe2x80x9cassessingxe2x80x9d refers to any method of evaluating, observing, noting, and/or comparing the condition (e.g., response) of a test site. As used herein, xe2x80x9cpate test gradexe2x80x9d refers to a visible skin response scored using a standardized scale (see table 17, page 99 in McNamara, 1976, in xe2x80x9cNew Concepts in Safety Evaluationxe2x80x9d, a modification of which is incorporated herein with detailed text). As used herein, xe2x80x9cdiaper rashxe2x80x9d refers to a response indicated by the occurrence on diapered epidermis of what is clinically defined as either erythema or dermatitis, or both, where persistent redness, dryness, pustules and/or other symptoms associated with such conditions may arise. As used herein, xe2x80x9crashxe2x80x9d refers to a response indicated by the occurrence on epidermis of what is clinically defined as erythema, dermatitis, psoriasis, or any of several other skin conditions where persistent redness, dryness, papules, pustules and/or other symptoms associated with such conditions may arise. As used herein, xe2x80x9cTEWLxe2x80x9d refers to trans-epidermal water loss, which is a measure of water movement across and out of the epidermis (skin). TEWL is related to the integrity of skin barrier function when measured under standardized conditions of temperature and humidity after the subject has been sufficiently equilibrated to those standardized conditions. As used herein, xe2x80x9cstoolxe2x80x9d refers to feces from human intestines. As used herein, xe2x80x9cstool analogxe2x80x9d refers to blends of irritative components commonly found in stool including, but not limited to, SHIME, enzymes, bile acids, candida species and mixtures thereof. As used herein, xe2x80x9cSHIMExe2x80x9d (Simulation for the Human Intestinal Microbial Ecology) refers to a biologically-simulated human fecal material created in laboratory digestion chambers having a bacterial consortia and both physical and chemical conditions representative of the various segments of the human intestinal tract. SHIME is designed to have representative characteristics of human feces from healthy adults or infants fed a varied diet, but lacks any pathogenic microbes to avoid the spread of disease and lacks any substantive amount of bulking or solidifying components, like cellulose. SHIME is further described in the following two references which are incorporated herein by reference in their entirety: 1. Molly, K., et. al., 1993. Development of a 5-step multi-chamber reactor as a simulation of the human intestinal microbial ecosystem. Appl. Microbiol. Biotechnol. 39:254-263; and 2. De Boever, P., et. al., 200X (in review). Development of a six-stage culture system for simulating the gastrointestinal microbiota of infants. Microb. Ecol. Health Dis. As used herein, xe2x80x9ctape-strippingxe2x80x9d refers to the act of applying a material of known adhesive properties to skin in a prescribed manner and removing that material for the purposes of subjecting the skin to a physical challenge. Materials of known adhesive properties useful for tape-stripping, which need not specifically be in a tape format, include adhesive tapes such as D-squame(copyright) and Sebutape(copyright) (CuDerm Corporation, Dallas, Tex.) or Blenderm(trademark) and ScotchTape(trademark) (3M Company, St. Paul, Minn.), and hydrogels such as Hypan(copyright) (Hymedix International, Inc., Dayton, N.J.), and other types of materials with adhesive properties such as glues, gums, and resins. As used herein, xe2x80x9ccontrol sitexe2x80x9d or xe2x80x9ccontrolxe2x80x9d refers to any test site and/or study treatment used to establish a standard of comparison for judging experimental effects and/or the degree of variation in effects, such as those associated with experimental noise, that occur during a study. As used herein, xe2x80x9cchallenge(d) sitexe2x80x9d refers to any test site that receives a primary and subsequent secondary challenge. As used herein, xe2x80x9cnegative controlxe2x80x9d refers to any control site that is treated identically to a challenged site except it receives neither a primary nor a secondary challenge. For instance, where a responsive system is first cleansed with water and then subjected to a primary and secondary challenge at a given temperature, the control site would also be cleansed with water and would be subject to the same given temperature, but would not be subject to the primary nor secondary challenge. As used herein, xe2x80x9cprimary controlxe2x80x9d refers to a control site that receives the primary challenge, but no secondary challenge. A primary control may or may not receive a concurrent-challenge intervention, pre-challenge intervention, or post-challenge intervention. As used herein, xe2x80x9csecondary controlxe2x80x9d refers to a control site that receives the secondary challenge, but no primary challenge. Where beneficial to a study design, a secondary control may receive a post-challenge intervention, even though it has not received a primary challenge. As used herein, xe2x80x9cpositive controlxe2x80x9d refers to a control site that receives a substitute primary challenge known to induce a defined response with or without the secondary challenge. All percentages, ratios, and parts herein, in the Specification, Examples, and Claims are by weight unless otherwise stated. The term xe2x80x9cm2xe2x80x9d, as used herein, means square meters. The term xe2x80x9ccm2xe2x80x9d, as used herein, means square centimeters. The term xe2x80x9ccmxe2x80x9d, as used herein, means centimeters. The term xe2x80x9cgxe2x80x9d, as used herein, means gram. The term xe2x80x9cmlxe2x80x9d, as used herein, means milliliter. The term xe2x80x9chrxe2x80x9d, as used herein, means hour. The term xe2x80x9cRHxe2x80x9d, as used herein, means relative humidity. The term xe2x80x9cpsixe2x80x9d, as used herein, means pounds per square inch. The term xe2x80x9cwtxe2x80x9d, as used herein, means weight. As used herein, the term xe2x80x9ccomprisingxe2x80x9d means that the various components, ingredients, or steps, can be conjointly employed in practicing the present invention. Accordingly, the term xe2x80x9ccomprisingxe2x80x9d encompasses the more restrictive terms xe2x80x9cconsisting essentially ofxe2x80x9d and xe2x80x9cconsisting of.xe2x80x9d
A. General Method
The test method of the present invention enhances and/or prolongs one or more of the effects of a primary challenge to a responsive system. The method enables the primary challenge to be better studied by using a different secondary challenge that does not alter the mechanism by which the primary challenge affects the responsive system nor does it confound results of the primary challenge with other spurious responses.
More specifically, the method generally comprises assessing a test site of the responsive system in its pre-challenge condition; subjecting the test site to a primary challenge; preferably but not necessarily, assessing the test site for a response; subjecting the same test site to a secondary challenge, wherein the secondary challenge is designed to enhance and/or prolong a response of the responsive system to the primary challenge, without confounding the response nor altering the mechanism by which the primary challenge elicits a response; and assessing the response subsequent to the secondary challenge. Preferably, the response is assessed at least twice following the secondary challenge, wherein the first assessment is made soon after the secondary challenge, and the second assessment is made after a recovery period. The primary and secondary challenges of the present invention can comprise physical challenges, chemical challenges, and/or biological challenges. The primary and secondary challenges may comprise multiple or complex components (for example, a primary challenge comprising a poorly-defined extract or comprising chemicals A and B dissolved in a buffered matrix and heated to a specific temperature) and/or steps (for example, a primary challenge comprising a first chemical challenge concurrently with or followed shortly thereafter by a second chemical challenge (same or different from the first) to the same test site). However, preferably, but not necessarily, the primary and secondary challenges are single steps (or challenges) in the process. The methods claimed herein also preferably comprise the additional step(s) of subjecting test site(s) to one or more pre-challenge intervention(s), post-challenge intervention(s), and/or concurrent-challenge intervention(s). The introduction of these interventions is useful for determining the ability of the intervention to prevent, cure, heal, and/or reduce disease or injury to a responsive system.
The methods of the present invention typically reduces the exposure duration needed for the primary challenge to induce a response to one that is relevant to normal exposure scenario(s) for the responsive system or subject, and is both minimally stressful to the responsive system and/or subjects and convenient for researchers. As a result, the present invention often significantly shortens the duration of and/or number of subjects needed for studies. In addition, it may enhance a low-level response that can be more easily assessed with current measurement techniques.
Thus, the methods of the present invention are also useful in a study design, also claimed herein, wherein the study comprises the steps of the method as outlined above in addition to comprising the steps of creating one or more controls selected from the group consisting of negative controls, primary controls, secondary controls, positive controls, and mixtures thereof. The studies and/or methods of the present invention are preferably designed to understand of the etiology of a disease and/or the ability of an intervention or challenge to prevent, cure, heal, and/or reduce and/or induce damage or injury to a responsive system.
B. Responsive Systems and/or Subjects
The responsive systems and/or subjects utilized in the methods of the present invention include but are not limited to: multi-cellular and unicellular organisms such as humans, animals, plants, fungi, bacteria, and the like; organs of multicellular organisms such as epidermis, liver, heart and the like; and to tissues or individual cells or cell cultures such as those isolated cells from multi-cellular organisms including but not limited to sperm, eggs, white blood cells, neurons, stoma, and the like.
C. Challenges
The primary and secondary challenges used in the method defined above can be of a physical, chemical, or biological nature. Some examples of physical challenges include, but are not limited to: heat, cold, humidity, desiccation ultraviolet or other forms of radiant energy, dark, friction, abrasion, lubrication, electric or magnetic energy, pressure, vacuum, visual images, occlusion, and sound. Some examples of chemical challenges are any element of the periodic table or non-living compositions of those elements including, but not limited to: organic and inorganic acids and bases or conditions caused by their presence in aqueous systems, surfactants, metal and complexes thereof, salts, proteins, lipids, vitamins, polymers, pharmaceuticals, feces, urine, perspiration, hair, extracts, and/or enzyme digests. Some examples of biological challenges include, but arc not limited to: microbials, cells, viruses, bacteria, parasites, and/or other living entities (e.g., fungi known to cause dermatitis, amoeba or protozoa known to cause dysentery or other diseases, mosquitoes or mites known to directly induce a range of responses or indirectly induce a range of responses when they are vectors for the transmission of viruses or parasites).
The methods of the present invention include but are not limited to the embodiments listed below:
1. human skin briefly exposed to ultraviolet radiation and subsequent tape-stripping (physical-physical/primary-secondary challenge) where skin redness and/or TEWL is measured to evaluate the efficacy of a UV-blocking agent applied as a pre-challenge intervention;
2. human skin exposed to trypsin (enzyme) and subsequent tape-stripping (chemical-physical/primary-secondary challenge) where interleukin 1 alpha (IL-1xcex1) induction and/or TEWL is measured to evaluate the efficacy of an enzyme inhibitor applied as a pre-challenge intervention;
3. human skin exposed to Candida albicans (fungus) dosed into SHIME and subsequent tape-stripping (biological(and chemical)-physical/primary-secondary challenge) where visual dermatitis and/or TEWL is measured to evaluate the efficacy of a fungal inhibitor applied as a pre-challenge intervention;
4. human skin exposed to trypsin (enzyme) and subsequent acetone exposure (chemical-chemical/primary-secondary challenge) where visual erythema score and/or TEWL is measured to evaluate the efficacy of an enzyme inhibitor applied as a pre-challenge intervention;
5. bovine eye exposed to cosmetic product(s) and subsequent sodium lauryl sulfate exposure (chemical-chemical/primary-secondary challenge) where interleukin 1 alpha (IL-1 a) is measured to evaluate the irritancy of various cosmetic products;
6. ovarian carcinoma cells exposed to treatment chemical(s) and subsequent exposure to growth factors (chemical-biological(or chemical)/primary-secondary challenge) where cellular division is measured by microscopy.
The specific embodiments of combinations of responsive systems exposed to primary and secondary challenges and then measured for various responses are numerous and a complete listing of such combinations is impractical. It is understood that one of ordinary skill in the art will be able to apply the general method of the present invention to suit his/her needs in a wide variety of applications, given the guidance of the present specification and/or examples.
D. Biological and/or Chemical Primary Challenge/Tape-stripping Secondary Challenge
One preferred embodiment of the present invention, useful in studies aimed at quickly assessing the effect of a biological and/or chemical substance on a responsive system, such as skin or cell cultures derived therefrom, comprises the steps of: assessing a test site of a responsive system in its pre-challenge condition; subjecting the test site to a primary challenge, wherein the primary challenge comprises a biological and/or chemical challenge; subjecting the test site to a secondary challenge, wherein the secondary challenge comprises the physical challenge of tape-stripping; and assessing the response subsequent to the secondary challenge, preferably at least twice, wherein the first assessment is made soon after the secondary challenge and the second assessment is made after a recovery period. By tape-stripping subsequent to the primary challenge of interest, the response of the responsive system to the primary challenge is enhanced and/or prolonged. Additionally, typically the duration of the application of the primary challenge necessary to provoke a response is substantially reduced.
A preferred embodiment of the invention is a clinical or non-clinical study involving male and/or female subjects of any age during which normal; healthy test sites on each subject are identified, and from which selected challenge sites receive both a primary challenge for a defined period of time and a secondary challenge at a defined period of time after the primary challenge. A variety of appropriate control sites may be established. Some may receive the same primary challenge only (i.e., primary control), or the same secondary challenge only (i.e., secondary control). Others may receive neither a primary nor a secondary challenge (i.e., negative control). Some may receive an appropriate alternative primary challenge (i.e., positive control), which may or may not receive a secondary challenge. The test sites may also receive other types of control interventions as may be required for the interpretation of study results. In the preferred embodiment of the present invention, test sites may be assessed several times to record response(s) that may occur during the study, including, but not limited to the following times: 1) at basal (baseline) conditions prior to the primary challenge, 2) subsequent to the primary challenge, 3) subsequent to the secondary challenge, and 4) subsequent to a recovery period of defined duration after the primary challenge was initiated and subsequent to any secondary challenge.
When this preferred embodiment is used for studies to determine the efficacy of an action, process, substance and/or product (an xe2x80x9cinterventionxe2x80x9d) to prevent, induce, reduce or heal an impaired state or disease, the intervention is applied to appropriate test sites before, during, or after the primary or secondary challenge occurs at those test sites. More specifically, the primary and/or secondary challenge may be preceded by one or more pre-challenge or concurrent-challenge interventions in studies to understand the etiology of the impairment or disease and/or determine the efficacy of a preventative measure, or the secondary challenge may be followed by one or more post-challenge or concurrent-challenge interventions in studies to determine the efficacy of a curative measure.
This protocol is designed to study the etiology of diaper rash due to skin exposure to stool. It is understood that amendments to the test protocol may be appropriate to study related objectives. The protocol comprises three visits by subjects to a test facility where the study is conducted. The first visit comprises interviewing subjects for possible inclusion in the study, and providing to those subjects who will potentially participate any applicable training and/or materials needed to initiate participation. The first visit is followed by a wash-out period generally comprised of the potential subjects exposing those areas of their skin that are of interest to standardized conditions intended to help minimize experimental noise by eliminating some confounding prior exposures of those skin sites to variable substances, actions and/or environmental conditions. After the wash-out period, the second visit to the test facility comprises re-evaluation of the potential subjects by investigators for inclusion in the study and, if accepted into the study, skin test sites are identified on the subjects which receive challenges for which assessments are made both before and after those challenges to discern skin responses to the challenges or lack thereof. The third visit to the test facility is comprised of assessments made of the challenged skin of subjects to discern persistence of any skin response or lack thereof.
A more specific description of a preferred protocol follows:
First Visit: Subjects are chosen from among healthy infants aged 1 to 36 months, preferably aged 9 to 27 months, and their healthy biological mothers aged 18 to 50 years, preferably 21 to 35 years. Preferably all potential subjects chosen, both adult and child, meet the following inclusion criteria (it is understood that the criteria may change depending upon the study objectives): 1) healthy and evenly-colored skin at all potential test sites with an absence of blemishes, burns, lesions, moles, scars and the like; 2) good general health as determined by having no communicable diseases nor chronic skin or other disorders; 3) neither currently taking nor having taken within two weeks of study initiation any medication(s), either topical or systemic, which in the opinion of the study investigator(s) might influence the skin condition or cause skin rash, such as erythema or dermatitis, or might increase BM frequency (e.g., oral antibiotics, anti-fungal agents, antihistamines, corticosteroids); 4) exhibit no significant hypersensitivity, rash or other abnormal skin reactions or lesions to topical or systemic medications, sunscreens, cosmetics, lotions, creams or fragrances within one year prior to study initiation; and 5) have adequate rash-free area as evaluated by an expert skin grader (i.e., patch test grade is less than 1.0 on a 0 to 4.0 half-point scale) for test sites on the child""s buttocks and on the adult""s forearms. All potential infant subjects chosen meet the following criteria: 1) child wears disposable diapers full-time; 2) child has no regular occurrence of diarrhea and no diarrhea at least four days prior to nor during the study; and 3) child is preferably transitioning to or already eating table food, where supplementation with formula is acceptable if it constitutes 50% to 99%, preferably 25% to 49%, most preferably 0% to 24% of the diet by caloric intake and where use of table foods and/or prepared baby and toddler foods such as baby cereals and jarred foods comprise the remainder of the diet. All potential adult subjects chosen meet the following criteria: 1) parent is willing to use standard diapers and standard wipes provided on her child instead of their normal brand(s) of diapers and wipes for the duration of the study; 2) parent agrees to use no lotions, creams, ointments, powders, topical medications, or other skin preparations in the diapered area of her child nor any such substance on her own forearm(s) at least 24 hours prior to the first challenge and through to the end of the study; 3) parent agrees to not bath her child""s diapered skin area nor bath her own forearms between the primary and secondary challenge of the study, nor bath any such skin areas during the recovery period; 4) parent agrees not to allow her child to consume nor to consume herself any food or beverage containing caffeine at least four hours before any clinical measurement(s) are made; 5) parent agrees not to use nicotine containing products at least 2 hours before clinical measurement(s) are made; and 6) parent must be willing to have her child""s buttocks and her own forearm(s) patched with the child""s own stool and subsequently have some skin sites tape-stripped.
It is generally understood that only the infant subjects can be studied or only the adult subjects can be studied by making appropriate changes to this general protocol. For example, if only infant subjects are studied, then adults need only participate to the extent necessary to enable study of their children.
Wash-out period: All subjects that meet inclusion criteria during an initial interview are provided with instructions to begin a wash-out period of 24 to 336 hours (1 to 14 days), preferably 72 to 96 hours (3 to 4 days), during which time the child wears exclusively the standard diapers and the parent uses exclusively the standard wipes to clean the child""s diapered skin during all diaper changes. Child and adult subjects typically wear their normal clothing and use their normal bathing practices including those soaps, shampoos and the like normally used. During wash-out subjects are not to apply any lotions, creams, ointments, powders, topical medications, and the like on potential test sites 6 to 168 hours prior, preferably 24 to 48 hours prior to the second visit to the test facility. In addition, all subjects are to bathe normally all potential test sites (i.e., baby diapered skin and adult forearms) 0.5 to 6 hours prior, preferably 1 to 2 hours prior to the second visit to the test facility. In addition, it is generally understood that the conditions of the wash-out period are defined by the needs of the study design such that modifications to the methods and materials given herein are acceptable provided they are recorded with a rationale.
Second visit: Subjects report to the test facility for their second visit at pre-determined appointments and the following procedures are performed:
1. Subjects are re-evaluated for suitability for patching against the inclusion criteria and for compliance with instructions for the washout period.
2. Typically, four healthy, unblemished, non-erythemic, non-dermatitic, non-overlapping skin sites approximately 5 cm by 5 cm in size or larger are identified on each infant""s buttocks and on one, or both, volar forearm(s) of each mother for use in the study, where the skin sites on each infant are preferably 2 sites located on contralateral (apposing) buttocks and on each mother""s forearm are 4 sites located linearly between the wrist and inner elbow. Fewer or additional sites and/or alternative site locations may be chosen as needed to meet the study objectives. The corners of each identified skin site are typically marked using non-toxic, water-soluble marking pens so they can be found during the course of the study.
3. Subjects are sent to a climate-controlled room having a standard temperature (typically 20 to 25xc2x0 C.) and humidity (typically 40%xc2x15% RH). Subjects"" skin sites are typically equilibrated to reach their basal (baseline) conditions by completely exposing their skin sites for 20 to 30 minutes. Longer equilibration time may be used if standardized for all subjects, but shorter equilibration time is often insufficient for most subjects"" skin to reach basal conditions.
4. After equilibration, assessments are made in the climate-controlled room at each test site to establish basal conditions of the test sites. Typically assessments are made for erythema by an expert skin grader using a patch grade scoring system (0 to 4.0 half-point scale) and for TEWL using a DermaLab(copyright) Evaporimeter with TEWL module (Cortex Technology, Hadsund, Denmark) that measures evaporation rate (g water/m2/hr) and computerized software for automated data collection and analyses (cyberDERM, inc., Media, Pa.). The general procedure for their use is as follows: the evaporimeter probe is applied to each skin site using a standard ring weight that applies equal pressure to all sites and TEWL data are collected for 60 seconds using automatic data collection by a computer linked to the evaporimeter, and where only the final 40 seconds of data are used to calculate a mean TEWL value. Details of operation for both the evaporimeter and software are available in their respective users manuals, which are incorporated herein by reference. In addition, a clean disposable evaporimeter probe cover is used to measure each site to avoid cross-contamination of sites with any challenges and/or interventions applied.
5. The test sites of each subject are randomly assigned to interventions for any combination of challenges, interventions and control conditions to meet the needs of the study design.
6. Stool is sampled from subjects, preferably from infant subjects, 48 to 168 hours, preferably 2 to 48 hours, more preferably 0.5 to 2 hours prior patching the primary challenge during to the second visit. Stool should be collected generally as soon after defecation as possible, such as within 60 minutes, preferably within 15 minutes. Stool can be sampled in various ways such as directly from the perianal grove of the child, from stool in a diaper that is uncontaminated by the diaper materials, or by any other appropriate means that are convenient and pose no harm to the subject. Stool should be sampled with a sterile implement, such as a wood or plastic cervical scraper or popsicle stick, and placed into sample containers, such as clean glass, polyethylene or polypropylene vials with lids. Stool analog such as a synthetic stool, such as SHIME, which is known to be free of pathogenic species, is a possible substitute primary challenge material. Once sampled, stool or SHIME for patching should preferably be stored at approximately 4xc2x0 C. until needed for preparing patches. Such storage should not exceed 168 hours, preferably not more than 48 hours, more preferably not more than 4 hours prior to patching, most preferably stored and used in patching within 1 hour after defecation.
7. Primary challenge patches are then prepared for subjects. It is preferred that infant subjects are patched with their own stool and parent subjects are patched with their child""s stool. The patches are preferably prepared prior to or concurrently with the assignment of skin sites to treatments (although patches could be prepared immediately and stored relative to the guidelines listed above for storing stool). An occlusive square (25.8 cm2) patch is recommended, such as a Hilltop Chamber Systems Patch (a.k.a. Hilltop Chamber Patch, Hilltop Research, Cincinnati, Ohio) consisting of a 2.5 cm diameter nonwoven cotton pad (Webril(copyright)) contained within a plastic chamber (e.g., Hilltop Chamber) covered by and held securely to the skin on all sides with an occlusive, hypoallergenic tape (e.g., Durapore(copyright)). Non-irritating, hypo-allergenic, occlusive patches made of natural and/or synthetic fibers like as cellulose, rayon or polyolefin may be acceptable alternatives, such as The Former Professional Medical Patch Pad (Kendall Company, Mansfield, Mass.) square of 14.5 cm2 consisting of a nonwoven cotton pad (e.g., Webril(copyright)) square of 3.6 cm2 covered by and held securely to skin on all sides with an occlusive, hypoallergenic tape (e.g., Blenderm(trademark), 3M Company, St. Paul, Minn.). Typically patches containing between 0.01 g and 1.0 g per cm2 skin surface, more preferably between 0.25 g and 0.35 g per cm2 skin surface of the stool are sufficient to elicit a desired response. However, it is understood that applying less stool (or less of some other primary challenge) is possible, but this may increase the exposure time necessary to elicit the desired response. Similarly, applying more stool is possible (or more of some other primary challenge) is possible, but this may not be appropriate, practical, economical or pleasant for the subject. Therefore, the amount of stool is not deemed a critical nor limiting aspect of the present invention. The patches may be wetted with between 0.1 g and 1.0 g of distilled and/or deionized water per cm2 skin surface, preferably where the patches may be wetted with between 0.01 g and 1.0 g of synthetic urine per cm2 skin surface, more preferably where the patches may be wetted with between 0.01 g and 1.0 g of natural urine per cm2 skin surface, and most preferably where the patches are unwetted except for liquid associated with the stool applied.
8. Subjects are patched for the primary challenge period for 0.5 to 16 hours, preferably for 1 to 8 hours, more preferably for 3.5 to 4.5 hours, such that the appropriate test sites receive the appropriate randomized interventions assigned in step 5. It is preferred that a standard cleaning method be used prior to applying patches to the skin test sites on child""s buttocks and parent""s forearm(s), as well as subsequent to removing all patches irrespective of treatment received. A recommended method is to use the standard wipes such that each individual skin test site is wiped 5 times where each time is a single stroke across only that site with the new standard wipe folded in thirds. Once patched, infants may be diapered and all subjects are free to engage in normal activities such as eating, sleeping, playing, etc., provided that the subjects remain at the test facility and avoid strenuous exercise or other activities that might cause perspiration to dislodge patches. In addition, infant subjects will have their diapers changed whenever soiled with stool as well as routinely during the primary challenge, preferably every hour, to avoid moisture accumulation under the patches.
9. Patches from the primary challenge period are removed and each patch site is cleaned using the same standard cleaning method (see 8 above). Subjects"" skin is equilibrated (as in 3 above) and assessments of any responses are made (as in 4 above).
10. While subjects are still in the climate control room a secondary challenge of five successive tape-strippings, using five different tapes, is made on test sites receiving the secondary challenge. Preferably the tape is left on for about 1 minute before removal. Tape stripping is preferably performed with D-Square tape (Cu-Derm, Dallas, Tex.), but alternative tapes, such as Blenderm(trademark) (3M Company, St. Paul, Minn.) or equivalent, or other appropriate adhesive materials may be substituted.
11. Tape-stripped test sites are allowed to re-equilibrate for about the same amount of time among all sites and among all subjects, preferably for 10xc2x12 minutes (not to vary by more than two minutes between sites within and among subjects) and assessments of any responses are made (as in 4 above).
12. Subjects leave the test facility and return the next day, preferably 24xc2x12 hours after the primary challenge was initiated. Subjects should not bath nor apply any substances (see inclusion criteria) to the test sites or neighboring skin until the third visit is complete.
13. During the third visit subjects"" skin is equilibrated (as in 3 above) and the final assessments of any responses are made (as in 4 above).

Method to enhance and/or prolong the effects of a primary challenge to a responsive system with a secondary challenge


An aircraft pitch control system which includes a movable tail composed of a powered stabilizer which is angularly movable about a first axis, and elevators mounted on the rear end of the stabilizer which are angularly rotatable about a second axis displaced from the first axis. The stabilizer is controlled by an electric, pneumatic or hydraulically powered actuator, and the elevators are controlled manually through appropriate cables or mechanical linkage. The stabilizer actuator is controlled by movements of the elevators through an appropriate servo mechanism, so that angular movement of the stabilizer follows angular movement of the elevators. In the event of failure of the stabilizer actuator, the stabilizer is locked in a selected position by an automatic lock, and the pitch of the aircraft is controlled manually by the elevators alone.

This application is a continuation-in-part of Copending Application Ser. No. 766,542 filed Aug. 19, 1985 now abandoned.
The aircraft pitch control system of the present invention is of the same general type as the "Flying Tail" described in Richter U. S. Patent 3,949,958. The Richter system involves a movable tail comprising a stabilizer actuated by a number of hydraulic actuators, and manually controlled hydraulically operated elevators. The resulting movable tail surfaces provide moments about the center of gravity of the aircraft when the stabilizer and/or elevators are inclined to the air flow.
The Richter "Flying Tail" is designed for large air-craft, and it includes four independent hydraulic systems for operating the stabilizer. These multiple hydraulic are provided for redundancy purposes, because the absence of hydraulic power eliminates all horizontal tail control in the Richter system.
The pitch control system of the present invention, on the other hand, includes an emergency lock for the stabilizer, which operates in the event of power failure, so that pitch control of the aircraft may be carried out manually in the event of such failure. The system of the invention is particularly intended for small aircraft, and because of its ability to exert a manual control in the event of power failure, obviates the need for redundant hydraulic controls for the stabilizer.
It is accordingly an objective of the present invention to provide an improved pitch control system of the type described above, and which is constructed to enable the pilot to revert to manual control in the event of failure of the stabilizer actuator.
A feature of the invention is that because of the ability of manual control of the system in the event of actuator power failure, the stabilizer in the pitch control system of the invention may be actuated by standard hydraulic, pneumatic or electrical power systems, as opposed to the powered stabilizer described in the Richter patent which requires a plurality of independent redundant hydraulic systems to control the stabilizer section of the tail, because absence of hydraulic power eliminates all horizontal tail control in such systems.
The pitch control system of the invention may be constructed to vary its control effectiveness by changing the relationship between the motions of the stabilizer and elevators as a function of flight speeds. At low speeds, large stabilizer movements provide more tail control in a situation where aerodynamic forces are low; whereas at high speeds, it is desirable to provide a lesser stabilizer motion relative to elevator motion because the aircraft is then sensitive to small stabilizer movements when the aerodynamic forces are large.
The foregoing requirement is implemented by an electronic control unit which adjusts the servo response to elevator motion as a function of indicated air speed. By such a control, the desired aircraft acceleration as a function of pilot pressure on the pitch control may be achieved over a wide speed range.


The present invention provides a process for producing a saturated aliphatic hydrocarbon prepared using an α-olefin as a raw material and represented by the general formula (1), including the steps of: (I) producing a vinylidene olefin by dimerizing the α-olefin in the presence of a metallocene complex catalyst; (II) further dimerizing the vinylidene olefin in the presence of an acid catalyst; and (III) hydrogenating the obtained dimer. Further, there are provided a lubricant composition containing the saturated aliphatic hydrocarbon compound produced by the above process, a bearing oil consisting of the lubricant composition, and making use of the same, a bearing and gyral equipment. The saturated aliphatic hydrocarbon compounds produced by the process of the present invention have low-temperature fluidity, exhibiting low evaporativity, and excellent in thermal stability and oxidation stability. Thus, the saturated aliphatic hydrocarbon compounds are suitable for use as, for example, a base oil of lubricant composition for hydraulic pressure, turbine, working machine, bearing, gear, metal-working, etc.

In late years, lubricants have been required to have fuel-saving characteristics and energy-saving characteristics from the view point of global environmental protection, and also long-drain characteristics from the view point of resource saving. Because of this situation, low-viscosity, thermal resistance, and evaporation resistance will be the challenges of lubricants in the future. Therefore lubricants, which are excellent in thermal stability and oxidation stability, evaporation resistance, and low-temperature fluidity, have been demanded.
In general, any of lubricants may cause a deleterious change in low-temperature startup and a decrease in power efficiency when the viscosity of base oil is too high. On the contrary, if the viscosity is too low, an increase in oil consumption and a bearing damage due to insufficient lubricity may occur. Further, the flow-point, which represents an index of the low-temperature fluidity of the base oil, is preferably −20° C. or less, but not particularly limited to.
In view of improvement of the thermal stability and oxidation stability, synthetic lubricants are preferable. Examples of base oil known in the art include poly-α-olefins, α-olefin copolymers, polybutenes, alkylbenzenes, polyol esters, dibasic acid esters, polyoxyalkylene glycols, polyoxyalkylene glycol esters, polyoxyalkylene glycol ethers, and silicone oils.
The synthetic lubricant has both good points and bad points depending on intended purposes. In many cases, poly-α-olefin is used in consideration of thermal stability and oxidation stability as well as low viscosity. However, the conventional poly α-olefins include many isomers even in the saturated aliphatic hydrocarbon compounds having the same molecular weight, so any particular component (isomer) cannot be taken out by any purification process such as distillation. Thus, even a synthetic oil with a certain viscosity becomes a mixture of a high-volatility component and a low-volatility component. When such a saturated aliphatic hydrocarbon compound is used as a lubricant, the high-volatility component will vaporize at first to cause an increase in viscosity of the lubricant in a machine at work. Therefore, the conventional poly-α-olefins cause frequent repetition of oil change before the maintenance time. The lubricant may be ideally configured to provide oil that allows a mechanical maintenance and a change of oil to be carried out at the same time or to provide oil that does not require any oil-change.
Further, with respect to compressor oils used in compression equipment and so on, in consideration of resource saving and non-pollution, rotary air compressors have been widely used because of their high efficiencies, small oscillations, and small noises, in place of the conventional reciprocating air compressors. The lubricating condition of the rotary air compressor, such as the contact of the lubricant with high-temperature and high-pressure air, is more stringent compared with the reciprocating type. In addition, the recent rotary air compressors have been downsized more than before, and their opportunities to be operated under bad ambient environment such as under oxidative gas (e.g., SOx or NOx) atmosphere or cutting-oil mist atmosphere have been increased. In such cases, sludge arises in the oil. The sludge attaches to the inside of the device and causes a filter blockage in an extremely short time, so the operation of the device may become impossible. Therefore, oil with a high sludge resistance under such an environment has been demanded.
As a process for improving the sludge resistance, in general, there are (1) a process of mixing a base oil having a high solubility of the generated sludge, such as alkylbenzene, alkyl naphthalene, or ester oil, with mineral oil; and (2) a process of adding a detergent-dispersant to mineral oil. However, as a process of most advantageously preventing the generation of sludge by the oxidation stability of base oil itself, a synthetic saturated aliphatic hydrocarbon compound has come to be used as the base oil of compressor oil in stead of mineral oil. In this case, the hydrogenation products of α-olefin oligomers using BF3 catalyst are widely used now. However, this manufacturing process cannot control the molecular distribution of oligomer and generate a myriad of isomers of each of compounds having the same degree of polymerization. Therefore, the product obtained by oligomerization of α-olefin with BF3 catalyst has a large amount of evaporation loss because of an extended boiling-point range with a difficulty in purification. Therefore, the development of a new synthetic oil, which can take the place of such poly-α-olefin has been demanded in the art.
With respect to vacuum-pump oil, as another example, vacuum technologies have been widely used in the fields of semiconductor production, solar cells, aircrafts, automobiles, and opto-electronics. In order to implement these technologies, conventionally, mechanical vacuum pumps such as a reciprocating vacuum pump and a rotary vacuum pump, and high vacuum pumps such as a rotary oil vacuum pump and an oil vacuum diffusion pump, have been widely known in the art. Further, a vacuum-pump oil based on synthetic oil has been used for lubricating, highly vacuating, and prolonging the life of movable parts of these vacuum pumps.
In late years, in association with the expansion of applicable field of the vacuum pump, thermal stability and an extensive degree of vacuum have been demanded and an improvement of vacuum-pump oil to satisfy such demands has been conducted. Further, in the field of application of the vacuum technology, the shortening of time leading to stable operation after activation of a vacuum pump has been demanded for productivity improvement. However, a vacuum-pump oil based on a saturated aliphatic hydrocarbon shows, in particular, poor low-temperature starting characteristics when used during the winter season or on cold district. In other words, such a vacuum pump requires a long time before leading to the stable operation. As a result, there are problems of a decrease in productivity of a target product and a difficulty in obtaining the stable quality of the product. Therefore, the development of novel synthetic oil has been demanded, in which the novel synthetic oil will have fluidity at low temperature and good thermal stability, and is capable of securing a high degree of vacuum and taking the place of the conventionally-used poly-α-olefin.
Further, rotational speeds of spindle motors used in electrical machineries and apparatuses, in particular, CD, DVD, HDD, polygon scanner, and the like have been increased year by year. At present, a high-rotational speed of 10,000 rpm or more is demanded. Conventionally, a rolling bearing typified by a ball-bearing has been used in each of these spindle motors. However, noncontact dynamic pressure fluid dynamic bearing or oil-impregnated sintered bearing have come to be used in terms of performance and cost effectiveness. The performances (mainly running torques) of these fluid dynamic bearing and oil-impregnated sintered bearing at high-speed revolution may be often defined based on the viscosity of lubricant to be used. The running torque at the high-speed revolution tends to lower as the viscosity decreases.
These lubricants should be prevented from undergoing the evaporative loss or destructive loss as far as possible because lubricity should be kept throughout the life without refilling, when these lubricants are once enclosed in a bearing mechanism.
The evaporative loss of hydrocarbon base oil typified by the general mineral oil increases as the viscosity (molecular weight) thereof decreases. Thus, both lowering the viscosity and lowering the evaporativity are hardly attained at the same time. In addition, aiming at this coexistence, the technology using ester, which is a polar compound, in a base oil has been known in the art.
However, for example, when a polar substance such as ester is used, disadvantages may occur such that various resin materials, for example, coating materials such as CD and DVD discs and a structural material such as a motor frame, are deformed or changed in color. In particular, in the case of each of CD and DVD that perform recording with optical signals, a coating resin should be prevented from optically clouding or deforming as far as possible.
In view of the above, there is an environment in that an ester-based oil solution having excellent characteristics cannot be substantially used. In contrast, in the case of CD and DVD discs and motor equipment using large amounts of resin materials, a lubricant using poly-α-olefin, which has lower evaporativities compared with that of mineral oil and excellent thermal resistance, has been conventionally used as a base oil.
The poly-α-olefin, which has been often used, is one obtained by cationic polymerization with BF3 catalyst to oligomerize α-olefin and then hydrogenation thereof. However, this method cannot control the molecular distribution of oligomer and many different isomers even from the respective compounds having the same degree of polymerization are generated. Therefore, the product obtained by oligomerization of α-olefin with BF3 catalyst has an extended boiling-point range with a difficulty in purification, so there is a disadvantage of a lot of evaporation loss.
As a process for manufacturing poly-α-olefin, a process for dimerizing a linear α-olefin using a Ziegler (organic aluminum compound) catalyst and then dimerizing a dimer using a Friedel craft catalyst is known (Patent Document 1).
The Ziegler catalyst of this Patent Document 1 leads to a low yield of a dimer even if a long-chain α-olefin is oligomerized, Therefore, an organic aluminum compound, which is a kind of the Ziegler catalyst, may be employed as dimerization catalyst. In this case, however, the content of vinyliden olefin in the dimer is low even though the dimerization of the organic aluminum compound advances. Thus, there is a disadvantage in that the dimer will lead to a low content of α-olefin tetramer even though it is subjected to dimerization and hydrogenation.
For the oligomerization of decene, acid catalyst (such as BF3) has been currently used and a decene trimer hydride with a low flash point has been produced while having a high viscosity (Patent Document 2). In addition, in late years, a dewaxing lubricant obtained by oligomerizing decenes has been introduced. However, even if kinematic viscosities can be coincident with each other, any lubricant having low-temperature fluidity with high flash point cannot be obtained in the same kinematic viscosity (Patent Document 3).
In addition, as a process for producing a decene oligomer, there is known that a decene oligomer having a number average molecular weight of 500 to 200,000 is produced using a metallocene catalyst, subsequently hydrogenated as needed, and used as a lubricant base oil (Patent Document 4). In this process, for example, the oligomerization of C10 (decene) leads to a decrease in a production ratio of C20, C30, and C40 in this order, and a high yield of C40 cannot be attained.    Patent Document 1: GB 961903 B    Patent Document 2: JP 10-504326 A    Patent Document 3: JP 2002-502436 A    Patent Document 4: JP 2002-518582 A

Process for producing saturated aliphatic hydrocarbon compound, and lubricant composition


A method for providing a 3D image data record of a physiological object with a metal object therein is proposed. To enable an image of the metal object in the physiological object, for instance a biopsy needle in a human patient to be recorded as a 3D image in this patient, two 2D x-ray images of the patient are obtained with the needle with the aid of a biplane x-ray system, and back projection allows a 3D image data record to be generated, which is then subject to a filtering with a gray-scale value window. After filtering, information relating to the position and shape of the metal object in space is obtained. The thus obtained first 3D image data record can be combined with another 3D image data record, in particular with a 3D image data record of the patient without the metal object obtained with the same biplane x-ray system.

Thus for instance, during the biopsy of a tumor, a hollow needle is pushed into the patient in order to take tissue samples of the tumor which can then be analyzed later in a lab. It must be ensured here that the removed sample is part of the non-necrotic tumor mass. The needle must therefore be pushed into the tumor very precisely. A type of needle navigation is therefore needed. The navigation takes place under the supervision of the physician, who observes images of the needle located in the tissue and refers thereto during insertion thereof. Automatic modes of navigation are also conceivable.
The said method for tumor biopsy applies equally to other methods in which a needle is inserted into the patient body, for instance to the so-called vertebroplasty, in which bone cement is introduced into a broken bone, in particular a vertebra.
Previously during the intervention, fluoroscopic images of the needle were overlayed with images taken prior to the intervention. Since only one representation of the needle from one single perspective was previously available, at best two with biplane x-ray systems, the positioning of the needle with the aid of images is not easy for the treating physician.

Method for providing a 3D image data record of a physiological object with a metal object therein


A device (10) is provided for matching the CTE between substrates (12, 14), e.g., a semiconductor substrate and packaging material. The first substrate (12) has a first coefficient of thermal expansion and the second substrate (14) has a second coefficient of thermal expansion. At least two layers (16) of liquid crystal polymer are formed between the first substrate (12) and the second substrate (14), each layer having a unique coefficient of thermal expansion progressively higher in magnitude from the first substrate (12) to the second substrate (14).

With the growth of the use of personal communication devices, e.g., cell phones and two way radios, high performance and high frequency packaging materials have increased in importance. Desired characteristics for electronic packaging include high electric and thermal performance, thinness, low weight, small size, high component density, and low cost.
When attaching an integrated circuit to a packaging material, e.g., a printed circuit board or a polymer material, it is known that the coefficient of thermal expansion (CTE) of the integrated circuit and the packaging material must be matched. When the CTE of the two materials are matched, the two materials will expand and contract simultaneously over temperature so as to avoid deformities, cracking, detachment, and loss of functionality, especially after a number of temperature cycles. The importance of this matched CTE becomes apparent in many applications having large temperature swings, e.g., automotive electronics.
Conventional packages are fabricated from materials such as plastic, Teflon or ceramics. The type of material that is used depends on a number of factors which include frequency of operation, environment and cost. Plastic packages are typically the lowest in cost but may not be suitable for high frequencies of operation or very high temperatures. Applications that require exposure to extreme temperatures will commonly use ceramics. The metallization that can be used will typically differ depending on the packaging material. As the frequency of operation increases, factors such as surface roughness and metal thickness become important. In addition to these factors, as the frequency of operation increases it becomes advantageous to utilize materials that have lower dielectric constants to allow for the implementation so that the final package, with interconnects, will avoid noise or signal loss associated with high speed circuits
One known solution is to place the integrated circuit on the substrate and within a hole formed in a liquid crystal polymer material; however, this adds complexity to the manufacturing process.
Another known solution involves the formation of a single layer of liquid crystal polymer between two non-liquid crystal polymer substrates; however, this results in layers that will not have as good a performance at a high frequency as liquid crystal polymer.
Accordingly, it is desirable to provide a liquid crystal polymer package that matches the CTE of an integrated circuit to that of the packaging material. Furthermore, other desirable features and characteristics of the present invention will become apparent from the subsequent detailed description of the invention and the appended claims, taken in conjunction with the accompanying drawings and this background of the invention.


A spoked bicycle wheel hub is provided. The hub has a central tubular portion and a pair of side caps, whose diameter is larger than the central tubular portion. The hub is a monolithic fiber-reinforced plastic structure where the central tubular portion and the side caps form a continuous surface.

This invention relates to a wheel hub for a bicycle, specifically a competition bicycle.
The main objective of the competition bicycle manufacturers is to reduce the weight of the single components as much as possible. In the case of wheel hubs, conventional technology involves the use of metallic light alloys, such as aluminium alloys and similar. Various solutions have been proposed to reduce the weight of the wheel hub in which the central tubular part of the wheel hub is made of carbon fiber incorporated in a plastic material resin and in which a pair of side caps made of aluminium alloy are fastened to the ends of the carbon fiber central portion. The inside caps are provided with housings for supporting rolling bearings and holes for anchoring the wheel spokes.
The objective of this invention is to provide a wheel hub which is lighter and presents better characteristics in terms of rigidity with respect to the known solutions mentioned above.


A process for deinking wastepaper, which comprises: (a) forming an organoclay deinking agent in an aqueous system; (b) contacting ink from wastepaper in the aqueous system with an amount of the organoclay deinking agent effective to deink the wastepaper; and ( c ) recovering deinked paper pulp from the aqueous system.

The present invention relates to a process for removing ink from wastepaper in order to provide paper pulp that may be reused to manufacture new paper-based products. In particular, the invention is directed to a process for removing both water-based and oil-based inks from wastepaper by means of a novel group of deinking agents. 2. Description of the Prior Art
Recycled wastepaper has traditionally been a source of raw fiber materials needed in the papermaking industry. In the past, fiber from wastepaper was only employed in the production of low grade paper and paperboard products. Today, however, reclaimed fiber comprises about 25 percent of the total fiber used to manufacture paper, thereby providing an incentive for improving the utility of reclaimed paper pulp materials. In particular, recent efforts have attempted to develop techniques for effectively removing ink from waste fibers, in order to permit their use in the manufacture of high quality paper.
In conventional paper reclamation processes, deinking is carried out by converting the wastepaper to a pulp and contacting the pulp with an alkaline aqueous deinking medium containing a chemical deinking agent, in order to remove ink and other impurities from the pulp fiber and produce a suspension or dispersion of the ink and other particles in the aqueous medium. The resulting mixture is subsequently treated to separate the suspended ink and other particles from the pulp, for example, by air sparging and floatation of the ink/deinking agent complex, followed by skimming to remove the ink and other particles from the treatment bath, or by filtration and subsequent water washing of the fiber mat to remove dispersed ink particles.
There have been numerous attempts in the prior art to improve the efficacy of conventional deinking processes. For example, U.S. Pat. No. 4,618,400 discloses a method for deinking wastepaper which involves converting the wastepaper to a pulp; contacting the pulp with an aqueous medium of alkaline pH containing about 0.2 to 2% by weight of a deinking agent which is one or a mixture of certain thiol ethoxylate compounds; and removing suspended or dispersed ink from the pulp-containing medium.
U.S. Pat. No. 4,666,558 illustrates a deinking process for waste newsprint, which involves contacting and agitating a pulped newsprint in an aqueous medium containing a deinking agent comprising a particular mixture of a water-soluble C.sub.9 to C.sub.16 alkanol ethoxylate component and an oil-soluble C.sub.9 to C16 alkanol ethoxylate component, and recovering deinked pulp from the aqueous medium.
U.S. Pat. No. 3,932,206 describes deinking agents which are said to be non-toxic to aquatic life; the disclosed compounds consist of ethoxylated aliphatic mono-or diols.
Japanese Patent Publication 59-150191 discloses a process for deinking wastepaper by macerating the paper in the presence of a fatty acid salt, and then subjecting the paper to a quaternary ammonium surfactant.
Soviet Union Patent 926129 provides a composition for removing printing ink from wastepapers, which contains quaternary ammonium and phosphonium surfactants, isoamyl alcohol, phosphine oxide, butyl xanthogenate, and solvent.
U.S. Pat. No. 4,867,844 discloses a method of treating fibrous materials, by applying an organophilic complex formed from a clay (preferably bentonite) and an organic radical derived from an onium compound (preferably quaternary ammonium compound).
Japanese Patent Publication JP3119189 discloses a method of removing fibrous contaminates from the white water resulting from paper making by separately adding clay and a cation-surface-active bonding agent. The bonding agent disclosed is stearyl-trimethyl ammonium chloride.
Despite the foregoing efforts, it is generally agreed that no completely acceptable process for deinking wastepaper presently exists. One shortcoming of many of the prior art deinking techniques is the inability of these processes to simultaneously remove both water-based and oil-based inks from the wastepaper. The removal of water-based (flexographic) inks from wastepaper has proved to be a particularly troublesome problem associated with known flotation deinking processes. For example, standard fatty acid soap chemistry cannot collect the highly dispersed water-based ink waste. The removal of water-based inks from wastepaper using washing deinking processes also presents problems because of the use of large volumes of water and the need to treat the water so that the water can be recycled. In this regard, substantial costs are associated with processing wastepaper materials to separate water-based ink containing materials from those which contain oil-based inks.
Moreover, deinking agents utilized to date have been ineffective in removing tacky contaminants from wastepaper. These tacky contaminants (from pressure sensitive labels, binding materials and glues) are frequently encountered in wastepaper deinking processes, and tend to limit the quality of the final recycled product.
It would therefore be highly desirable to provide a process for deinking various types of wastepaper which contain water-based and/or oil-based inks. In addition, it would be advantageous if such a deinking process could also remove tacky contaminants from the treated wastepaper, in order to enhance the quality of deinked paper pulp yielded by the process.

Process for deinking wastepaper utilizing organoclays formed in situ


The indoor blower scroll structure includes integrally formed vent and exhaust port walls with associated doors attached thereto. A single actuator mechanism is also attached to the scroll structure and is mechanically linked to both doors to thereby provide a single and reliable actuation assembly, all of which is mounted on the scroll structure. In a preferred embodiment, the actuator comprises a single, lever actuated cam which directly engages levers on both the vent and exhaust doors.

This invention relates generally to air conditioning systems and, more particularly, to a mechanism for actuating the vent and exhaust doors of a room air conditioner.
A room air conditioner is a self-contained unit having outdoor and indoor sections which are divided by a transversely extending partition wall. The outdoor section includes a condenser coil and a fan for circulating outdoor air through the condenser coil to thereby cool the refrigerant flowing through the system. The indoor section includes an evaporator coil and a blower which draws in the relatively warm room air, passes it through the evaporator coil to be cooled, and then discharges the cooled air back into the room.
Rather than continuously recirculating the same room air, it is sometimes desirable to exhaust some of the stale room air to the outside. Further, it may be desirable, especially in cooler ambient temperature conditions, to bring in the outdoor air for distribution into the room. These functions have traditionally been accomplished with the use of exhaust and vent ports, respectively, which, when opened, allow the selective flow of air between the outdoor and indoor sections. The doors are commonly located in strategic positions so as to take advantage of the pressure differences to selectively cause the outdoor air to flow through the vent port into the indoor section or for the indoor air to flow through the exhaust port to the outdoor section.
Since the pressure differences are normally sufficient only for one or the other of the vent and exhaust functions but not for both simultaneously, it has become common practice to provide a single selector mechanism to operate both devices, with a single handle operating to open one door at a time. However, because of the need to locate the two doors in different locations, as required by the pressure drop needs discussed hereinabove, the control mechanism has normally been mounted on a different component from one or both of the doors. In some cases, even the vent and exhaust doors are mounted on different components. Typical of such devices is that shown in U.S. Pat. No. 3,823,574 assigned to the assignee of the present invention. While effective, these devices have been relatively complex and have traditionally involved a relatively large number of interconnecting parts. Thus, besides the obvious disadvantages of complicating the assembly and operation processes, the proper spacial interrelationships between the various parts have been found to be somewhat difficult to establish and maintain. That is, not only is there a tolerance stackup from the combination of the numerous parts, but the difficulties in maintaining proper alignment in operation are exacerbated by the fact that these various components are attached to different mounting members whose relative positions are difficult to control. For example, in the system described in the above mentioned patent, the doors are mounted to the partition but the operating levers are mounted to the control box. Since the position of the control box relative to the partition may vary, it may lead to an improper fit or operation of the control mechanism interconnecting the lever and the doors.
It is therefore an object of the present invention to provide an improved vent/exhaust door actuation mechanism.
Another object of the present invention is the provision in a room air conditioner for a reduced number of parts in the mechanism which operates the vent and exhaust doors.
Yet, another object of the present invention is the provision for maintaining the proper operational alignment between the various components of the vent and exhaust door actuation mechanism.
Yet, another object of the present invention is the provision for a vent/exhaust door mechanism which is easy and simple to manufacture and assemble, and is effective and reliable in use.
These objects and other features and advantages become more readily apparent upon reference to the following description when taken in conjunction with the appended drawings.

Actuation mechanism for vent and exhaust doors


General purpose methods for the fabrication of integrated circuits from flexible membranes formed of very thin low stress dielectric materials, such as silicon dioxide or silicon nitride, and semiconductor layers. Semiconductor devices are formed in a semiconductor layer of the membrane. The semiconductor membrane layer is initially formed from a substrate of standard thickness, and all but a thin surface layer of the substrate is then etched or polished away. In another version, the flexible membrane is used as a support and electrical interconnect for conventional die bonded thereto. Multiple die can be connected to the membrane, which is then packaged as a multi-chip module. Other applications are based on membrane processing for bipolar and MOSFET transistor fabrication, low impedance conductor interconnecting fabrication, flat panel displays, maskless (direct write) lithography, and 3D IC fabrication.

1. Field of the Invention
This invention relates to methods for fabricating integrated circuits on and in flexible membranes, and to structures fabricated using such methods.
2. Description of Related Art
Mechanically and thermally durable free standing dielectric and semiconductor membranes have been disclosed with thicknesses of less than 2 xcexcm. (See commonly invented U.S. Pat. No. 4,924,589, and U.S. patent application Ser. No. 07/482,135, filed Feb. 16, 1990, now U.S. Pat. No. 5,103,557, both incorporated herein by reference). This disclosure combines the novel use of these technologies and other integrated circuit (IC) processing techniques to form ICs as membranes typically less than 8 xcexcm thick. This approach to IC fabrication falls under the generic industry-established title known as Dielectric Isolation (DI), and is inclusive of subject areas such as Silicon-on-Insulator (SOI) and Silicon-on-Sapphire (SOS). ICs formed from dielectric and semiconductor membranes can reduce significantly the number and complexity of processing steps presently used to provide complete IC device isolation; dielectric isolation techniques that provide dielectric isolation on all surfaces of the individual circuit devices comprising the complete IC are not as yet widely used in volume IC fabrication. Integrated Circuits are defined as commonly understood today when referring to SSI, MSI, LSI, VLSI, ULSI, etc. levels of circuit complexity.
This invention is directed to a general method for the fabrication of integrated circuits and interconnect metallization structures from membranes of dielectric and semiconductor materials. The fabrication technology in accordance with this invention is referred to herein as Membrane Dielectric Isolation (MDI), and the circuits made from it as circuit membranes. The novel use of materials and processing techniques provides for the fabrication of high temperature, mechanically durable, large area free standing membranes (greater than 1 square cm in area) from low stress dielectric and/or semiconductor films. These membranes permit the application (continued use) of most of the established integrated processing methods for the fabrication of circuit devices and interconnect metallization.
In accordance with the invention, an integrated circuit is formed on a tensile low stress dielectric membrane comprised of one layer or a partial layer of semiconductor material in which are formed circuit devices and several layers of dielectric and interconnect metallization. Also, a structure in accordance with the invention is a tensile membrane of semiconductor material in which are formed circuit devices with multiple layers of tensile low stress dielectric and metallization interconnect on either side of the semiconductor membrane.
The membrane structure is a processing or manufacturing structure for enabling the manufacture of novel and more cost effective integrated circuits. This is in addition to an objective to manufacture an integrated circuit, or portion thereof, in a membrane or thin film form.
The general categories of circuit membranes that can be made by this invention are:
1. Large scale dielectric isolated integrated circuits formed on or from semiconductor or non-semiconductor substrates.
2. Multi-layer interconnect metallization circuits formed on or from semiconductor or non-semiconductor substrates.
The primary objectives of the MDI fabrication technology disclosed herein are the cost effective manufacture of high performance, high density integrated circuits and integrated circuit interconnect with the elimination or reduction of detrimental electrical effects on the operation of individual circuit devices (e.g. diodes, transistors, etc.) by completely isolating with a dielectric material each such circuit device from the common substrate upon which they are initially fabricated, and therefore, from each other, and to provide a more versatile and efficient physical form factor for the application of integrate circuits. Some of the benefits of the MDI IC fabrication process are the elimination or reduction of substrate current leakage, capacitive coupling and parasitic transistor effects between adjoining circuit devices. The MDI IC fabrication process benefits extend to several other categories of IC fabrication such as lower IC processing costs due to fewer IC isolation processing steps, greater IC transistor densities through the capability to use established IC processing techniques to fabricate interconnect metallization on both sides of a MDI IC circuit membrane, and greater IC performance through novel transistor structures.
The strength of the MDI processes is primarily drawn from two areas:
(1) The ability to make a large area flexible thin film free standing dielectric membrane, typically framed or suspended or constrained at its edges by a substrate frame or ring, or bonded frame or ring. This membrane is able to withstand a wide range of IC processing techniques and processing temperatures (of at least 400xc2x0 C.) without noticeable deficiency in performance. The present dielectric materials that meet these requirements are silicon dioxide and silicon nitride films when prepared with specific low stress film deposition recipes for instance on equipment supplied by Novellus Systems, Inc. Dielectric free standing films created by CVD process methods such as silicon carbide, boron nitride, boron carbon nitride aluminum oxide, aluminum nitride, tantalum pentoxide, germanium nitride, calcium fluoride, and diamond have been produced, and can potentially be used as one of the dielectric materials in a MDI circuit membrane when deposited at an appropriate level of surface stress. Advances in the technology for making low stress dielectric films will likely produce additional free standing films that can be used as described herein.
(2) The ability to form a uniform thin film single crystal semiconductor substrate either as the primary substrate of semiconductor devices or as a carrier substrate upon which semiconductor devices could be grown epitaxially. Several methods toward this end are disclosed herein, and other techniques which are modifications thereof exist. Further, in certain applications polycrystalline semiconductor membranes such as polysilicon can be used in substitution for monocrystalline material.
It is the combination of the use of low stress free standing dielectric films with the appropriate processing qualities and membrane or thin film single crystalline (monocrystalline), polycrystalline or amorphous semiconductor substrate formation that provides much of the advantage of the MDI IC fabrication process. The following methods are encompassed within the present disclosure:
1. Methods for the fabrication of low stress free standing (thin film) dielectric membranes that encapsulate each semiconductor device that comprises an IC.
2. Methods for the formation of uniform thickness semiconductor membrane (thin film) substrates for use in combination with low stress dielectric materials.
3. Methods for the fabrication of semiconductor devices within and on a dielectric membrane that comprises a circuit membrane.
4. Methods for the formation of interconnect metallization structures within and on a dielectric membrane that comprises a circuit membrane.
The MDI circuit fabrication process in one embodiment starts with a semiconductor wafer substrate, and results in an IC in the form of a circuit membrane where each transistor or semiconductor device (SD) in the IC has complete dielectric isolation from every other such semiconductor device in the IC. Only interconnect at the specific electrode contact sites of the semiconductor devices provides electrical continuity between the semiconductor devices. The primary feature of the MDI process is complete electrical isolation of all semiconductor devices of an IC from all of the intervening semiconductor substrate on which or in which they were initially formed and to do so at lower cost and process complexity than existing bulk IC processing methods. Other features of the MDI process are vertical electrode contact (backside interconnect metallization), confined lateral selective epitaxial growth, non-symmetric dopant profiles, and the use of a MDI circuit membrane to serve as a conformal or projection mask for lithography processing. Even if the initial substrate with which MDI processing begins with is the most commonly used semiconductor silicon, the resulting IC need not be composed of silicon-based devices, but could be of any semiconductor device material such as GaAs, InP, HgCdTe, InSb or a combination of technologies such as silicon and GaAs grown on a silicon substrate through epitaxial means. Silicon is an inexpensive and well understood semiconductor substrate material with superior mechanical handling properties relative to most other presently established semiconductor materials. The MDI process is not limited to starting with a silicon substrate and the process definition of MDI is not dependent on use of silicon; however, there are presently clear advantages to using silicon as a starting semiconductor substrate, and the chief embodiment disclosed herein of MDI uses a starting semiconductor substrate material of silicon.
The benefits to fabricating an IC with the MDI process are significant over prior art methods, some of these benefits being:
1. Complete electrical isolation of semiconductor devices.
2. Vertical semiconductor device structures.
3. Lower processing costs through lower processing complexity or fewer device isolation processing steps.
4. Conformal mask lithography through the membrane substrate.
5. Control of depth of focus during lithography exposure due to control of substrate thickness.
6. Application of interconnect metallization to both sides of the IC.
7. Through-membrane (substrate) interconnect metallization routing.
8. Three dimensional IC structures through the bonding of circuit membrane IC layers.
9. Efficient conductive or radiant cooling of IC components of circuit membrane.
10. Direct optical (laser) based communication between parallel positioned membrane ICs.
11. Higher performance ICs.
12. Vertical semiconductor device structure formation.
13. Novel selective epitaxial device formation.
In some semiconductor technologies it is not necessary to have complete isolation between each transistor or semiconductor device, such as certain applications using polycrystalline or amorphous TFTs (thin film transistors). This is not a limitation on the MDI process, because semiconductor device side wall isolation is an option in the MDI process. What is novel is that the MDI process provides general methods by which thin films or membranes of dielectric and semiconductor materials can be formed into a free standing IC or circuit membrane.