Ultraweak Photon Emission as a Non-Invasive Health Assessment: A Systematic Review

We conducted a systematic review (SR) of the peer reviewed scientific literature on ultraweak photon emissions (UPE) from humans. The question was: Can ultraweak photon emissions from humans be used as a non-invasive health assessment? A systematic search was conducted across eight relevant databases: PubMed/MEDLINE, BIOSIS, CINAHL, PSYCHINFO, All of Cochrane EBM databases, GIDEON, DoD Biomedical Research, and clinicaltrials.gov from database inception to October 2011. Of the 1315 studies captured by the search strategy, 56 met the inclusion criteria, out of which 1 was a RCT, 27 were CCT, and 28 were observational and descriptive studies. There were no systematic reviews/meta-analyses that fit the inclusion criteria. In this report, the authors provide an assessment of the quality of the RCT included; describe the characteristics of all the included studies, the outcomes assessed, and the effectiveness of photon emission as a potential health assessment tool. This report demonstrates that the peer reviewed literature on UPE and human UPE measurement in particular is surprisingly large. Most of the human UPE literature is of good to high quality based on our systematic evaluation. However, an evaluation tool for systematically evaluating this type of “bio-evaluation” methodology is not currently available and would be worth developing. Publications in the peer reviewed literature over the last 50 years demonstrate that the use of “off-the-shelf” technologies and well described methodologies for the detection of human photon emissions are being used on a regular basis in medical and research settings. The overall quality of this literature is good and the use of this approach for determining inflammatory and oxidative states of patients indicate the growing use and value of this approach as both a medical and research tool.


Introduction
Bioluminescence is the process of production and emission of light by a living organism via chemiluminescence-based processes. Many examples are known in biology such as fireflies, Antarctic krill, fungi (for instance Panellus stipticus), various squid species, etc.
In fact, all cells produce some form of light emission, but most of this light is not visible to the unaided human eye. This photonic emission has characteristic wavelengths, duration, timing and patterns of flashes. These are features often associated with information and, while not proof in and of itself, it is reasonable to assume that these light emissions contain and carry information about the biological systems that produced it.
Ultraweak photon emission by living systems, sometimes called low level chemiluminescence, is the result of normal biochemical reactions in which electrons transition in and out of electronically excited states. Detection and identification of these excited states is easily achieved in well-defined chemical systems. However, the task becomes more problematic in complex biological systems, e.g., in studies of isolated cells, organs, or intact organisms.
The advent of new photon counting technologies in the early 1960's provided the tools to demonstrate the existence of a ubiquitous low level luminescence in organisms. This provided convincing evidence that light from living organisms was not restricted to life forms having special organs containing enzyme systems such as luciferase/luciferin. This early work was primarily done in the USSR [1,2] with a few exceptions [3]. Russian research was sometimes translated into English [4]. By that time it had been established in inorganic chemical systems that chemiluminescence could occur in oxidative reactions as a consequence of the recombination of oxygen-containing radicals [5,6] and thus provided information about radical reactions and oxidation mechanisms. Outside the USSR, the existence of this radiation was neglected or considered a phenomenon that could be caused by external interferences of an unknown nature [7]. In the 1970's, the existence of this photonic emission from living organisms was confirmed by research teams from Australia [8], Poland [9], Japan [10] and the USA [11]. Emissions are in the order of 10-10 4 photons/s.cm 2 , and have been demonstrated in bacteria, yeast, whole animals and plants as well as cells and homogenates from organisms.
For yeasts (Saccharomyces cerivisiae and Schizosaccharomyces pombe) it was established that ultraweak photon emission was dependent on oxygenation and that spectral composition differed between the exponential growth and the stationary phase of the culture [8,12,13,14]. Similar studies were later performed on the bacterium Escherischia coli [15,16]. In mammalian systems UPE was studied at the organ, cellular and subcellular level. Ultraweak photon emission of rat liver was oxygen dependent, and increased by infusion of hydroperoxides. Spectral analysis indicated a predominance of red light-emitting species arising from the singlet oxygen dimole-emission peaks [11,17]. Similar spectral data as well as oxygen dependency were obtained with isolated hepatocytes. Estimations of biochemical markers of lipid peroxidation combined with counts of photon emission led to the conclusion that UPE monitors the steady state concentration of singlet molecular oxygen [10,11,17,18,19]. Therefore, ultraweak photon emission can provide a useful tool to examine oxygen-dependent radical damage which affords an advantage over parameters (such as malondialdehyde levels) measuring accumulative effects.
Since the early 1980's, it has been known that peroxidal lipid reactions are important components in the etiology of diabetes, liver and lung diseases, arteriosclerosis, ageing and cancer [20,21,22,23,24]. The production of oxygen radicals during the respiratory burst of phagocytic cell activity plays an essential role in bacterial killing and in regulating the processes of acute inflammation [25,26]. In view of the damaging effects of oxygen radicals on tissues, it follows that anything causing abnormal activation of phagocytes has the potential to provoke a selfdestructive response, most strikingly seen in autoimmune diseases [27]. This realization led to the idea that ultraweak photon emission determined in blood might be a general marker for health and could be used for diagnostic and clinical purposes [28,29]. Early studies established the interdependence between various diseases and UPE intensity by measuring the differences between the luminescence of the blood of healthy and diseased human subjects. UPE of blood from patients with diabetes mellitus, carcinomas and hyperlipidemia showed higher emission levels than those of the samples from healthy people [28].
The development of a diagnostic assay based on ultraweak photon emission remained limited due to difficulties and requirements of ultra-high sensitive photon counting systems in the application to biomedical measurements [10,28]. The use of chemiluminigenic probes -substances whose oxidation gives a high yield of electronically excited products -solved many of these issues by increasing the photon output by several orders of magnitude. For this purpose luminol at concentration 0.1-10 mM has been employed, for instance in assays of phagocytosis [25,30,31,32]. Lucigenin has also been sporadically used as a chemiluminigenic enhancer [26].
The next great challenge for the field of ultraweak photon emission detection (in relation to oxidative processes) was to provide images of these low signals in addition to physiological information. A two-dimensional photon counting imaging of a rat's brain was technically achieved in 1999 [33,34]. The equipment used in this first experiment consisted of a twodimensional photon counting tube, a highly efficient lens system, and an electronic device to record time series of a photoelectron train with spatial information. Another application of twodimensional imaging of these photon emissions has been in the field of cancer. In bladder cancer, transplanted into the feet of nude mice, the increase in photon emission in early developing cancer indicates the actively proliferating cancer before any detection of necrosis, haemorrhage, leukocyte infiltration or crusta formation [35]. Cancer imaging in mice transplanted with ovarian cancer cells utilizing a highly sensitive charge-coupled device (CCD) camera system has confirmed the increased UPE of tumours [36].
The major trends over the last 50 years are schematically shown in Figure 1. Since the original observation of the effect, UPE detection methodology has matured to be uniquely positioned for not only providing insight into detailed biochemical processes but also provide a non-invasive tool for observing and even understanding system organisation.
Knowledge of the excitation state of biochemical reactions in organisms and isolated biological systems is of significant value for assessing basic biological function. In the case of whole organisms, a general and often specific assessment of health and wellness is possible with knowledge of the ''reactive'' or relative excitation state of intrinsic biochemical reactions. Therefore, it is possible, using detection and quantification of ultraweak photon emission, to non-invasively assess a person's health, specifically the level of stress on biochemical and metabolic systems from the production of reactive oxygen species (ROS) as ROS are the principle source of these photons [5,6,22]. The 50 years of progress in this field has, thanks to advances in technologies for measuring ultraweak photon emissions, led to the emerging discipline of 'human photon emission'.
To date, there have been no reviews of the literature to ascertain if ultraweak photon emission can be effectively used as a noninvasive health assessment tool. The purpose of this systematic review was to: 1) survey the literature on ultraweak photon emissions as they relate to human studies; 2) assess the quantity and quality of the research found; and 3) characterize the results by whether the study had an intervention or not, 4) what research model was studied, and 5) the potential value of using photons as a health assessment tool.

Search strategy
A systematic search was conducted across eight relevant databases: PubMed/MEDLINE, BIOSIS, CINAHL, PSY-CHINFO, All of Cochrane EBM databases, GIDEON, DoD Biomedical Research, and clinicaltrials.gov from database inception to October 2011. The keywords related to photon were preidentified by the team with guidance from subject matter experts. The final search terms decided upon and searched across databases were: photon, external bioenergy, spontaneous photon emission, ultraweak photon emission, ultraweak chemiluminescence, low level light emission, spontaneous chemiluminescence, ultraweak photons, ultra-weak photon emission, ultra-weak photons, ultra-weak chemiluminescence. See Appendix S1 for a full detail of the search in PubMed. Variations of this strategy were adapted for each unique database and are available upon request.
The search was limited to English language and human population only where databases allowed for these limitations. There was no limitation to study design in the initial search. Grey literature was searched by accessing and communicating with subject matter experts in the field and sharing their database collections as a cross reference to what the original search strategy retrieved as well as conducting basic internet searching across the keyword scheme. The reviewers also hand-searched bibliographies of all included studies to ensure that a comprehensive search strategy was used.
control trial (RCT) study designs were considered. Studies were included in the analysis if they were: 1) in human populations, 2) describing the use of photons as a health assessment tool, 3) used in comparison with a placebo control or untreated control for the systematic review assessment, and 4) measuring ultraweak photon emission. Studies were excluded if they were categorized as: thought pieces, descriptive reviews, editorials, and all studies relating primarily to the physics of photons.

Study selection
Three reviewers independently screened the titles and abstracts of all retrieved references according to the inclusion criteria presented above. All studies had to have some discussion concerning intrinsic light from live subjects in order to be considered for inclusion. Full text articles were pulled for all publications where a reviewer felt there was a potential for meeting inclusion criteria. At this point all study designs were included.

Quality assessment and data extraction
The retrieved full-text articles were put into buckets of study designs by RCT, CCT, observational, descriptive, and mixed methods in order to assess the quantity and quality, and describe the characteristics of the individual included studies.
The RCT study design was assessed for quality according to the Scottish Intercollegiate Guidelines Network (SIGN 50) [37], a well-accepted and validated tool for assessing quality used widely in both complementary and alternative medicine (CAM) and conventional literature (see Table 1 for a full description of the SIGN 50 criteria). Because all of the rest of the studies reported here involved photons as an adjunctive assessment of the inflammatory state and not as the primary diagnostic assessment or necessarily including an intervention per se, the authors felt that the full SIGN criteria was not a good fit for evaluating the quality of the photonic portion of these studies. After examining the other quality assessment tools, the authors decided that none fit the photonic literature examined here. Because of this, the CCT study designs were only assessed across one of the criteria addressed in SIGN that fit. The other study designs (observational, descriptive and mixed methods) were only tallied as to how many fit the inclusion criteria laid out above.
A data extraction form was created during the protocol development stage and tested by the team before use. This form captured details on the system of research, the objective of the study, the conditions and descriptions of the study population, the type of control, the specific outcomes and results related to photon emission and the authors' main conclusions in order to provide a descriptive detail of the characteristics of the included studies.
All five reviewers were trained in the methodology for quality assessment and data extraction by the review manager (C.C.) and a rule book was created to assist in answering the questions objectively and consistently, which ensured reproducibility in the end, which was pilot tested among the team members. Forms were created in an online system offered through the Samueli Institute's SharePoint cite to allow the reviewers to complete the data extraction. The 5 trained reviewers simultaneously extracted the data independently of each other (two reviewers assigned to each individual article) and all answers were tracked through this system. Any and all conflicts were resolved through discussions in team meetings. Once collected, all data was downloaded into an Excel table for each study and formatted in preparation for inclusion in Tables 2-4.
All included studies were then characterized as to whether there was an intervention and what system of research they fell into (whole body, cells [blood cells, other cells], fluids [blood plasma, urine, cerebral fluid, saliva], and other [tissue]). These categories were chosen not only because the articles naturally broke into these categories but also they make intrinsic bio-medical sense.
The effect size was not calculated due to the heterogeneity of the trials identified during the review phase. All assessments were Each item in Section 1 is to be evaluated using these criteria: 1) Well Covered, 2) Adequately Addressed, 3) Poorly Addressed, and 4) Not Applicable (NA) only for question 1.10.

1.1
The study addresses appropriate and clearly focused question.

1.2
The assignment of subjects to treatment groups is randomized.

1.3
An adequate concealment method is used.

1.4
Subjects and investigators are kept blind about allocation.

1.5
The treatment and control groups are similar at the start of the trial.

1.6
The only difference between groups is the treatment under investigation.

1.7
All relevant outcomes are measured in a standard, valid and reliable way.

1.8
What percentage of subjects in each treatment arm dropped out before the study was completed?
1.9 All subjects are analyzed in the groups to which they were randomly allocated (intention to treat analysis).

1.10
Where the study is carried out at more than one site, results are comparable for all sites.

Section 2: Overall Assessment
How well was the study done to minimize bias? How valid is the study? Score options: ++, +, -based on following (modifications to SIGN criteria in italics):

++
All or most of the criteria have been fulfilled. Where they have not been fulfilled the conclusions of the study are thought very unlikely to alter. An article receives this score if there are 0 criteria scored as poorly addressed.

+
Some of the criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions.
An article receives this score if 1-2 criteria are scored poorly addressed.
-Some of the criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions.
An article receives this score if 1-2 criteria are scored poorly addressed.
Note that only the RCT in Table 2 was assessed across all quality criteria in SIGN 50. For all CCT study designs in Tables 3 and 4 A based on information provided in the published manuscripts that met the inclusion criteria.

Results
Of the 1315 studies captured by our search strategy, 56 met the inclusion criteria, out of which 1 was a RCT, 27 were CCTs, and 28 were observational and descriptive studies. There were no systematic reviews/meta-analyses that fit our inclusion criteria. See Figure 2 for a graphical depiction of the study selection and elimination process throughout the review phases. In this report, the authors provide an assessment of the quality of the RCT included; describe the characteristics of all the included studies, the outcomes assessed, and the effectiveness of photon emission as a potential health assessment tool. The RCT and CCT study designs are presented descriptively in Tables 2-4. Other formal study designs included are narratively summarized below and will be reported on in more detail in future publications.

Quality assessment of RCT
Of the 56 included studies, only one was categorized as a RCT. In this study, the effect of plant adaptogens on human ultraweak photon emission was determined by providing subjects with supplements of Rhodiola rosea, placebo pills, or ADAPT-32 (mix of adaptogens) for one week, and measuring the ultraweak photon emission from the dorsal side of their hands. The results show a significant decrease in photon emission (p = 0.027), as well as in reported fatigue levels (p = 0.049) in the Rhodiola group compared to the placebo group. However, this work would have been better with the groups approximately matched for age. This RCT received an overall quality score of (+) according to the SIGN 50 criteria. The authors did not provide a full description of the randomization process and allocation concealment methodology in the published report. Although they did not address these important components, because of the strength in the other criteria assessed the conclusions of the study are thought unlikely to be altered by the inclusion of this missing information. We also believe there is a low level of bias being introduced to this study. Further studies employing an RCT design are needed to determine the value of photon emission measurement as a tool for assessing the impact of supplement use as well as other interventions meant to improve health. See Table 2 for further details of the study [38].

Controlled clinical trials
Of the 56 included studies, 27 were characterized as CCT study design, out of which 17 studies involved no intervention (Table 4) while the remaining 11 studies had an intervention (Table 3). It is interesting to note that most interventional studies came up in the literature post-2003 with the exception of Hans 1997 [39], whereas all of the research in the last two decades of the 1900's  involved no intervention. In the Hans study, the effect of total intravenous anesthesia on the plasma antioxidant capacity of neurosurgical patients during a cerebrospinal shunt was studied. It was a first of its kind to measure ultraweak chemiluminescence of patients' plasma before and after an intervention. All the other research was focused on assessing and comparing the state of inflammation among different groups for future diagnosis purposes. These studies were grouped by their system of research. The most commonly studied system of research was blood cells (9) [40,41,42,43,44,45,46,47,48] followed by whole body (8) [49,50,51,52,53,54,55,56], blood plasma (4) [39,57,58,59], tissues (2) [60,61], urine (2) [62,63], saliva (1) [64], and other cells (1) [65]. SIGN50: How well does the study address an appropriate and clearly focused question? U = Untreated control; P = Placebo; C = Crossover; UPE = Ultraweak photon emission; cps = counts per second; CL = chemiluminescence; A = Adequately covered; W = Well covered; P = Poorly addressed; * No substance was used to amplify the ROS to photon reaction; ** Luminol was used to amplify the ROS to photon reaction; *** Lucigenin was used to amplify the ROS to photon reaction; **** Hydrogen peroxide in presence/absence of iron sulfate was used to amplify the ROS to photon reaction; ***** UVA was used to amplify the ROS to photon reaction doi:10.1371/journal.pone.0087401.t003   A SIGN50: How well does the study address an appropriate and clearly focused question? U = Untreated control; P = Placebo; C = Crossover; UPE = Ultraweak photon emission; cps = counts per second; CL = chemiluminescence; A = Adequately covered; W = Well covered; P = Poorly addressed; * No substance was used to amplify the ROS to photon reaction; ** Luminol was used to amplify the ROS to photon reaction; *** Lucigenin was used to amplify the ROS to photon reaction; **** Hydrogen peroxide in presence/absence of iron sulfate was used to amplify the ROS to photon reaction; ***** UVA was used to amplify the ROS to photon reaction doi:10.1371/journal.pone.0087401.t004 The inflammatory states studied in the various publications included respiratory inflammations such as anthrax, chronic bronchitis, pneumonia, lung injury, and smoking as well as a number of other conditions such as, ulcerative colitis, multiple sclerosis, cancer, ankylosing spondylitis, hemodialysis, and varicocele. There were three studies [53,54,56] that looked at the ultraweak photon emission of experienced meditation practitioners compared to practitioners with no experience. All three studies found decreased photon emission in the experienced meditation groups compared to the control groups.

Main findings
Publications in the peer reviewed literature over the last 50 years clearly demonstrate that the use of ''off-the-shelf'' technologies and well described methodologies for the detection of human photon emissions are being used on a regular basis in medical and research settings. Our search turned up only one RCT. While of good quality (SIGN score of ''+''), clearly this field needs more RCTs to truly test the use of UPEs as a diagnostic tool. The overall quality of this literature is good and the use of this approach in medical oncology settings for determining inflammatory and oxidative states of patients indicate the growing use and value of this approach.

Strength and limitations
Because of this system of research, there is no quality rating tool available in the literature to accurately assess the quality of UPE research. This type of research is neither diagnostic as defined in some of the quality tools for diagnostic studies nor do the studies Figure 2. Flow chart. There were a total of 1315 records identified through the literature search, out of which 1113 were screened based on abstracts after removal of duplicates. The first level of screening based on abstracts resulted in exclusion of 1048 records (descriptive reviews, editorials, theories, books, book sections, non-human studies, and grey literature that didn't fit our inclusion criteria), and the second level of screening based on full-text resulted in exclusion of 9 more additional records. Therefore, a total of 56 studies (1 randomized controlled clinical trial, 27 controlled clinical trials, and 28 observational/descriptive studies) were included in this review. doi:10.1371/journal.pone.0087401.g002 we found consist of clinical trials with clearly defined intervention and control. SIGN 50 Diagnostic Tool for assessing quality looks at whether the results reflect the accuracy of the diagnostic test being evaluated. This is not what these groups of studies did as they were looking at photons as an adjunctive assessment of the inflammatory state and not as the primary diagnostic assessment, or including an intervention necessarily which made finding a tool to fit these designs of studies very challenging [37]. Other tools were explored and they too did not fit within the scope of the research examined in this review. The limitation of this systematic review is that we are not able to fully comment on the overall quality of these studies captured in this review without this tool in place. Since this research seems promising, it would be worthwhile to determine how best to assess quality of this system of research for future reviews. We were however able to document the quantity of the literature that exists in a rigorous, systematic way in this area and describe the literature as it exists today which is beneficial to understanding how it could be used as a health assessment tool and what has been done to date using this method. Since this research seems promising, it would be worthwhile to determine how best to assess quality of this system of research for future reviews. At this point, provided this limitation, the authors can only say subjectively that the quality is ''good'' for the CCT study designs evaluated.

Implications for research
Technological advances and improved understanding of the underlying biology have combined to enable the measurement of human photons in a rapid and reliable manner. The technology has advanced sufficiently to allow for non-invasive whole body measurements of these relatively rare photons and there is some evidence that measuring from the hands is sufficient [92]. This has the potential to provide both the researcher and the diagnostician with a powerful tool to look within the body, in real-time, at the fundamental biochemistry and production of ROS and correspondingly the REDOX state of the metabolism [93]. While the production of ROS is an unavoidable by-product of metabolism [94], when it is not properly managed by the body or when it is excessive as under certain kinds of stress [95,96] it can lead to a number of pathologies.
As ROS have been shown to be associated with a number of disease states it is clearly of use to assess their presence and prevalence. Therefore, assessing ROS levels may be useful for tracking the impact of various interventions, behaviors or medications. Doing so in a non-invasive and easy way is of great import.

Conclusion
Our study demonstrates that the peer reviewed literature around UPE and human UPE measurement in particular is surprisingly large. Most of the human UPE literature is of good to high quality based on our systematic evaluation. However, an evaluation tool for systematically evaluating this type of ''bioevaluation'' methodology is not currently available and would be worth developing. The authors applied their experience in performing systematic reviews to perform this evaluation from the available tools.
In addition, the field of human photon detection and the technology for measuring same has matured to the point where RCTs should be performed. In this way, it will be possible to determine if this approach can deliver a tool for non-invasively evaluating the specific inflammatory state of the individual while simultaneously providing a general measure of overall health. Finally, detection of human photon emissions has the potential for broad applicability to human health and disease monitoring at the whole systems level.

Supporting Information
Checklist S1 PRISMA 2009 Checklist. PRISMA checklist contains the preferred reporting items for Systematic Reviews and Meta-Analyses. The section of this article where each item is addressed is provided here. (DOC) Appendix S1 Pubmed Search Details. The search terms and limits used in Pubmed, and the dates the search was conducted is provided here. (DOCX)