“Cold” X5 Hairlaser™ used to treat male androgenic alopecia and hair growth: an uncontrolled pilot study

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“Cold” X5 Hairlaser™ used to treat male androgenic alopecia and hair growth: an uncontrolled pilot study
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Blum, Kenneth
Han, David
Madigan, Margaret A.
Lohmann, Raquel
Braveman, Eric R.
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Background: Various trials have been conducted on the management and treatment of androgenic alopecia (AGA) or male pattern hair loss using a variety of laser and light sources. Methods: For this feasibility study, the population was composed of males between the ages of 20 and 60 years who have been experiencing active hair loss within the last 12 months and the diagnosis of AGA. They also had a Norwood-Hamilton classification of 3, 3A, 3 V, 4, 4A, or 5 for the hair thinning patterns and skin type I, II, III, or IV on the Fitzpatrick skin type scale. This two-arm randomized, parallel group study design employed stratifying randomization to balance treatment assignment within three investigational centers with at least 2 subjects enrolled in each Fitzpatrick skin type. Results: A statistically significant positive trend in hair growth was observed from this pilot study, to evaluate the efficacy of the novel cold X5 hairlaser device for treating male androgenic alopecia. From the repeated measures analysis of variance, difference in mean hair counts over time was statistically significant (F = 7.70; p-value < 0.0001). Subsequent, linear regression of mean hair counts at each time point was performed, and post-hoc analysis found an increasing trend of hair growth over time that was statistically significant (p-value < 0.0001) with the estimated slope of 1.406. Increased hair counts from the baseline to the end of the 26-week period were found to be strongly significant (p-value = 0.0003). Conclusion: Albeit, sham device failure and resultant missing data from the control group, the positive trend hair growth, was observed due to the chronic use of X5hairlaser device. This positive benefit while in full agreement with other low laser hair devices requires intensive further investigation. Trial registration: NCT02067260 Keywords: Androgenic alopecia, Distributed laser light, Monochromatic light, Linear regression
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Blum et al. BMC Research Notes 2014, 7:103 http://www.biomedcentral.com/1756-0500/7/103; Pages 1-12
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doi:10.1186/1756-0500-7-103 Cite this article as: Blum et al.: “Cold” X5 Hairlaser™ used to treat male androgenic alopecia and hair growth: an uncontrolled pilot study. BMC Research Notes 2014 7:103.

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Blum etal.BMCResearchNotes 2014, 7 :103 http://www.biomedcentral.com/1756-0500/7/103 “ Cold ” X5Hairlaser ™ usedtotreatmale androgenicalopeciaandhairgrowth: anuncontrolledpilotstudyBlum etal.

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RESEARCHARTICLEOpenAccess“ Cold ” X5Hairlaser ™ usedtotreatmale androgenicalopeciaandhairgrowth: anuncontrolledpilotstudyKennethBlum1,3,4*,DavidHan2,MargaretAMadigan3,RaquelLohmann4andEricRBraverman1,4AbstractBackground: Varioustrialshavebeenconductedonthemanagementandtreatmentofandrogenicalopecia(AGA) ormalepatternhairlossusingavarietyoflaserandlightsources. Methods: Forthisfeasibilitystudy,thepopulationwascomposedofmalesbetweentheagesof20and60years whohavebeenexperiencingactivehairlosswithinthelast12monthsandthediagnosisofAGA.Theyalsohada Norwood-Hamiltonclassificationof3,3A,3V,4,4A,or5forthehairthinningpatternsandskintypeI,II,III,orIVon theFitzpatrickskintypescale.Thistwo-armrandomized,parallelgroupstudydesignemployedstratifying randomizationtobalancetreatmentassignmentwithinthreeinvestigationalcenterswithatleast2subjectsenrolled ineachFitzpatrickskintype. Results: Astatisticallysignificantpositivetrendinhairgrowthwasobservedfromthispilotstudy,toevaluatethe efficacyofthenovelcoldX5hairlaserdevicefortreatingmaleandrogenicalopecia.Fromtherepeatedmeasures analysisofvariance,differenceinmeanhaircountsovertimewasstatisticallysignificant(F=7.70;p-value<0.0001). Subsequent,linearregressionofmeanhaircountsateachtimepointwasperformed,andpost-hocanalysisfound anincreasingtrendofhairgrowthovertimethatwasstatisticallysignificant(p-value<0.0001)withtheestimated slopeof1.406.Increasedhaircountsfromthebaselinetotheendofthe26-weekperiodwerefoundtobestrongly significant(p-value=0.0003). Conclusion: Albeit,shamdevicefailureandresultantmissingdatafromthecontrolgroup,thepositivetrendhair growth,wasobservedduetothechronicuseofX5hairlaserdevice.Thispositivebenefitwhileinfullagreement withotherlowlaserhairdevicesrequiresintensivefurtherinvestigation. Trialregistration: NCT02067260 Keywords: Androgenicalopecia,Distributedlaserlight,Monochromaticlight,LinearregressionBackgroundEpidemiology:definingandrogenicalopeciaAndrogenicalopecia(alsoknownasandrogeneticalopecia or alopeciaandrogenetica )isthemostcommoncauseof hairloss,andthinninginhumans[1].Androgenicalopecia (AGA)affectsanestimated50millionmenand30million womenintheUnitedStates.Geneticpredispositionto hereditaryhairlosscanbeinheritedfromeithersideofa person ’ sfamilyorbothparents.Itisfoundinmenand womenofallracesandethnicities.Byage40,fortypercent ofwomenandnearlyfortypercentofmenhavevisible symptomsofhereditaryhairloss.Byage50,fiftypercent ofbothgendersshowsignsofthecondition.Hairloss isacommonanddistressingcondition.Americansare expectedtospendaboutonebilliondollarsannuallyfor treatmentstocombatandcoveruphairloss[2,3]. ItiswellknownthatbothFinasterideandMinoxidil areeffectivetreatmentmethods,butpatientswhoexhibit apoorresponsetothesemethodshavenoadditional adequatetreatmentmodalities[4,5].Inthisregard, Kim etal. reportedthatafter24weeksoftreatment,a *Correspondence: drd2gene@gmail.com1DepartmentofPsychiatryandMcKnightBrainInstitute,UniversityofFlorida, CollegeofMedicine,Gainesville,FL,USA3DepartmentofNutrigenomics,IGENE,LLC,Austin,TX,USA Fulllistofauthorinformationisavailableattheendofthearticle 2014Blumetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycredited.Blum etal.BMCResearchNotes 2014, 7 :103 http://www.biomedcentral.com/1756-0500/7/103

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low-levellighttherapyLLLTgroupshowedsignificantly greaterhairdensitythantheshamdevicegroup[6].In additionLeavitt etal. [7]reportedthattheHairMax LaserCombtreatmentgroupshowedasignificantlygreater increaseinmeanterminalhairdensitythansubjectsinthe shamdevicegroup(p<0.0001).Moreover,significant improvementsinoverallhairregrowthweredemonstrated intermsofpatients'subjectiveassessment(p<0.015)at 26weekswhencomparedtobaseline. Variantsappearinbothmenandwomen.However, AGAisalsocommonlyknownasmalepatternbaldness. Inmales ’ classicpatternbaldness,hairislostinawelldefinedpattern,beginningabovebothtemples.Hairalso thinsatthecrownofthehead.Oftenarimofhair aroundthesidesandrearoftheheadisleft.Thispattern isdubbed"Hippocraticbalding"andmayrarelyprogress tocompletebaldness.Womendonotsufferclassicmale patternbaldness,insteadthehairbecomesthinneraround thewholescalp,andthehairlinedoesnotrecede.This isdubbed"femalepatternbaldness"andmayoccurin males.ThisvarietyofAGAinwomenrarelyleadsto totalbaldness[1,8].AndrogenicalopeciaMorethan95percentofhairlossinmeniscausedby AGA.Malepatternbaldnessisconsideredagenetic condition,inheritedfromeitherthemotherorthe father'ssideofthefamily.However,malepatternbaldness alsorequiresthepresenceofthemalehormonetestosterone.Geneticscausehairfolliclestobecomesensitivetodihydrotestosterone(DHT),abyproductoftestosterone[9]. Thefolliclesbegintogrowsmaller,haveashorterlifespan andeventuallyfalloutaltogetherorleavebehindfuzz. Variousgenetic(andpossiblyenvironmental-epigenetic) factorsapparentlyplayaroleinAGA.Althoughresearchershavelongstudiedthefactorsthatmaycontributetothiscondition,manyremainunknown. Recentlytheexistingtheorieshavebeenchallengedon thegroundthatwhiletheandrogensinquestionare responsibleforhairgrowthonthefaceandalloverthe bodyofmen,hairlossonlyoccursatthetopofthe scalp.Forexample,ithasbeensuggestedthatAGAisa consequenceoftheanaboliceffectofandrogenssuchas hormonalchangesleadingtostructuralchangesinskin andscalpwhichinturncausehairloss[10].Itshouldbe noted,however,thatthereareasofyetnoexperiments testingthishypothesis.Thegeneticandhormonalcomponentofmale patternbaldnessMuchresearchconcernsthegeneticcomponentofmale patternbaldness,orAGAr esearchindicatesthatsusceptibilitytoprematuremalepatternbaldnessislargely X – linked,whichmeansitislinkedtogenesonan X-chromosome.Othergenesthatarenotsexlinkedare alsoinvolved.Menwhosefathershadexperiencedhair loss,were2.5timesmorelikelytoexperiencehairloss themselves,regardlessofthemother'ssideofthefamily [11,12].Largestudiesin2005and2007stresstheimportanceofthematernallineintheinheritanceofmale patternbaldness.Germanresearchersnametheandrogenreceptorgeneasanecessaryconditionforbalding [11].TheyconcludedthataspecificvariantoftheandrogenreceptorisneededforAGAtodevelop.This studyhasbeenconfirmedbyotherresearchers[13]. Theandrogenreceptorgeneisrecessive.Thus,afemale wouldneedtwoXchromosomeswiththedefectto showtypicalmalepatternalopecia.Sinceandrogens andtheirinteractionwiththeandrogenreceptorare thecauseofAGA,theandrogenreceptorgeneplaysan importantpartinitsdevelopment.Thereisaplethoraof researchconcerningtheroleofgenesandhormonesinthe developmentofmaleandrogenicalopeciaandreviewed elsewhere[14-22].Studiesonhormonalimbalancehave alsobeenwelldocumentedintheliteratureincluding conceptsinvolvinginhibitionof5-alpha-reductase[23].DescriptionofX5hairlaserTheX5HairLaserdeliversdistributedlaserlighttothe scalpforstimulatinghairgrowthinmendiagnosedwith AGA.TheX5HairLaserisaprecisioninstrumentutilizingcoldbeamlow-levellaserlight.TheX5HairLaser provides15distinctpointsoflaserlighttocoveranarea overninesquareinches(23cm.)ofthescalp.Separately moldedhighqualitylensesallowthelaserbeamstobe directedatthescalpdirectly.TheX5HairLaserprovides directscalpcontactsincethelaserlightisdeliveredby proprietarylaserchannels,whichmakedirectcontact withthescalp.Thelaserlightisnotobstructedbyexistinghair.TheX5HairLasercontainsafloatingmembranesystemthatinsuresthatlightchannelsconformto theshapeoftheheadandscalp.TheX5HairLaserisa cordlessdevicethatcontainsarechargeablebatteryin itsbase.Onechargewillsupplycordlesspowerfor severaltreatments. TheX5HairLaserhasfifteenlasersdiodesandfifteen beam-focusingtines.Eachtinehousesitsownlaser diode.Thefifteentinesarearrangedintofivegroupsof three.Eachgroupofthreetinesmovesindependently providingperpendicularlaserdeliverytotheuser ’ sscalp. Thebeamfocusinglensesareintegrallyattachedto tines,thetinesalignthelasers,directly(axially)withthe lens.Thebeamisprojectedtowardstheuser ’ sscalp.The tinesthroughwhichthelaserbeamisdelivered,alsopart theuser ’ shairtodeliverthelaserbeamdirectlytothe scalpwithoutobstruction(seeFigure1). TheX5HairLaserincorporatesacoloredLCDdisplay thatdisplaysthepreciseelapsedtimeofthetreatmentBlum etal.BMCResearchNotes 2014, 7 :103 Page2of12 http://www.biomedcentral.com/1756-0500/7/103

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session,aswellasthebatterypowerremainingandthe chargingstatusoftheunit.TheX5HairLaserdeviceis operatedby;turningiton,holdingthedeviceagainstthe scalpforapproximately15seconds,thenmovingit slightly,toadifferentpositiononthehead.Thedeviceis repositionedevery15secondsinaclockwiseorcounterclockwisedirection.After10 – 15minutes,thesessionis completeonceallofthetargetareasofthescalphave beengivensignificantexposuretolow-levellaserlight.HypothesisBasedontheliteraturetodatewedecidedtosystematicallytestthe “ Cold ” X5Hairlaser ™ asalaserdevice knowntodeliverdistributedlaserlighttothescalpfor stimulatinghairgrowthinmendiagnosedwithAGA.MethodsStudydesignThisfeasibilitystudywasdesignedtoevaluatetheefficacyoftheX5HairLaser,ahand-held,low-levellaser device,forthestimulationofhairgrowth.Thisstudyof theX5HairLaserintendedtoincreaseterminalhair growthinmaleswithAGA,wasamulti-center,randomized,placebo-controlledstudyconductedatthreesitesin theUnitedStates.ThetrialwasprovidedaclinicalprotocolnumberbyClinicalTrials.govProtocolRegistration SystemnumberNCTO2O67260.SubjectsInthispilotstudywereliedontheAmericanAcademy ofDermatologyforhairlossguidelinesaspartoftheinclusioncriteriaforenrolledpatients[24].Theparticipants whometallentrycriteriawererandomizedina2:1fashiontoreceivetreatmentwitheithertheX5HairLaseror anidenticalshamdevicethatdoesnotemitlaserlight. Thestudypopulationwascomposedofmalesbetweenthe agesof20and60yearswithdiagnosisofAGAwho hadbeenexperiencingactivehairlosswithinthepast 12months.TheywerealsorequiredtohaveaNorwoodHamiltonclassificationof3,3A,3V,4,4A,or5forthe hairthinningpatternsandhavetheskintypeI,II,III,or IVontheFitzpatrickskinty pescale(seeInclusionand ExclusionCriteriabelow).Thestudywasapprovedby InstitutionReviewBoards(IRB)ofthethreeselected sites.Eachsubjectfilledoutanapprovedconsentform. Specifically,theIRBwasBiomedicalResearchAlliance ofNewYork(BRANY),1981MarcusAvenueSuite210, LakeSuccess,NewYork11042(filenumber08-02-31-161). ThethreeresearchlocationsarelistedbelowtheIRB coveredallofthem:1)NYUSchoolofMedicine560First Avenue,Room158NewYork,NY10016;(2)Burke PharmaceuticalResearch3633CentralAvenueSuiteI, HotSprings,AR71913;(3)HilltopResearch6699 13thAvenueN,St.Petersburg,FL33710.InclusioncriteriaMalewithAndrogenicAlopecia.Activehairlosswithinthelast12months.Goodgeneralhealth.Norwood-Hamiltonclassificationof3,3A,3V,4, 4Aor5.SkinTypeI,II,III,orIVontheFitzpatrickSkin TypeScale.Hasnotstartedanynewvitaminsornutritional supplements.Continuednormalgroominghabits.Adheringtoscheduledofficevisitsina timelymanner.DiagnosedaccordingtoGuidelinesoftheAmerican AcademyofDermatologyAssociation.Subjectmusthaveminiaturizedhairpresentinthe targetarea.SubjectmustbefluentinEnglish.Signedaninformedconsent.ExclusioncriteriaActivemalignancyofanytypeorhistoryofany malignancy,includinganymalignancyinthe treatmentareainthepastfiveyears.Historyofhypogonadism.Subjecthasusedphytotherapy(e.g.,sawpalmetto) withineightweekspriortobaseline.Anyactiveskininfectioninthescalpareaor scarringinthetargetarea. Figure1 X5HairLaser. Blum etal.BMCResearchNotes 2014, 7 :103 Page3of12 http://www.biomedcentral.com/1756-0500/7/103

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Photosensitivitytolaserlight.HasusedAccutaneinthepreviousyear.Historyofpoorwoundhealing.Historyofanticoagulantorantiplateletuse (otherthanaspirin 325mg.,QD,whichisstable forthreemonths.Has"buzz"cuthairstyle,definedashaircuttoless thanoneinchinlength.Haslightblond,lightgrayorwhitehair.Hasachronicdermatologicalcondition (eczema,psoriasis,infection,etc.)ofthescalp.Hasapacemaker.Hashadhairtransplants,scalpreduction,current hairweave,ortattooinginthetargetarea.Haseverreceivedradiationtherapytothescalp,or hashadchemotherapywithinthepastyear.HasHIVinfection,connectivetissuedisease,a thyroidcondition,inflammatoryboweldisease.Hasahistoryorevidenceofdrugand/or alcoholabusewithinthe12monthspriorto Visit1.Historyorthepresenceofanyseriousand/or chronicmedicalcondition(s)[includingpsychiatric illnesses.HasusedorcurrentlytakesMinoxidil(Rogaine ™ ) duringtwelvemonthspriortoscreening.Hastakenanyofthefollowingmedicationsduring thesixmonthspriortoscreening: finasteride,(oranyother5 – reductase inhibitormedications), medicationswithanti-androgenicproperties (e.g.,cyproteroneacetate,spironolactone, ketoconazole,flutamide,bicalutamide), topicalestrogen,progesterone,tamoxifen, anabolicsteroids, medicationswhichcanpotentiallycause hypertrichosis(e.g.,cyclosporine,diazoxide, phenytoin,psoralens), oralglucocorticoids(inhaledglucocorticoidsare permitted),lithium,phenothiazines.DesignandsubjectdemographicsAtwo-armrandomized,parallelgroupdesignwas employedforthisstudy,str atifyingtherandomization tobalancetreatmentassignmentwithin3investigational centers.Additionally,inthesamplingscheme,atleast2 subjectswererequiredtobeenrolledineachFitzpatrick skintype. Atotalof143studyparticipantswerescreenedon theirfirstvisit,basedontheinclusion/exclusioncriteria and119subjects(83.22%)wereenteredintothestudy. ThediagnosisofmaleAndrogenicAlopeciawasmade byatrainedmedicalDermatologistutilizinginmany casesmodernhairimagingtechniquesincludingtrichoscanandortrichoscopy. Theywerealmostuniformlydistributed,resultingin approximately40subjectsenrolledateachofthe3differentstudysites.Ofthose119subjects,70ofthem (58.82%)weretreatedwiththeX5hairlaserdevicewhile others(41.18%)receivedtheplacebo.Thestudyconsistedof5follow-upvisitsfortheperiodof26weeks. Oneachvisitofthesubject,someclinicalmeasurements weretakenalongwiththehaircountdatawhichwas providedbytheimagingvendor,Canfield. TheprimaryobjectiveofthestudywastoprovetheefficacyandsafetyoftheX5hairlaserdevicefortreating maleAGAthroughcomparisontothecontrol.However, duetoaproblemintheimplementationoftheproposed Table1FrequencydistributionoftheNorwoodHamilton classificationinthetreatmentgroup( n =70)ClassFrequency 37 3A2 3V20 419 4A1 521 Total 70 Table2Samplestatisticsofthehaircountsfromthecompletedata( n =48)SamplestatisticsBaselineWeek4Week8Week14Week20Week26 Minimum 22.037.031.021.026.011.0 25%Percentile 130.8144.0137.0155.3144.0136.5 Median 168.0181.0168.5184.5176.5183.0 75%Percentile 204.5210.0217.0227.5216.3229.5 Maximum 297.0302.0329.0335.0311.0321.0 Mean 163.80174.70173.80185.20176.20180.30 Standarddeviation 65.6061.8771.3269.9068.4373.05 Standarderror 9.478.9310.2910.099.8810.54 95%Confidenceinterval (144.8,182.9)(156.7,192.6)(153.1,194.5)(164.9,205.5)(156.3,196.1)(159.1,201.5) Blum etal.BMCResearchNotes 2014, 7 :103 Page4of12 http://www.biomedcentral.com/1756-0500/7/103

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protocol,wherebyafterevaluationoftheentirestudy theshamdeviceunbeknowntousconstitutedalaser typelightingeffect.Thislightaffectedsubsequentanalysisonthisreport.Whilewearecognizantofthe impactofthelossofshamcontroldatawedecidedto conductpilotdatafromthetreatmentgrouponly,excludingthedatafromthecontrolplacebogroup.Hence, thefocusofthisreportistoinvestigatethepresenceof positivehairgrowthinthetreatmentgroupbyexaminingthetrendinhaircountsofthe70treatedsubjects (viz.,asampleoftheIntent-to-Treat(ITT)population). Foreachsubjectinthisstudy,thehaircountswere supposedtobetakenat6differenttimepoints:Baseline, Week4,Week8,Week14,Week20,andWeek26. Twenty-twosubjects(31.4%)fromthetreatmentgroup arehowevermissingatleastonesuchmeasurement fromthegivendatasetduetolosstofollow-uporwithdrawalfromthestudy,etc.Sinceitiscrucialtohavea completedatasetforrunningarepeatedmeasuresanalysisofvariance(ANOVA)andtotestanylineartrend overtime,datafrom48subjectswhocompletedall studyvisitswith6validhaircountmeasurementswere analyzedfirstinordertoconfirmanypositivetrendin thehairgrowthovertime(i.e.,aper-protocolanalysis). Then,themissinghaircountsof22remainingsubjects withthebaselineandatleastonevalidpost-baseline assessmentwereimputedbycarryingthemostrecent observationfromthepreviousvisitstothemissingone (s)foreachsubject(viz.,themethodoflastobservation carriedforward(LOCF)).Theanalysiswasconducted againonthedatasetofall70subjects,mixedwiththe imputedobservations. Thebriefdemographiccharacteristicsofthetreatment groupareasfollows.Theagedistributionwasfoundto be47.607.82(meanSD)forthepartialgroupof48 subjectswithcompletehaircountsand47.048.55for thegroupofall70subjects.Therewere7Hispanicor Latinoparticipants(10.0%)whileother63(90.0%)were neitherHispanicnorLatino.TheracewasallwhiteexceptforoneAfricanAmericanandonenativeHawaiian Figure2 Box-and-whiskerplotsofthehaircountsfromthecompletedata(n=48). Figure3 Box-and-whiskerplotsofthehaircountsfromthecompletedata(n=48). (Emptydotsindicatetheoutliersfromeach measurementgroup). Blum etal.BMCResearchNotes 2014, 7 :103 Page5of12 http://www.biomedcentral.com/1756-0500/7/103

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Table3Samplestatisticsofthehaircountsfromthemixeddata( n =70)SamplestatisticsBaselineWeek4Week8Week14Week20Week26 Minimum 22.033.022.021.026.011.0 25%Percentile 121.0125.3130.8137.3135.3129.5 Median 164.0172.0165.0182.5172.0181.5 75%Percentile 201.5203.5214.8224.5214.3225.3 Maximum 303.0302.0329.0335.0311.0321.0 Mean 159.00167.90169.30178.90170.00174.80 Standarddeviation 65.3963.5571.2469.6367.4668.97 Standarderror 7.827.608.528.328.068.24 95%Confidenceinterval (143.4,174.6)(152.7,183.1)(152.4,186.3)(162.3,195.5)(153.9,186.1)(158.4,191.2) Table4Samplestatisticsofthehaircountsfrom3agegroupsofthecompletedata( n =48)SamplestatisticsBaselineWeek4Week8Week14Week20Week26 (a) Agegroup:Young(40orbelow)( n =10) Minimum 26.089.033.063.074.064.0 25%Percentile 119.8137.8105.0114.887.885.5 Median 191.0198.0220.5224.0202.0227.0 75%Percentile 224.8249.3261.0264.8257.8239.5 Maximum 280.0279.0286.0292.0311.0321.0 Mean 170.40193.60188.30203.90187.00192.60 Standarddeviation 81.7862.1187.6379.5983.6985.27 Standarderror 25.8619.6427.7125.1726.4626.96 95%ConfidenceInterval (111.9,228.9)(149.2,238.0)(125.6,251.0)(147.0,260.8)(127.1,246.9)(131.6,253.6) (b) Agegroup:Mid(between41and50inclusive)( n =19) Minimum 43.051.042.038.026.011.0 25%Percentile 138.0155.0152.0159.0157.0147.0 Median 165.0182.0166.0186.0178.0180.0 75%Percentile 194.0207.0208.0219.0204.0228.0 Maximum 269.0262.0272.0259.0265.0264.0 Mean 161.60171.90170.30183.30174.60178.70 Standarddeviation 54.9853.1056.8255.0158.5862.84 Standarderror 12.6112.1813.0312.6213.4414.42 95%Confidenceinterval (135.1,188.1)(146.4,197.5)(142.9,197.7)(156.7,209.8)(146.3,202.8)(148.5,209.0) (c) Agegroup:Old(between51to60inclusive)( n =19) Minimum 22.037.031.021.031.029.0 25%Percentile 109.0114.0110.0126.0133.0114.0 Median 169.0164.0159.0175.0168.0157.0 75%Percentile 203.0203.0206.0196.0203.0206.0 Maximum 297.0302.0329.0335.0308.0320.0 Mean 162.50167.40169.60177.20172.20175.40 Standarddeviation 69.5670.6177.8979.3672.1778.97 Standarderror 15.9616.2017.8718.2116.5618.12 95%Confidenceinterval (129.0,196.1)(133.4,201.5)(132.0,207.1)(139.0,215.5)(137.4,206.9)(137.3,213.4) Blum etal.BMCResearchNotes 2014, 7 :103 Page6of12 http://www.biomedcentral.com/1756-0500/7/103

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(orotherpacificislander).Thefrequencytableofthe NorwoodHamiltonclassificationofthetreatedsubjects isalsoshownintheTable1below. Wedidnotsystematicallyruleoutotheroverlapping causesofhairlossbutwewereconfidentthatthesubjectstestedhadawell-documenteddiagnosisofmale androgenicalopecia.ResultsOveralltrendofhairgrowthWithanappropriateaggregationoftheclasses,none ofthevariablesaforemention edincludingthedistributionoftheFitzpatrickskintypeclassificationandthe groupedagevariablewasfoundtohaveastatistically significantassociationwithoneanotherat5%level ofsignificance. Table2belowsummarizestheessentialsamplestatisticsfromthehaircountsof48subjectswithcomplete observationsateachmeasurementpointovertheperiod of26weeks.Themeanprofilewasplottedtovisualize theresults,anditisshowninFigure2below,assuming thatthemeasurementsweretakeninanapproximately uniforminterval. FromFigure2,anoverallincreasing-trendisapparent. Theamountofvariabilityisalsoincreasingateach measurementpoint(asshowninthecomparativeboxand-whiskerplotsofFigure3above).Fromtherepeated measuresanalysisofvariance,itwasshownthatthe differenceinmeanhaircountsovertimeisstatistically significant(F=7.70;p-value<0.0001).Subsequently,a linearregressiononthemeanhaircountsateachmeasurementtimepointwasperformedasapost-hocanalysis,anditwasfoundthatasystematicallyincreasing trendofhairgrowthovertimeisstatisticallysignificant (p-value<0.0001)withtheestimatedslopeof1.406. However,theR2valueof0.0050indicatedthepresence ofalargeamountofvariabilitywhichcannotbeexplainedbythedurationofthedeviceusageonly.Forthis reason,itwasnotsuccessfultomodelthetrendinthe haircountsovertimeusingagrowthcurveapproach. Whentheendpointsalonewereconsidered,anincrease inthehaircountsfromthebaselinetotheendofthe 26-weekperiodwasneverthelessfoundtobestrongly significant(p-value=0.0003). Consistentresultswereobtainedusingthemixeddatasetof70subjectswithsomeimputedvalues.Table3 summarizesthesamplestatisticscalculatedfromthis Figure4 Meanprofileplotsofthehaircountsfrom3agegroupsofthecompletedata( n =48). Table5TestresultsforalineartrendofthehairgrowthforeachagegroupDatasetAge group Sample size( n ) RepeatedmeasuresANOVAPost-hoclineartrendtest Fp -value p -valueSlope R2value Completedata( n =48) Young101.650.1663 ––– Mid193.760.00390.00131.5200.0086 Old193.240.00980.00091.2290.0033 Mixeddata( n =70) Young152.660.02950.10541.2150.0036 Mid295.120.00020.00041.3370.0066 Old265.380.0002<0.00011.4550.0046 Blum etal.BMCResearchNotes 2014, 7 :103 Page7of12 http://www.biomedcentral.com/1756-0500/7/103

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mixeddatasetofhaircountsateachmeasurementpoint overtheperiodof26weeks.Againfromtherepeated measuresanalysisofvariance,thechangeinmeanhair countsovertimewasshowntobestatisticallysignificant (F=10.60;p-value<0.0001).Fromthepost-hocanalysis, alinearregressiononthemeanhaircountsateach measurementtimepointrevealedthestatisticallysignificantpresenceofalinearly-increasingtrendofthehair growthovertime(p-value<0.0001)withtheslightly smallerslopeestimateof1.355.Again,averylowR2valueof0.0047indicatedthepresenceofalargeamount ofvariability.TrendofhairgrowthbyAgegroupInordertoexamineanydifferentialeffectofthedevice onthehairgrowthtrendofdifferentagegroups,the treatedsubjectsweregroupedinto3differentclasses:(a) Young(40orbelow),(b)Mid(between41to50inclusive),and(c)Old(between51to60inclusive).The3 classeswerechosensuchthateachholdsanapproximatelyuniformnumberofobservationsfromthedataset.Table4belowprovidesthesamplestatisticsofthe haircountsfromeachoftheseagegroupsformedfrom thedatasetof48subjectswithcompleteobservations. Figure4describesthemeanprofileplotsofthehair countsoftheseagegroupsovertheperiodof26weeks. FromFigure3,asimilaroverallincreasingpatternis observedamongthe3agegroups.AlthoughtheYoung grouphadhigheraveragehaircountsatthebaseline comparedtotheMidorOldgroups,theincrementsof haircountsbytheendofthe26-weekperiodwerequite comparableamongall3groups.Allthreeagegroups sharedremarkablysimilarmeanprofiles,butthepattern oftheYounggroup,wasobservedtobemoreerratic, withalargervariation,whiletheMidandOldgroups exhibitedsimilarandconsistenttrendsofincreasinghair countsovertime. Table5belowsummarizestheresultsofformalstatisticalteststodetectthemeandifferenceofhaircounts acrossthemeasurementtimepointsbytherepeated measuresanalysisofvariance.Thetestswereperformed foreachofthe3agegroups,andoncetheresultswere foundtobesignificant,thepost-hocanalysisofalinear trendovertimewasconducted. Betweenthecompletedatasetof48subjectsandthe mixeddatasetof70subjects,theresultsofanalysis werelargelyconsistent.Althoughtheimputationhelped tocapturethemarginalsignificanceofthemeandifferenceofhaircountsovertimefortheYounggroup (p-value=0.0295),alineartrendofthehairgrowthwas stillnotdetected(p-value=0.1054)fromthepost-hoc analysisasinthecompletedatacase.Thismaybedue toasmallersamplesizeallocatedforthegroupYoung, resultinginhighervariabilityandamoreerraticprofile asshowninFigure3.Althoug hthegraphicaltrendsare similaracrossthegroups,itseemsthattheoldergroups exhibitslightlymoreconsistentandstrongerlineartrend ofthehairgrowthovertimeFigure5.Aspointedout earlierthough,lowR2valuesindicatedthepresenceof alargeamountofvariabilitywhichcannotbeexplained bythedurationofthedeviceusageonly.TrendofhairgrowthbyskintypeTodeterminethepresence,ofanyeffectofthedevice onthehairgrowthtrendsthatwasdependentonskintype,thesubjectsweredividedinto4groupsaccording Figure5 Meanprofileplotsofthehaircountsfrom4Fitzpatrickskintypesofthecompletedata( n =48). Blum etal.BMCResearchNotes 2014, 7 :103 Page8of12 http://www.biomedcentral.com/1756-0500/7/103

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totheirFitzpatrickskintypes(1beingthemostsensitive andIVbeingtheleastsensitive).Eachclassheldan approximatelyuniformnumberofobservationsfromthe dataset.Table6belowsummarizesthesamplestatistics ofthehaircountsineachoftheseskintypesfromthe completedatasetof48subjects.Figure5showsthe meanprofileplotsofthehaircountsofthese4skin typesovertheperiodof26weeks.Themoresensitive Table6Samplestatisticsofthehaircountsfrom4Fitzpatrickskintypesofthecompletedata( n =48)SamplestatisticsBaselineWeek4Week8Week14Week20Week26 (a) FitzpatrickskintypeI( n =6) Minimum 22.037.031.021.026.011.0 25%Percentile 37.851.346.033.829.824.5 Median 119.0119.0131.0124.5133.5139.5 75%Percentile 197.0213.8199.8217.0203.8242.3 Maximum 227.0279.0256.0250.0269.0264.0 Mean 119.50133.70130.20127.30129.20136.30 Standarddeviation 83.4794.2187.4394.1596.38107.30 Standarderror 34.0838.4635.6938.4439.3543.82 95%Confidenceinterval (31.9,207.1)(34.8,232.5)(38.4,221.9)(28.5,226.1)(28.0,230.3)(23.7,249.0) (b) FitzpatrickskintypeII( n =13) Minimum 26.089.033.063.074.064.0 25%Percentile 104.5116.5101.5120.0121.0109.0 Median 150.0180.0156.0185.0157.0163.0 75%Percentile 192.0196.0185.5223.0200.5213.5 Maximum 297.0302.0329.0335.0308.0313.0 Mean 150.30166.50155.20179.60166.70164.90 Standarddeviation 72.7956.9071.0870.2562.8969.72 Standarderror 20.1915.7819.7119.4917.4419.34 95%Confidenceinterval (106.3,194.3)(132.2,200.9)(112.2,198.1)(137.2,222.1)(128.7,204.7)(122.8,207.1) (c) FitzpatrickskintypeIII( n =15) Minimum 48.051.042.077.052.075.0 25%Percentile 138.0144.0137.0149.0143.0133.0 Median 166.0167.0166.0177.0168.0163.0 75%Percentile 214.0211.0217.0226.0224.0226.0 Maximum 280.0274.0309.0314.0304.0320.0 Mean 167.70172.00172.20182.10173.40177.80 Standarddeviation 62.8959.8267.8964.6467.0071.35 Standarderror 16.2415.4517.5316.6917.3018.42 95%Confidenceinterval (132.8,202.5)(138.9,205.1)(134.6,209.8)(146.3,217.9)(136.3,210.5)(138.3,217.3) (d) FitzpatrickskintypeIV( n =14) Minimum 128.0142.0130.0156.0140.0153.0 25%Percentile 163.0160.0155.5179.5171.5179.3 Median 185.5197.0211.5200.0196.0211.0 75%Percentile 225.8244.8269.0265.5256.0244.8 Maximum 269.0268.0286.0292.0311.0321.0 Mean 191.20202.60211.40218.40208.20216.10 Standarddeviation 42.6143.4855.4049.1951.4448.74 Standarderror 11.3911.6214.8113.1513.7513.03 95%Confidenceinterval (166.6,215.8)(177.5,227.7)(179.4,243.4)(190.0,246.8)(178.5,237.9)(187.9,244.2) Blum etal.BMCResearchNotes 2014, 7 :103 Page9of12 http://www.biomedcentral.com/1756-0500/7/103

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theskintypeis;thelessaveragehaircountsare,atthe baselinefromFigure5.Itwasalsointerestingtoobserve thatamongthe4skintypes,thetypeIVexhibitsthe strongestpatternofhaircountsincreasinglinearlyover time,andthiswasstatisticallyconfirmedbythetest resultsshowninTable7. Table7abovesummarizestheresultsofstatisticaltests todetectthemeandifferenceofhaircountsacrossthe measurementtimepointsbytherepeatedmeasuresanalysisofvariance.Justlikeintheanalysisoftheage groups,thetestswereperformedforeachofthe4skin typegroups,andoncetheresultswerefoundtobesignificant,thepost-hocanalysisofalineartrend,overtime wasconducted.Betweenthecompletedatasetof48subjectsandthemixeddatasetof70subjects,theresultsof analysiswereagainlargelyconsistenteventhoughthe imputationcapturedthemarginalsignificanceofthe meandifferenceofhaircountsovertimefortheskin typeIII( p -value=0.0346).TheskintypeI,hadtheleast numberofsubjectsassignedinbothcases,anditdidnot showanysignificantmeandifferenceofhaircountsnor alineartrendovertime.Althoughnotclear,itseems thattheleastsensitiveskintyperespondsthebesttothe deviceforthehairgrowthovertime.Again,low R2values indicatedthepresenceoflargevariabilitywhichcannotbe accountedforbythedurationofthedeviceusageonly.DiscussionWhilethismulti-centeredstudywasoriginallyplanned asarandomized – sham – controlleddouble-blindedclinicalstudy,itwasdeterminedfollowingtheinvestigation asplanned,thattheshamdevicewasemittinghair growthlightthatruinedthecontroldataandsubsequent results.However,thepresentresultsprovidesignificant impetustodevelopabettershamdeviceanddesigna clinicalstudyinalargercohort. Withthatstated,thispilotstudytoevaluatetheefficacyofthecoldX5hairlaserdevicefortreatingmale AGAresultedinastatisticallysignificantpositivetrend, inhairgrowth.Fromtherepeatedmeasuresanalysisof variance,itwasshownthatthedifferenceinmeanhair countsovertimeisstatisti callysignificant(F=7.70; p-value<0.0001).Subsequently,alinearregressionon themeanhaircountsateachmeasurementtimepoint wasperformedasapost-hocanalysis,anditwasfound thatasystematicallyincreasingtrendofhairgrowthover timeisstatisticallysignificant(p-value<0.0001)withthe estimatedslopeof1.406.Theincreaseinhaircounts, attheendpoints,fromthebaselinetotheendofthe 26-weekperiod,wasnevertheless,foundtobestrongly significant(p-value=0.0003).Asstatedearliertoconfirmthatthiseffectwascausedbythedeviceandnotby arandomchance,amoresystematiccomparativestudy shouldbeconductedwithanappropriatecontrol. Themainlimitationofthisinvestigationistheinability toshowthedifferencebetweenthedeviceandanappropriateshamcontrol.Theinvestigationisalsolimitedby thesizeofthepopulationstudied.Infuturestudieswe intendtoincreaseourpopulationsincethisisanoninvasiveprocedure.However,weareencouragedthat becauseofthestringentinclusion/exclusioncriteriathese potentiallyimportantresultswillbeconfirmedinnecessarylarger – controlledclinicaltrials,inthefuture. Theshort-termsafetyofthedevicewasensuredsince duringthe26weeksofthisstudy,noanyclinically severeadverseeventswereassociatedwiththeX5hairlaserdevice. Whilewecannotdetailthemechanismofactionof theX5(seebelow)thedevicewasdesignedtodeliver lowlevellaserlightdirectlytothescalpbypassingany interveninghair.Thelightisdeliveredbylighttines (15lightpipesmountedonfivetripods)sothatthe deviceconformstothecontourofthescalpandmakes directcontact.Otherdevicessimplydirectbeamsinto thehairandscalpatanglesthatcannotbeprecisely controlled. Moreover,thislow-levellasertherapyisintendedto bio-stimulate.Theeffectsarebiochemicalnotthermal becausethelowpowernatureoflow-levellaser ’ s,cannot causeheatingdamagetolivingtissue.Lasersareoftwo Table7TestresultsforalineartrendofthehairgrowthforeachskintypeDatasetFitzpatrick skintype Sample size( n ) RepeatedmeasuresANOVAPost-hoclineartrendtest Fp -value p -valueSlope R2value Completedata( n =48) I60.610.6897 ––– II133.160.01350.04641.4000.0053 III151.540.1879 ––– IV144.620.00110.00032.1140.0229 Mixeddata( n =70) I70.660.6599 ––– II205.190.00030.00061.7910.0083 III272.490.03460.00460.9530.0025 IV164.730.00080.00041.8460.0169 Blum etal.BMCResearchNotes 2014, 7 :103 Page10of12 http://www.biomedcentral.com/1756-0500/7/103

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principaltypes,"hot"and"cold",andtheyaredistinguishedbytheamountofpeakpowertheydeliver."Hot" lasersdeliverpoweruptothousandsofwatts.Theyare usedinsurgerybecausetheycanmakeanincisionthat isverycleanwithlittleornobleedingandbecausethe lasercauterizestheincisionasitcuts.Theyarealsoused insurgerythatrequirestheremovalofunhealthytissue withoutdamagingthehealthytissuethatsurroundsit. "Cold"laserssuchastheX5HairLaserproducea loweraveragepowerof100milliwattsorless.Thisisthe typeoflaserthatisusedfortherapeuticpurposesandit istypically,althoughnotalways,pulsed.Thelightison foronlyafractionofasecondbecauseitispulsed, (turnedonandoff)atsomanypulsespersecond.Pulsationresultsinanaveragepoweroutputthatisverylow comparedtothemaximumorpeakoutput.Therefore, mosttherapeuticlasersproduceahighpeakbutlow averagepoweroutput.Therapeuticlaserislow-levellaser therapy(LLLT)withphotochemicalratherthanthermal effects[25-28].Thelightiseithervisible(red),inmost casesorinvisible(infrared).ProposedmechanismofactionEnergyistransferredintheformofphotons[25].Photonsaretransmittedthroughtheskin'slayers(thedermis,epidermisandthesubcutaneoustissueortissuefat undertheskin).Lightwavesinthenearinfraredranges penetratedeeperthanalllightwavesinthevisible spectrum.Photonsenterthetissueandareabsorbedin themitochondriaandatthecellmembrane[26].The photonenergyisconvertedtochemicalenergywithin thecellintheformofadenosinetriphosphate(ATP) [27].Lightemittingdiode(LED)intheredregionand low-levellaserinthenearinfraredregioncorrespond wellwiththecharacteristicenergyandabsorptionlevels oftherelevantcomponentsoftherespiratorychain.This LEDandLaserstimulationvitalizesthecellbyincreasingthemitochondrialATPproduction[28]. Itisbelievedthatsuccessfullasertherapytreatment startswiththestimulationofcellfunctionsbythelaser light.Researchhasshownthatmitochondriaaresensitivetoirradiationwithmonochromaticlight[29].Irradiationwithlightatawavelengthof650nmenhances ATPsynthesis[28].TheincreaseinATPisbelievedto beoneoftheunderlyingmechanismsthathelptostimulatehairfollicles[30]. Althoughitisdifficulttoascribeanaccuratemechanismofactionofthe “ Cold ” X5L,thehypothesis,that irradiationofthescalpwiththishairlaserdevicewill resultinastatisticallysignificantincreaseinhairgrowth ascomparedtoacontrol,issupportedbythecombinationofmechanismsthatincreasebothATPproduction andmicrocirculation.ConclusionsWhiletherearenumberofdrugsandevenothertechniquestoinducehairfolliclegrowthalternativesarestill important[31-33].Albeit,shamdevicefailureandresultantmissingdatafromthecontrolgroup,thepositive trendhairgrowthduetothechronicuseofX5hairlaser devicewasobserved.Thispotentialpositivebenefitisin fullagreementwithotherlowlaserhairdevicesand followingrequiredlargerconfirmatorystudiesshould haveclinicalutilityfortreatingmaleAGA.Competinginterests KennethBlum,PhDisapaidconsultantandreceivedremunerationfrom MarkKress.Therearenootherfinancialconflicts. Authors ’ contributions KBwrotetheinitialdraftofthemanuscriptandcoordinatedthestatistical analysis;DHperformedalltherequiredstatisticalanalysisanddevelopedthe methodologyinvolvedinthepresentationofresults;MAMassistedinwriting portionsofthemanuscriptandassistedinallaspectsofthewritingandedits; RLprovidedrequiredliteraturecitations;ERBprovidedliteraturecitationsand clinicalexpertise.Allauthorsreadandapprovedthefinalmanuscript. Acknowledgements TheauthorswouldliketothankMarkKresswhofundedthestudyandisthe ownerofthe5XLdevice. Authordetails1DepartmentofPsychiatryandMcKnightBrainInstitute,UniversityofFlorida, CollegeofMedicine,Gainesville,FL,USA.2DepartmentofBiostatistics, UniversityofTexasatSanAntonio,SanAntonio,TX,USA.3Departmentof Nutrigenomics,IGENE,LLC,Austin,TX,USA.4DepartmentofClinical Neurology,PathFoundationNY,NewYork,NY,USA. Received:26January2013Accepted:10February2014 Published:24February2014 References1.SoniVK: Androgenicalopecia:acounterproductiveoutcomeofthe anaboliceffectofandrogens. MedHypotheses 2009, 73 (3):420 – 426. 2.DuvergerO,MorassoMI: Togrowornottogrow:hairmorphogenesis andhumangenetichairdisorders. SeminCellDevBiol 2013, S1084-9521(13)00135-3. 3.LiangB,YangC,ZuoX,LiY,DingY,ShengY,ZhouF,ChengH,ZhengX, ChenG,ZhuZ,ZhuJ,FuX,WangT,DongY,DuanD,TangX,TangH, GaoJ,SunL,YangS,ZhangX: Geneticvariantsat20p11conferriskto androgeneticalopeciaintheChineseHanpopulation. PLoSOne 2013, 8 (8):e71771. 4.ChinEY: Androgeneticalopecia(malepatternhairloss)intheUnited States:whattreatmentsshouldprimarycareprovidersrecommend? JAmAssocNursPract 2013, 25 (8):395 – 401. 5.KaufmanKD,OlsenEA,WhitingD,SavinR,DeVillezR,BergfeldW,PriceVH, VanNesteD,RobertsJL,HordinskyM,ShapiroJ,BinkowitzB,GormleyGJ, FinasterideMalePatternHairLossStudyGroup: Finasterideinthe treatmentofmenwithandrogeneticalopecia. JAmAcadDermatol 1998, 39 (4Pt1):578 – 589. 6.KimH,ChoiJW,KimJY,ShinJW,LeeSJ,HuhCH: Low-levellighttherapy forandrogeneticalopecia:a24-week,randomized,double-blind,sham device-controlledmulticentertrial. DermatolSurg 2013, 39 (8):1177 – 1183. 7.LeavittM,CharlesG,HeymanE,MichaelsD: HairMaxLaserComblaser phototherapydeviceinthetreatmentofmaleandrogeneticalopecia:a randomized,double-blind,shamdevice-controlled,multicentretrial. ClinDrugInvest 2009, 29 (5):283 – 292. 8.SehgalVN,SrivastavaG,AggarwalAK,MidhaR: Hairbiologyandits comprehensivesequenceinfemalepatternbaldness:diagnosisand treatmentmodalities – PartI. Skinmed 2013, 11 (1):39 – 45. 9.SperlingLC,MezebishDS: Hairdiseases. MedClinNorthAm 1998, 82 (5):1155 – 1169.Blum etal.BMCResearchNotes 2014, 7 :103 Page11of12 http://www.biomedcentral.com/1756-0500/7/103

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10.GaoW,KimJ,DaltonJT: Pharmacokineticsandpharmacodynamicsof nonsteroidalandrogenreceptorligands. PharmRes 2006, 23 (8):1641 – 1658. 11.HillmerAM,HannekenS,RitzmannS,Be ckerT,FreudenbergJ,BrockschmidtFF, FlaquerA,Freudenberg-HuaY,JamraRA,MetzenC,HeynU,SchweigerN, BetzRC,BlaumeiserB,HampeJ,SchreiberS,SchulzeTG,HenniesHC, SchumacherJ,ProppingP,RuzickaT,CichonS,WienkerTF,KruseR, NthenMM: Geneticvariationinthehumanandrogenreceptorgeneis themajordeterminantofcommonearly-onsetandrogeneticalopecia. AmJHumGenet 2005, 77 (1):140 – 148.doi:10.1086/431425. 12.CobbJE,ZaloumisSG,ScurrahKJ,HarrapSB,EllisJA: Evidencefortwo independentfunctionalvariantsforandrogeneticalopeciaaroundthe androgenreceptorgene. ExpDermatol 2010, 19 (11):1026 – 1028. doi:10.1111/j.1600-0625.2010.01132.x. 13.Levy-NissenbaumE,Bar-NatanM,FrydmanM,PrasE: Confirmationofthe associationbetweenmalepatternbaldnessandtheandrogenreceptor gene. EurJDermatol 2005, 15 (5):339 – 340.PMID16172040. 14.ProdiDA,PirastuN,ManincheddaG,SassuA,PicciauA,PalmasMA, MossaA,PersicoI,AdamoM,AngiusA,PirastuM: EDA2Risassociated withandrogeneticalopecia. JInvestDermatol 2008, 128 (9):2268 – 2270. 15.EllisJA,ScurrahKJ,CobbJE,ZaloumisSG,DuncanAE,HarrapSB: Baldness andtheandrogenreceptor:theARpolyglycinerepeatpolymorphism doesnotconfersusceptibilitytoandrogeneticalopecia. HumGenet 2007, 121 (3 – 4):451 – 457. 16.HillmerAM,FlaquerA,HannekenS,EigelshovenS,KortmAK,BrockschmidtFF, GollaA,MetzenC,ThieleH,KolbergS,ReinartzR,BetzRC,RuzickaT,HenniesHC, KruseR,NthenMM: Genome-widescanandfine -mappinglinkagestudyof androgeneticalopeciarevealsalocusonchromosome3q26". AmJHumGenet 2008, 82 (3):737 – 743.doi:10.1016/j.ajhg.2007.11.014 doi:10.1016%2Fj.ajhg.2007.11.014. 17.ShimomuraY,WajidM,IshiiY,Shapiro bY,PetukhovaL,DerekG,ChristianoAM: DisruptionofP2RY5,anorphanGprotein – coupledreceptor,underlies autosomalrecessivewoollyhair. NatGenet 2008, 40 (3):335 – 339. doi:10.1038/ng.100doi:10.1038%2Fng.100.PMID18297072. 18.PetukhovaL,SousajrE,MartinezmirA,VitebskyA,DosSantosLG,ShapiroL, HaynesC,GordonD,ShimomuraY,ChristianoAM: Genome-widelinkage analysisofanautosomalrecessivehypotrichosisidentifiesanovelP2RY5 mutation. Genomics 2008, doi:10.1016/j.ygeno.2008.06.009doi:10.1016% 2Fj.ygeno.2008.06.009.PMID18692127 (5):273 – 278.doi:10.1016/j. ygeno.2008.06.009doi:10.1016%2Fj.ygeno.2008.06.009.PMID18692127. 19.PasternackSM,vonKgelgenI,AboudKA,LeeYA,RschendorfF,VossK, HillmerAM,MolderingsGJ,FranzT,RamirezA,NrnbergP,NthenMM, BetzRC: Gprotein-coupledreceptorP2Y5anditsligandLPAareinvolvedinmaintenanceofhumanhairgrowth. NatGenet 2008, 40 (3):329 – 334. 20.StrkaL,CermkovI,DuskovM,HillM,DolezalM,PolcekV: Hormonal profileofmenwithprematurebalding. ExpClinEndocrinolDiabetes 2004, 112 (1):24 – 28.doi:10.1055/s-2004-815723doi:10.1055%2Fs-2004-815723. PMID14758568. 21.Denmark-WahnefriedW,LeskoSM,ConawayMR,RobertsonCN,ClarkRV, LobaughB,MathiasBJ,StrigoTS,PaulsonDF: Serumandrogens: associationswithprostatecancerriskandhairpatterning. JAndrol 1997, 18 (5):495 – 500. 22.EllisJA,PanagiotopoulosS,AkdenizA,JerumsG,HarrapSB: Androgenic correlatesofgeneticvariationinthegeneencoding5 -reductasetype 1. JHumGenet 2005, 50 (10):534 – 537. 23.deSousaICVD,TostiA: Newinvestigationaldrugsforandrogenetic alopecia. ExpertOpinInvestDrugs 2013, 22 (5):573 – 589. 24.DrakeLA,DinehartSM,FarmerER,GoltzRW,GrahamGF,HordinskyMK, LewisCW,PariserDM,WebsterSB,WhitakerDC,ButlerB,LoweryBJ,Price VH,BadenH,DeVillezRL,OlsenE,ShupackJL,AmericanAcademyof Dermatology: Guidelinesofcareforandrogeneticalopecia. JAmAcad Dermatol 1996, 35 (3Pt1):465 – 469. 25.OtaY,IwamotoS,KumagaiN,ArakawaY: Spontaneoustwo-photon emissionfromasinglequantumdot. PhysRevLett 2011, 107 (23):233602. 26.LimCS,MasantaG,KimHJ,HanJH,KimHM,ChoBR: Ratiometricdetection ofmitochondrialthiolswithatwo-photonfluorescentprobe. JAmChem Soc 2011, 133 (29):11132 – 11135. 27.KaruTI,PyatibratLV,AfanasyevaNI: Anovelmitochondrialsignaling pathwayactivatedbyvisible-to-nearinfraredradiation. Photochem Photobiol 2004, 80 (2):366 – 372. 28.HegerM,HeemskerkAA,vanderZwanG: Absenceof633-nmlaser irradiation-inducedeffectsonglucosephosphorylationbyhexokinase. JPhotochemPhotobiolB 2010, 98 (3):216 – 222. 29.ShorterK,FarjoNP,PicksleySM,RandallVA: Humanhairfolliclescontain twoformsofATP-sensitivepotassiumchannels,onlyoneofwhichis sensitivetominoxidil. FASEBJ 2008,22 (6):1725 – 173. 30.VidaliS,KnueverJ,LerchnerJ,GiesenM,BrT,KlingerM,KoflerB,FunkW, PoeggelerB,PausR: Hypothalamic-pituitary-thyroidaxishormones stimulatemitochondrialfunctionandbiogenesisinhumanhairfollicles. JInvestDermatol 2014, 134 (1):33 – 42. 31.RossiA,CantisaniC,ScarnM,TrucchiaA,FortunaMC,CalvieriS: Finasteride,1mgdailyadministrationonmaleandrogeneticalopeciain differentagegroups:10-yearfollow-up. DermatolTher 2011, 24 (4):455 – 461. doi:10.1111/j.1529-8019.2011.01441.x. 32.KritskyMS,TeleginaTA,VechtomovaYL,KolesnikovMP,LyudnikovaTA, GolubOA: Excitedflavinandpterincoenzymemoleculesinevolution. Biochemistry(Mosc) 2011, 75 (10):1200 – 1216. 33.KaruTI,PyatibratLV,KalendoGS: Cellattachmenttoextracellularmatrices ismodulatedbypulsedradiationat820nmandchemicalsthatmodify theactivityofenzymesintheplasmamembrane. LasersSurgMed 2001, 29 (3):274 – 281.doi:10.1186/1756-0500-7-103 Citethisarticleas: Blum etal. : “ Cold ” X5Hairlaser ™ usedtotreatmale androgenicalopeciaandhairgrowth:anuncontrolledpilotstudy. BMC ResearchNotes 2014 7 :103. Submit your next manuscript to BioMed Central and take full advantage of: € Convenient online submission € Thorough peer review € No space constraints or color “gure charges € Immediate publication on acceptance € Inclusion in PubMed, CAS, Scopus and Google Scholar € Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Blum etal.BMCResearchNotes 2014, 7 :103 Page12of12 http://www.biomedcentral.com/1756-0500/7/103