f
`
`(
`
`!
`
`No, 7733
`
`VOL.
`
`THE LANCE
`r
`
`BOSTON, MASS, AND LON;;~~-~o~~TURDAY 13 NOVEMBER 1971
`C 0 N TE NT S
`LETTERS TO THE EDITOR~.cÄt.
`Griseofulvin
`in Raynaud's Phenomenon
`Tin;: WIIOLll
`(Dr. P:jNnidoo; Dr. A, Herxheimer; Dr.
`OP THE LITERARY MATTER IN THE LANGET IS COPYRIGijT~~\CR! &'
`R. A'llen) ..... , ........................ 1090
`r ~--
`lteiatio
`.
`philos Disease and Ccll-surface Anti-
`nsh1p between p tt
`fl fi
`ti
`d D
`(Dr. D. C. Turk) ................... 1090
`1
`h
`.<:tYpoaib
`.
`a ern o n ec on an
`eve opment
`RECEIVEilm
`suppressive Elfect of_ Surgery (Dr.
`unlln~mia and Hypo·~·lipoprotein~mia in Rural ib
`U
`. owell, Sheila G. Radford) ...... 1091
`J.
`"'""" 2,.,
`J. gDanLdan Children
`'7 io-Aspaf ginase ancl Lymphocyte Blasto-
`Fnoon
`.
`4.1!,, gcnes s (Dr, Isaiah J, F1dler and others)
`~W1f if'o
`'
`, ••• 1047
`'M,B,, R, G. WHITEHEAD, l'H.D., W, A. COWARD, PH.D.
`1091
`C
`SEIIW.S~--,aJ; us-chloride Treatment for Ana:mia
`Olfip
`.R.. ~nl'ative Effectiveness of Tetracycline and Ampicillin in
`•v.:Hmmodlalysis Paticnrs (Dr. L. s.
`9 IJI'\1
`-~Y'a!berg) .... , ............................... 1092
`I<s, M.R.C,I', J ELLIS M
`lJ
`' •
`,
`spirln-induced H)'Eoglyclcmla in a Patient
`.R,C,P, •• , , , ••.•. , ••• , • , , ••. • • • · • • • · • • • • ·
`l'ain Trau
`on Hrumodialysis (Dr. David S, David and
`b, W rr '<tna and the Postconcussional Syndrome
`others)
`.................................... 1092
`'-· "' AY M R c PSY
`T A K
`Bchocardiography
`in Gongenital Heart-
`'
`L. 1>. LASSM~N .p . .R '0
`diseasc (Dr. Robert Solinger and others)
`ERR, M.R.C,I'SYCH,,
`CI-I,,
`'
`'
`:p
`' . ' .s.
`. ... '.'.'.''' ' •... ''' ' .. ' '.'.'. '.'' .. '' '' .. ' 1052
`1093
`henytoin
`ti
`Vitamin E lnelfccrive in Recurrent Psychosis
`3 ter Recovery from Myocardia1 Infarction
`(Mr. R. H:. Gosling, n.sc., and otheri- 1094
`CoLLA!l
`Hf:i!~risji~~:~~.'' ... ~·-~ ... ~~-~~~~-.:~~.' .... W8~1
`lnd
`O.RAtrvn Gnoup
`. , .. , ...... , . , .. , .. , , ...... , , . , , . , , . , , .. , .. , , . 1055
`Uction f M'
`Multiple Sclerosis: Occupation and Social
`Id-trimester Therapeutic Abortion by Intra~amniotic
`0
`Ul'e
`Group at Onset (Dr. A. M. G. Campbell)
`lA» c · a and lntl'avenous Oxytocin
`1095
`1058 When to Remave rhe I.U.D, (Mr. Gracme R.
`RAFT, M.R.c.O.G BABAYO Mu
`C
`SA, M • .R.
`Duncan, P.n.c.s.) '"""'"""'""""' 1095
`· • • • · · · • • • • • • · • · • • · •' · • ·
`-.-.
`''
`·
`,O.G,
`'-'ed-biood
`11
`Complement-fixing and .Fluorescent Anti-
`~ce • Survival after SpJenectomy in Congenitai
`Sphe
`bodies in Diagnosis of E.-B.-virus !nfec-
`"
`rocytosis
`.
`tions (Dr, R. N. P. Sutton and others) 1095
`-"-· N. BArnn F n
`' · .C,S,Il., A. I. S, MACPHERSON, I•',R,C.S.E,,J, RICHMOND, P,R.C.P. 1060
`Royal College of Psychlntrisrs (Dr. Anthony
`r.
`W. Glare) """"""""'"""""""" 1096
`epuk:a:mia and B C G
`Treatment of Lupus Nephritis (Dr. J, M.
`·
`rof G
`• • •
`Simister) .................................... 1096
`· W CoM
`The Human Predicament (Dr. S, Bradshaw)
`STOCK, M.D., V, T. LIVIlSAY, n.s,, R. G, WEBSTER, R.N.
`'
`•
`1096
`Kvcim Tests in Crohn's Diseuse (Dr. J, A.
`PnELIMINARy
`Chapman and others) .................. 1097
`Cellular Origin of Grnnulocyte Coionies in
`;lOMMliNICA TIONS
`terect u ·
`Chronic Mycloid Lcukmmia (Dr. Richard
`Itum
`K. Shadduck, Dr. Howard R. Nankin)
`~nary Kallikrein Excretion in
`I{ an Ypertension
`1097
`Glucose Thcrapy in Sh<irt-bowel Syndrome
`n :;\RRY S · MARGOLXUS M D
`(Dr. Charles D, Gcrson, Dr, Henry D.
`<'-ONALD GELLER PH ~ , .,
`}anowitz)
`................................. 1098
`JOI-tN' J, P!SANö 1PH ~ ,,
`Prevcntion of Dccp-vein Thrombosis with
`S
`'
`' ''
`Subcutancous Heparin (Dr, B, Y. Pai,
`ALBE
`bo ,
`, , , , 1063
`RT
`JOERDSMA, M.D,
`'Mr. D. Negus, r.R.c,s.) '"'""""""" 1099
`d R·
`,
`lllJnant
`Early Introduction to Pathology (Prof, N, F.
`her't
`an
`ecesstve Modes of In-
`Mctcalf, M.D,, nnd othcrs) ............ 1099
`~ ance in Idiopathic Cardiomyopathy .
`Neocortical Denth nfter Cardiac Arrest (Miss
`R~CHA!U) EMANUEL, P.R.C.P.,
`Anne Rot, 1\l.D., Baroness H. A. H. vnn
`., N'ALD Wrn-mns M sc
`Till, LL,D,) ................................. 1099
`<(Ay O'B
`'
`'
`''
`Bluc Sclerotics
`in Iran Deficiency (Dr,
`RIEN • , , , , , • , • , , , , , 1065
`Robert M. Bennctt) '"""'"""""'" I JOO
`Viruscs and Whooping-cough (Prof, N, R.
`!PECIAL ARTICLES
`Grist1 F.R.C.PATfl., Dr. C. A. C, Ross) 1100
`J.he:a· h
`Medical Oncology (Dr, R. M. Clnrk) ... 1100
`Te ll't of an Abnormal Child:
`Bromism (Dr. M. W. P. Camey) ......... 1100
`~ling the Parents
`~lONALASSOCIATION FORMENTAL
`OBITUARY
`1075
`llALTII WORI<ING-PARTY
`Cecil Charles Worster-Drought.,
`..
`0
`Joseph Stanley Hopwood,,,.,, ..
`CCA.SIONAL SlJRVEY
`Tl'anspi
`.
`Margaret FitzHerbert., . , , , .. , ...
`antation-Nature's
`S
`Uccess
`J. MAXWELL ANDBRSON, F.R.C.S, 1077
`llosprrAL PRACTICE
`lnfluenc
`•
`.
`f H
`p
`. e o
`ospital S1ting on
`atlent Visiting
`Prof. THOMAs McKEOWN, F.R.c.P.,
`K. W, CRoss, PH,n.,
`._D. M, KEATING, M.R.C.P,I., , • , 1082
`
`• • • •
`
`1062
`
`Treatment and Prevention
`of Siekle-eeil Crisis. . . . . . 1069
`Sudden Death in Infants, ... 1070
`Is Phenytoin Carcinogenic? 1071
`Talking to Parents , , .. , , , , . . 1072
`Cogs in Nced of Oil. , ..••.. , . 1073
`Pesticides as Mutagens. , .. , . , . 1073
`Treatment of Malnourished
`Children .. ,.,, .. , . , . , , , .•. 1074
`Abortion: New Restraints on
`Private Clinics.,., .. ,, .•. ,, 1074
`
`LETTERS TO THE EDITOR
`Amnesia after Clioquinol
`(Dr. Knud
`Kjrersgaard) .............................. 1086
`Treatment of Stage-u Gareinoma of the
`Fernale Breast (Dr. Diana Brinkley, Dr.
`J, L, Haybittle) ........................... 1086
`Hepatitis-associated Antigen and Hepatoma
`in the U.S. (Dr. E. Alpert, Dr. K. J.
`Isselbacher) ........... , .................. )087
`Chondroitin-6-sulphaturia, Defective Ccllu-
`Jar Immunlty, and Nephrotic Syndrome
`(Dr. R. Neil Schimke and othm) ... 1~88
`Low X-chromatin Frcqucncy ln Gongenttal
`Adrenal Hyperpjasia (Dr. J, H. Schneer,
`Dr. Al. Naghi) ............................ 108,9
`Mental Retardation und Spnsttc Paraparests
`in Four of Eight Siblings (Dr. Robcrt B,
`Allport) ...... " ........................... , J 089
`Is Menkes' Syndrome a Heritable Disorder of
`Connective Tissue? (Dr. David M, Danks
`and others) .. .. .. .. .. .. .. .. .. .. .. . .. .. .. .. .. 1089
`
`1101
`1102
`1102
`
`NOTES AND NEWS
`Sterile Nursing Unitat the
`Middlesex Hospital
`. , ....... .
`Christmas Cards .. , . , , ... , , , , , , ,
`University of Dundee, ... , •. , , , ..
`Univcrsity of Edinburgh , •. , , , , .
`University of Glusgow , , .. , . , ..•
`Royal College of Physicians of
`Edinburgh .. , . , . , , . , •.... , , , 1103
`
`1103
`1103
`1103
`1103
`1103
`
`Editorial Office: 7 Adam Street London WC2N 6AD, Englund. North Americail Edition published
`$~d Com~any, 34 Beacon St,, B~ston, Mass, 02106.
`In U,S, and Canada, annual s_u,bscriptio?. $18.50;
`13 1.50; smgle copy $2.00, Second class postage paid at Boston, Mass,, and at addltlonai mathng office
`· November 1971. Notification on Form 3579 is to be mailed to The Lancet, 34 Beacon Street,
`
`Dr. Reddy's Laboratories, Ud., et al.
`V.
`Galderma Laboratories, lnc.
`IPR2015-__
`Exhibit 1007
`
`

`
`No, 7733
`
`•
`e;.:-"
`BOSTON, MASS. AND LONDON · SATURDAY 13 NOVEMBER 1971
`
`/
`/
`VOL. I! Foy197y
`
`THE LANCE~
`r
`
`CONTENTS
`
`LETTERS TO THE EDITOR-.cLt.
`Griseofulvin
`in Raynaud's Phenomenon
`1'HB WHOLB 0
`(Dr. P.'{Naidoo; Dr. A. Herxheimer; Dr.
`1
`R. ~llen) ............................... 1090
`F THE LITERARY MATTER IN THE LANGET IS COPYRIGI:ITX\)\CI"'{ /.
`h
`/ ~ ..
`J:\elation h.
`phllus Dtsease and Cell-surface Anti-
`s lp hetween Pattern f I ~ t'
`d D
`I
`(Dr. D. C. Turk) .................. 1090
`b
`0
`n.~.ec Ion an
`QYPoaib
`eve opment ·
`•
`•
`RECE.IVEOm
`. suppressive Etfcct of Surgery (Dr.
`ununremta and Hypo-~-Iipoproteinremia in Rural 55'
`, ~well} Sheila G. Rndford) ...... 1091
`D
`J.
`7 A--Aspartgmase and Lymphocyte Blasto-
`J. tanLdan Children
`~. genes s
`· FRoon M
`R
`.
`(Dr. Isaiah ] . Ftdler and others)
`.B.,
`• G. WHITEHEAD, PH.D., W. A. COWARD, PH.D.
`'
`, ... 1047
`1091
`C
`0 lllpar
`~ cdl.. baly6us-chloride Treatment for Amcmia
`•
`R MAn!sttve Effectiveness of Tetracycline and Ampicillin in
`".d"~n/.:Hmmodialysis Patients (Dr. L. s.
`, M R c p J E
`2fgi\\~.)Va1berg) .. .. . .. . .. .. • .. .. . .. .. .. .. .. . .. . .. .. 1092
`"
`• LLIS, M.R,C.P. · · · · · · · · · · · · · · · · • · · · · · • · · • · · · · • · · ·
`:t\spirin-induced H)'Eoglyca!mia in a Patiem
`}l
`' . ' '>
`l'ain l'l"au
`on Hremodialysis (Dr. David S. David and
`b. w. I< Ktna and the Postconcussional Syndrome
`others)
`.................................... 1092
`L. p L. AY, M.H.C.PSYCI-I., T. A. KERR, M.R.C.PSYCH.,
`Echocardiography
`in Congenital Heart-
`. ASSMAN, F.R.c.s
`disease (Dr. Robert SoHnger and others)
`Pb
`. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·
`1093
`enytoin afi
`Vitamin E Inetfective in Recurrcnt Psychosis
`CotLABOR
`ter Recovery from Myocardia1 Infarction
`(Mr. R. H. Gosling, n.sc., and others) 1094
`ATrvE GRoup .............................................. 1055
`lnd
`Uction of M· d
`.
`Multiple Sclcrosis: Occupation and Social
`1 •trtmester Therapeutic Abortion by Intra-amniotic
`d
`Drea
`Group at Onset (Dr. A. M. G. Campbell)
`lAN C an
`lntravenous Oxytocin
`1095
`RAFT, M.R.C.O.G BAB
`M
`1058 When to Remove the I.U.D. (Mr. Graeme R.
`!{
`''
`· • · · · • · · · · · · • · · · · · · • · · · ·
`AYO
`USA, M.R.C.O.G,
`Duncan, F.R.C.$.) ........................ 1095
`ed .. blood-
`CompJement-fixing and Fluorescent Anti-
`•
`]l
`•
`Sphe
`ce : Survtval after Splenectomy in Congemtal
`bodies in Diagnosis of E.-B.-virus Infec-
`.R
`rocytosis
`tions (Dr. R. N. P. Sutton and others) 1095
`· N". BAnm FR '
`A
`,
`Royal College of Psychiatrists (Dr. Anthony
`' ' .C.S,E.,
`· l. S. MACPHERSON, F.R.C.S.E., J, RJCHMOND, F.R.C.P.
`W. Clare) ................................. 1096
`epuk;:emia and ß C G
`·
`Treatment of Lupus Nephritis (Dr. J, M.
`• • •
`rof. G W
`Sin1istcr) .................................... 1096
`The Human Predicament (Dr. S. Brads\1~~J
`· COMSTOCI<, M.D., V. T. LIVESAY, B.s., R. G. WEBSTER, R.N.
`'
`Kveim Tests in Crohn's Diseuse (Dr. }. A.
`~REtlMINARY
`Chapman and others) .. .. .. .. .. .. .. .... 1097
`Cellular Origin of Granulocyte Colonies in
`A.IOM.MtJNICA TlONS
`Chronic Myeloid Leukmmia (Dr. Richard
`terect Uri
`.
`K. Shadduck, Dr. Howard R. Nankin)
`I-Iurn H nary Kalhkrein Excretion in
`1097
`I-I an YPertension
`Glucose Thcrapy in Short~bowel Syndrome
`RgRRY S. MARoouus, M.D.,
`(Dr. Charles D. Gcrson, Dr. Henry D.
`J NALD GELLER PH D
`Ül-{ J
`] anowitz)
`...... · .. · · ... · · .. ·.............. I 098
`Prevention of Deep~vein Thrombosis with
`Atn N
`· PISANo, PH.D.,
`Subcutaneous Heparin (Dr. B. Y. Pai,
`.
`bo
`ERT SJOERDSMA, M.D .. • .. 1063
`Mr. D. Negus, F.R.c.s.) .................. 1099
`d R
`.
`llllllant
`Early Introduction to Pathology (Prof. N. F.
`~n . ecesstve Modes of In-
`herit
`Metcalf, M.D., and othcrs) ............ 1099
`RI ance lU ldtopathic Cardiomyopathy .
`Neocortical Death after Cardiac Arrest (Miss
`RoCHARn EMANUEL, F.R.c.P.,
`Anne Rot, M.D., Baroness H. A. H. van
`}( NALD WITHERs, M.Sc,,
`Till, LL.D.) .............. •••••••·· .......... 1099
`Blue Sdcrotks in
`Iron Deficiency (Dr.
`AY O'BRIEN
`Robert M. Bennctt) .. . .. .. . .. .. .. .. . .. .. I 100
`!PECIAt ARTIC~~~· ........ .
`Viruscs and Whooping-cough (Prof. N. R.
`Grist, F.R.C.PATH., Dr. C. A. C. Ross) 1100
`.t.hea· h
`Medical Oncology (Dr. R. M. Clark) ... 1100
`l'e] ~rt of an Abnormal Child:
`Bromism (Dr. M. W. P. Carncy) ......... 1100
`N hng the Parents
`~ION AL ASSOCIA TION FORMENTAL
`EALTH WaRKING-PARTY .. 1075
`0
`l' CCASIONAL SURVEY
`l'anspi
`•
`antatton-Nature's
`S
`Uccess
`lJ J. MAXWELLANDERSON~ F.R.C.S. 1077
`1 OSPITAL PRACTICE
`f H
`.
`.
`nfluence
`P
`.
`o
`ospttal Stting on
`attent Visiting
`~ro&r THOMAS McKnowN, F.R.C.P.,
`D ·
`· CRoss, PH.o.,
`--- . M. KEATING, M.R.C.P.I. .... 1082
`
`Treatment and Prevention
`of Siekle-eeil Crisis .. ,... 1069
`Sudden Death in Infants .... 1070
`Is Phenytoin Carcinogenic? 1071
`Talking to Parents ......... .
`1072
`Cogs in Need of Oil. ..•.•....
`1073
`Pesticides as Mutagens ....... .
`1073
`Treatment of Malnourished
`Children ................. .
`Abortion: New Restraints on
`Private Clinics ........... .
`
`t
`
`~
`
`l
`
`• • ,
`
`1065
`
`105~
`-
`
`H~!~risYi~~~~~.s ... ~~.l ... ~~.~~~~ .. ~~~: ... ·~);r0~~
`
`1060
`
`. ... 1062
`
`1074
`
`1074
`
`OBITUARY
`Cecil Charles Worster-Drought. . 1101
`Joseph Stanley Hopwood ........ 1102
`Margaret FitzHerbert. . . . . . . . . . . . 1102
`
`NOTES AND NEWS
`Sterile Nursing Unitat the
`Middlesex Hospital ......... .
`Christmas Cards ............... .
`University of Dundee ........... .
`University of Edinburgh , ...... .
`University of G1asgow ......... .
`Royal Coiiege of Physicians of
`Edinburgh .... , ............ .
`
`1103
`1103
`1103
`1103
`1103
`
`1103
`
`Exh. 1007
`
`

`
`THE LANCET, NOVEMBER 13, 1971
`
`We are now investigating these metabolic processes.
`They are partly the reason why a child is precipitated
`into a clinical episode of kwashiorkor. These factors
`and also the role of the immune response will be
`enlarged upon in future communications.
`Few other studies have been madeon the effects of in-
`fection on serum-albumin, except where these infections
`have led to specific loss of prorein through the gut or
`kidney. There was no gross proteinuria in the children
`in this series, although a trace was sometimes observed
`during pyrexial episodes, as might be expected. Loss
`of albumin through the gut could not be investigated,
`but this possibility is now being pursued as a separate
`project, although it is anticipated this will be of only
`minor significance except perhaps during measles,
`gastroenteritis, or when there is severe worm infesta-
`tion. Albumin concentration does fall significantly
`after surgery, 8 but the cause is not known. Of par-
`ticular relevance to the ß-lipoprotein results are the
`investigations of Platt, 0 , 1 o who showed that infection
`could lead to a fatty liver in laboratory animals even
`when the prorein content of the diet was apparently
`adequate.
`It is becoming more obvious that the pathogenesis
`of kwashiorkor is complex and is a product of the
`child's whole environment.
`It is just as important
`to combat disease as it is to improve diet, and any
`public-health scheme aimed at eradicating malnutrition
`should give equal consideration to both these crucial
`aspects of the problem.
`We thank the medical and nursing staff of this unit who run
`the outpatient clinics, and Mr. J. B. Kiwanuka, who analysed the
`blood specimens.
`Requests for reprints should be addressed to R. G. W.
`
`REFERENCES
`1. Mata, L. J,, Urrutra, J, J,, Garcia, B. Ciba Fndn Swdy Grp, 1967,
`no. 31, p, 112. London, 1967.
`2. Whitehead, R. G., Frood, J. D. L., Poskitt, E. M. E. Lanc.Jt, 1971,
`ii, 287.
`3. Coward, W. A., Whltchead, R. G. Br. J, Nutr. (in the press),
`4. Flores, H., Pak, N., Maccioni, A., Mönckebcrg, F. ibid. 1970, 24,
`1005.
`5. Poskitt, E, M. E. La11cet, 1971, ii, 68.
`6. Coward, D, G., Sawyer, M. B., Whitehead, R. G. Am.J. cli11. Nutr.
`1971, 24, 940.
`7. Hciskell, C, L., Fisk, R. T., Florsheim, W. H., Tachi, A., Goodman,
`J, R., Carpentcr, C. M. Am. J, c/i11, Path. 1961, 35, 222.
`8, Mouridson, H. T. CUu. Sei. 1967, 33, 345,
`9. Orraca-Tetteh, R., Platt, B. S, Proc, Ntttr. Soc. 1964, 23, iii.
`10. AI-Rnbii, H. A., Platt, B. s. ibid. 1964, 23, iv.
`
`H ••• I will not labour my own conviCtiOn that the
`normal state of most people is to feel faintly tired, harassed,
`and under the weather-and that my clinical observations
`lead me to believe that an abounding sensation of positive
`health usually presages either a cardiac infarction or incipient
`hypomania. The fact remains that the concept of positive
`health is as popular with some apostles of preventive
`medicine as with lay journalists. It postulates a state that
`could apparently be achieved by the careful observation
`of a set of rules that · vary with the writer, but which are
`always inconvenient and uncomfortable and usually eccen-
`tric. I question the whole concept of positive health and
`the validity of the prescriptions claimed to ensurc it.>'-
`HENRY MILLER, M.D., in Medical History and Medical
`Care ( edited by GoRDON McLACI-ILAN and THOMAS
`McKnowN); p. 224. London, 1971.
`
`1049
`
`COMPARATIVE EFFECTIVENESS OF
`TETRACYCLINE AND AMPICILLIN IN
`ROSACEA
`A Controlle<l Trial
`R. MARKS
`J, ELLIS*
`Institute of Dmnatology> St. John's Hospital jor Diseases
`of the Sldn) London W.C.2
`
`56 patients with papular rosacea were
`S
`treated with tetracycline, ampicillin, or
`ummary
`placebo in a randomised double-blind clinical trial.
`Patients were evaluated by counting the number of
`papules in predetermined sites on the forehead and
`left cheek at fortnightly intervals over a six-week
`period. The results showed that both tetracycline and
`ampicillin produced a significant decrease, at the 5%
`level, in the number of papules, compared to the
`placebo treatment. When the results were assessed by
`a scoring system, tetracycline and ampicillin proved
`significantly better than placebo (P =0·05); tetracycline
`was better than ampicillin, but the difference did not
`quite reach the 5% significance level.
`Introducdon
`THE tetracycline group of antibiodes has been used
`in the treatment of acne vulgaris since shortly after
`their introduction in the early 1950s,
`In controlled
`clinical trials some groups have found that the tetra-
`cyclines improve acne, 1 • 2 whereas another has found
`that these antibiodes were of little help. 3 The present
`consensus is that tetracyclines improve acne slowly,
`incompletely, and irregularly.
`In contrast to many reports on the use of antibiodes
`in acne, there have been few similar reports on rosacea
`and even fewer which describe a controlled clinical
`trial.
`In this study we have compared the effectiveness of
`tetracycline and ampicillin in the treatment of rosacea
`in order to determine (1) whether, with objective
`assessment, there is significant improvement, and (2)
`whether the action of the tetracyclines is unique or
`is shared by other antibacterial agents.
`
`Patients and Methods
`Patients were admitted to the trial if they had typical
`rosacea characterised by the presence of persistent erythema
`of the cheeks and nose, chin, and forehead and papules
`(and/or pustules) on these areas. Patients without easily
`definable papules were not included. In addition, patients
`who had received treatment with. antibiodes in the previous
`six weeks were not included. Patients who satisfied these
`criteria were randomly allocated to one of three coded
`treatment groups by the hospital dispensary. The placebo,
`tetracycline, and ampicillin were supplied in identical
`capsules, and neither patients nor investigators knew the
`identity of the group to which each participant belonged.
`The instructions given to each patient were to take one
`tablet three times a day for the first week, and then to
`reduce the dose to one twice daily for the subsequent five
`weeks. No other treatment was permitted apart from the
`use of an aqueous cream as an cmollient.
`Patients were seen and assessed at fortnightly intervals,
`whenever possible, for six weeks. At each visit the nurober
`• Present nddress: Slnde Hospital, Oxford.
`
`Exh. 1007
`
`

`
`1050
`
`THE LANGET, NOVEMBER 13, 1971
`
`TABLE I-NUMBER OF PAPULES RECORDED AT BACH ATTENDANCE IN EACH PATIENT
`
`0
`
`1
`
`-
`
`Tetracycline
`
`Week
`
`3
`
`-
`
`-
`
`5
`
`4
`
`8
`6
`1
`
`5
`
`-
`
`-
`
`0
`
`6
`
`4
`9
`0
`
`2
`
`-
`
`9
`6
`10
`
`12
`
`Ampicillin
`
`Wcek
`
`0
`
`1
`
`-
`
`2
`
`-
`
`3
`
`-
`
`4
`
`-
`
`4
`
`-
`
`6
`
`6
`4
`10
`11
`6
`
`-
`
`5
`
`6
`
`6
`
`Placebo
`
`3
`
`Weck
`4
`4
`
`-
`
`-
`
`5
`
`-
`
`6
`
`7
`
`-
`
`Patient
`no.
`----
`1
`9
`2
`10
`54
`7
`17
`10
`18
`12
`20
`11
`22
`28
`27
`14
`7
`32
`33
`14
`36
`48
`25
`37
`39
`24
`32
`40
`46
`7
`25
`48
`49
`15
`59
`16
`60
`28
`25
`61
`
`8
`5
`
`6
`
`3
`
`5
`
`5
`
`21
`16
`
`22
`23
`17
`
`11
`10
`12
`37
`1
`
`4
`2
`13
`8
`
`31
`25
`19
`14
`1
`0
`9
`15
`1
`
`4
`
`0
`
`1
`
`4
`0
`5
`8
`0
`17
`7
`23
`
`1
`0
`0
`2
`8
`0
`
`Patient
`no.
`7
`- ----
`24
`3
`10
`4
`16
`6
`12
`11
`21
`23
`6
`26
`9
`28
`8
`29
`9
`31
`84
`41
`16 17
`42
`28
`44
`6
`50
`20
`52
`53
`17
`13
`57
`59
`62
`
`3
`
`9
`7
`9
`14
`9
`13
`8
`
`73
`
`1
`35
`17
`11
`37
`
`2
`
`23
`
`4
`10
`7
`6
`8
`1
`19 18
`4
`2
`15
`11
`10
`21
`
`16
`
`7
`3
`5
`7
`1
`15
`0
`36
`6
`8
`
`2
`2
`17
`12
`6
`1
`10
`
`8
`
`Patient
`no.
`1
`7
`0
`- --------
`8
`5
`12
`9
`13
`22
`17
`15
`24
`16
`21
`7
`4
`24
`28
`25
`30
`8
`20
`35
`38
`9
`7
`43
`45
`60
`47
`11
`51
`23
`24
`54
`34
`55
`17
`56
`19
`64
`
`8
`38
`75
`34
`21
`18
`
`-
`5
`12 16
`9
`13
`9
`0
`10
`13 22
`11
`14
`15 28
`35
`
`0
`23
`28
`31
`18
`13
`
`11
`18
`10
`0
`14
`
`10
`15
`
`1
`30
`20
`41
`23
`15
`
`55
`
`18
`45
`
`of papules and pustules in predetermined areas on the
`forehead and right cheek were counted (see accompanying
`figure). In order to use the identical area, in each patient
`at each visit two flexible frames were used. The internal
`measurements for the forehead frame were 8 x 4 cm., and
`those for the right cheek frame were 4 X 5 cm. When counting
`lesions on the forehead the centre of the frame was made to
`coincide with the midline of the nose and its Iower margin
`was placed on the supraorbital ridges. When using the
`frame for the cheek the upper and outer angle of the
`reetangle was placed on the lateral orbital tubercle so that
`one of the Ionger 5 cm. edges touched the lower border of
`the orbit. Lesions touching the lower and left margins of
`the frames were not counted. All palpable lesions were
`counted. To check that this method of assessment was
`reliable, repeated lesion"counts were made on the same
`patients by both observers at the beginning of the investi-
`gation. The values obtained were almost always identical,
`occasionally differing by one or, when many papules were
`present, two lesions. At each visit the patient's assessment
`of his progress and the observer's subjective assessment of
`the amount of erythema present were also recorded. In
`addition, patients were asked at each attendance whether
`the prescribed treatment had agreed with them, and any
`symptoms present were recorded.
`
`Tested areas on forehead and right check.
`
`56 patients completed the trial-20 in the tetracycline
`group, 17 in the ampicillin group, and 19 in the p1acebo
`group. The mean age of the 56 patients was 47·8 years
`(range 20-69) and there were 27 men and 29 women.
`
`Results
`Table I gives the number of papules and pustules
`for each patient at each attendance in the three treat-
`ment groups. Table n shows the mean numbers of
`papules and pustules before and at the end of the
`treatment period.
`
`TABLE Il-MEAN NUMBER OF LESIONS±STANDARD DEVIATION
`IN BACH TREATMENT GROUP
`
`-
`Pre-treatment
`Post-treatment
`
`Tetracycline
`
`Ampicillin
`
`Placebo
`
`21·05±12·79
`
`21·06±20·48
`
`18•47±13-14
`
`4·60± 6·20
`
`9·53± 8·79
`
`16·63 ± 12·81
`
`These means were subjected to analysis of variance,
`which indicated significant differences between some
`of the means. Duncan's multiple-range test showed
`that:
`(1) The pre-treatment means were not significantly
`different from each other or from the post-treatment mean
`of the placebo group.
`(2) The post-treatment mean for the ampicillin group
`did not differ from the post-treatment means for the
`tetracycline and placebo groups, but was significantly lower
`than the pre-treatment means.
`(3) The post-treatment mean for the tetracycline group
`was significantly Iower than all the other means except the
`ampicillin post-treatment mean.
`The overall significance level'is 5%.
`The results were also analysed by. giving a score to
`the change in the number of lesions between the first
`and last attendance in each patient, thus: a decrease in
`lesions by 75% or more (+3); a decrease by 50-75%
`( + 2); a decrease by 30-50% ( + 1); a change in the
`number of lesions ±30% (O); an increase in lesions
`by more than 30% ( -1). The scores that result from
`this analysis are shown in table nr. The mean scores
`
`Exh. 1007
`
`

`
`THE LANCET, NOVEMBER 13, 1971
`
`1051
`
`TADLE III-NUMBERS OF PATIENTS WITH SCORES FROM +3
`TO -1 IN BACH OF THRllll TREATMENT GROUPS
`
`Score
`
`Tetracycline Ampicillin
`
`Placebo
`
`Totals
`
`-1-3
`+2
`+1
`0
`-1
`
`Totals
`
`9
`8
`0
`3
`0
`20
`
`3
`6
`4
`.3
`1
`
`17
`
`I
`
`2
`2
`4
`5
`6
`
`19
`
`15
`16
`8
`11
`7
`
`57
`
`TADLE IV-RESULTS OF PATIENTS' OWN ASSESSMENTS
`
`Category
`Much better
`Better
`Same
`Worse
`
`Tetracycline
`
`Ampicillin
`
`5
`9
`4
`2
`
`8
`6
`2
`1
`
`Placebo
`
`6
`3
`7
`3
`
`by dermatologists because of their successful use in
`acne and because in rosacea they were found empiri-
`cally to be effective.
`The lack of evidence for a bacterial cause raised the
`question of how the tetracyclines work in this condi ...
`tion. It was decided to determine whether an anti-
`bacterial action is involved, by comparing the clinical
`effectiveness of tetracycline with an antibacterial agent
`that worked in a different way to the tetracyclines-
`i.e., ampicillin. Our finding that both ampicillin and
`tetracycline are statistically better than placebo in the
`treatment of papular rosacea is presumptive evidence
`for the involvement of bacteria in the pathogenesis of
`the disease.
`In acne it is believed that Corynebacterium acnes, a
`member of the normal sldn flora, is responsible for
`hydrolysis of the triglycerides of sebum, with the
`liberation of irritant and comedogenic fatty acids. 8
`The tetracyclines have been shown to reduce the
`fatty-acid content of sebum, and this may explain their
`action in acne. 0
`It is difficult to accept that anti-
`biodes act in a like manner in rosacea. In rosacea the
`inflammatory response is characterised by redema and
`a loose admixture of lymphocytes and large histio-
`cytes which is not markedly centred around the
`follicles, while in acne there is an acute folliculitis.
`Comedones are not usual in rosacea, and, in addi-
`tion, rosacea is not common areund puberty when
`sebum is secreted at a high rate. None the less, it
`appears likely that bacteria play some as-yet un-
`defined role in the disease, and that antibiotics are
`etfective clinically by virtue of their action on these
`microorganisms.
`I t has been shown that tetracyclines are deposited
`preferentially in the sldn, 10 •11 and this may explain the
`better result that we obtained with tetracycline than
`with ampicillin.
`In this trial we tested the effect of antibiotics on the
`papules of rosacea because these lesions can be readily
`counted. Furthermore, it had previously been observed
`that they are more readily affected than the erythe-
`matous component of the disease. In the short time
`that we observed our patients there did not seem to be
`any pronounced or consistent change in the depth or
`extent of erythema in any of the treatment groups.
`The persistence of the erythema may explain the less
`dramatic results obtained when the patients' own
`subjective assessments were compared.
`There are few published reports of formal clinical
`trials involving the use of the tetracyclines in rosacea.
`Sneddon u reported that in a controlled clinical trial
`tetracycline was effective in 87% of 78 patients.
`Wereide 13 also noted "excellent or good ,, results in
`82% of 74 patients treated with methyl-L-lysine tetra-
`cycline. Both these workers noted that small doses of
`tetracycline sufficed to suppress the appearance of
`papules. The present trial seems to have been the first
`in which objective criteria have been adopted to show
`that the tetracyclines are effective in the treatment of
`rosacea.
`
`We are grateful to Pfizer Ltd. for supplying the tetracycline,
`ampicillin, and placebo packed in identical capsules; and to Miss
`C. Pullin, of the Wellcome Research Laboratories, for statistical
`analysis of the results. R. M. is in receipt of a grant from the
`Medical Research Council.
`
`I
`I
`I
`for each group are as follows: tetracycline 2·15, ampi-
`cillin 1·41, placebo 0·42. The tetracycline and ampi-
`cillin scores differ significantly from placebo score at
`the 5% level. The difference between tetracycline and
`ampicillin does not quite reach the 5% significance Ievel
`but is probably real.
`Brythema
`There did not seem to be any significant change in
`the extent or depth of erythema present during the
`trial.
`Patients' Subjective Assessment
`When patients were asked whether they considered
`themselves much better, better, the same, or worse,
`both tetracycline and ampicillin appeared to score
`better than placebo. Ampicillin seemed marginally
`better than tetracycline (table IV).
`Side-effects
`No serious side-effects were encountered in this
`study. 2 patients developed troublesome diarrhcea
`after the first few days' treatment and were withdrawn
`from the trial; these were found tobeleng to the ampi-
`1 patient in the tetracycline group
`cillin group.
`experienced diarrhcea on 750 mg. daily but not on
`500 mg. daily; and 1 other in the ampicillin group
`complained of " persistent slight looseness of the
`bowel " not necessitating withdrawal from the trial.
`Interestingly, 1 patient (who was later found to be in
`the placebo group) developed a transient maculo-
`papular erythema and was withdrawn from the trial.
`Other mild transient complaints included " a funny
`taste in the mouth ", "nausea ,,, "constipation ", and
`" secretions drying up ".
`Discussion
`Rosacea is a common and troublesome disease
`characterised by persistent erythema and crops of
`papules and pustules.
`Its cause is unknown, and
`various hypotheses on its retiology have been found
`unacceptable when their assumptions have been put
`to the test. ·t- 6
`In particular, cultures from biopsy
`material and pustules have not revealed pathogenic
`bacteria, and histologically there is no evidence that
`the disease is caused by microorganisms. 7 None the
`less the tetracycline group of antibiodes has been used
`
`Exh. 1007
`
`

`
`1052
`
`Requests for reprints should be addressed to R. M., Institute
`of Dermatology, St. John's Hospital for Diseases of the Skin,
`Lisle Street, Lciccster Square, London WC2H 7BJ.
`
`REFERENCES
`1. Smith, M. A., Mortimer, P. R. Br. J. Dcrm. 1967, 79, 78.
`2. Lane, P., Williamson, D. M. Br, med. J. 1969, ii, 76.
`3. Crounse, R. G. J, Am. med. Ass. 1965, 193, 906,
`4. S0bye, P. Acta derm.-vener., Stockh. !950, 30, 137.
`5. Marks, R., Beard, R. J,, Clarkc, M. L., Kwok, M., Robcrtson,
`W. B. Lancet, 1967, i, 73,
`6. Marks, R. Br.J. Derm. 1968,80, 170.
`7. Marks, R., Rarcourt Webster, N. Archs Derm. 1969, 100, 683.
`8. Kligman, A. M., Wheatley, V. R., Mills, 0. H. ibid. 1970, 102,267.
`9. Frcinkel, R. K., Strauss, J, S., Yip, S, V., Pochi, P. E. Ncw Ellgi,J·
`Med. 1965, 273, 850.
`10. Rashleigh, P. L., Rife, E., Goltz, R. W. J. invest. Derm. 1967,
`49, 611.
`11. Marks, R., Davies, M. Br.J. Dmn. 1969,81,448.
`12. Sneddon, I. B. ibid. 1966, 78, 649.
`13, Wercide, K. Acta derm.-vmer., Stodth. 1969, 49, 176.
`
`BRAIN TRAUMA AND THE
`POSTCONCUSSIONAL SYNDROME
`T. A. KERR
`D. W.K. KAY
`L. P. LASSMAN
`Department of Psychological MedicineJ Royal Victoria In-
`jirmary and Um'versity of Newcastle upon Tyne)· and Neuro-
`surgical Unit" Newcastle General Hospital
`In a retrospective case-note study of
`Summary 474 patients with head injury admitted
`consecutively to a specialised unit, the hypothesis was
`tested that the outcome would depend on the severity
`of the initial trauma. The hypothesis was confirmed
`in regard to survival without definite brain damage,
`survival with brain damage, and death. But within
`the first group the difference between the " post-
`concussional " and recovered patients in terms of
`severity of the initial brain trauma was small. Patients
`with the postconcussional syndrome were better
`distinguished by psychosocial factors and by distur-
`bances of the special senses.
`
`Introducdon
`PoSTCONCUSSIONAL syndrome is used to describe
`symptoms-headache, dizziness, emotional instability,
`and impairment of concentration-which frequently
`develop after head injury. Sometimes these complaints
`become persistent and disabling despite the absence
`of obvious physical signs. As Critchley 1 pointed out,
`opinion has swung from a concept of organic to
`mainly neurotic causation and back again.
`The
`case for an organic cerebral retiology has been forcefully
`argued by Taylor. 2 But if brain trauma is a factor,
`the trauma must be of a subtle kind, since neither
`neurological signs nor the characteristic intellectual or
`personality changes associated with brain darnage are
`present.
`A study of a consecutive series of head injuries 3
`presented a