Reynolds and Wilson's article on obsessive compulsive disorder and
psychopathic behaviour in Babylon gives us unprecedented insights into how
these psychiatric disorders were identified and - to some extent -
conceptualised by an ancient civilization. Surprisingly, the Babylonian
descriptions are accurate and modern, and thoroughly objective. As noticed
by the Authors, this objectivity is one of the most interesting aspect...
Reynolds and Wilson's article on obsessive compulsive disorder and
psychopathic behaviour in Babylon gives us unprecedented insights into how
these psychiatric disorders were identified and - to some extent -
conceptualised by an ancient civilization. Surprisingly, the Babylonian
descriptions are accurate and modern, and thoroughly objective. As noticed
by the Authors, this objectivity is one of the most interesting aspects of
the accounts that we can find in Sumerian and Akkadian tablets. The lack
of a subjective perspective over obsessional thoughts and pathological
ruminations is remarkable, given the intrinsically subjective nature of
anxiety and psychotic symptoms.
One possible hypothesis for this interesting observation is implicitly
suggested by the Authors when they write that Babylonians, considering the
origin and nature of mental illness as deeply mysterious, restricted
themselves to the simple observation and record of the abnormal behaviour,
rather than trying to give a physical or a supernatural account of these
disorders. According to this hypothesis, the position of Babylonians was
surprisingly wise and scientifically-minded: they did not speculate on
psychiatric disorders mainly because they were aware of their limitations
in understanding them. This attitude would reveal ante-litteram
reflections on suspension of judgment (Socrates: "The only true wisdom is
in knowing you know nothing") and appropriate use of language
(Wittgenstein: "Whereof one cannot speak, thereof one must be silent.").
Although this hypothesis has many merits, including its logical linearity,
it falls short of accounting for certain historical inconsistencies. Why
Babylonians provided supernatural explanations, such as the bad influence
of gods or evil spirits on the human soul, for a variety of medical
disorders but not for mental illness? What was so special that
distinguished pathological behaviours from other disorders? If we take for
granted the mystery-hypothesis, these questions are destined to remain
unanswered.
At least two other hypotheses can be put forward in order to account for
the objective stance taken by Babylonians in describing psychiatric
disorders. The first one is that psychopathic behaviours, obsessive
compulsive symptoms and phobic reactions were regarded as performed in
absence of free will. Since the abnormal behaviour was taken to be
involuntary, Babylonians accounted for it entirely in objective terms. In
so doing, they might have intended to underline that the aberrant actions
were beyond the subject's will and control. This hypothesis clarifies why
the psychopathic behaviour was regarded as different from other disorders.
On the other hand, this solution is still subjected to the criticism
aforementioned with regards to the mystery-hypothesis. Why did Babylonians
not resort to a supernatural explanation, if people who suffered from
psychosis seem to act under the control of an external will? Moreover, the
absence-of-free-will-hypothesis raises the fascinating issue about whether
or not Babylonians had a concept of volition similar to ours.
This issue leads us to the second and perhaps most intriguing
hypothesis, which is based on Julian Jaynes' model of the bicameral mind
(1). On the ground of detailed philological evidence, Jaynes' thought-
provoking book The Origin of Consciousness in the Breakdown of the
Bicameral Mind (1976) argued that in the second millennium B.C. the
ancient populations had not as yet developed our modern concept of
consciousness. According to Jaynes' theory, the notions of volition and
decision, intimately bound with the idea of conscious will, did not emerge
until a more sophisticated language allowed introspection and self-
visualization. Since its development, this controversial evolutionary
model for the origin of consciousness has been the subject of a continuing
debate (2, 3). Among other things, Jaynes argued that Babylonians and
other ancient civilizations lacked the linguistic sophistication of mental
concepts which might be a pre-requisite for higher-order awareness or a
fully fledged self-representation.
This hypothesis gains support from philological studies of the Iliad
lexicon, which notoriously lacks words directly translating our concepts
of "consciousness" and even "mind" (4). In fact, in the passages of the
poem which come from the oldest oral tradition, the Homeric heroes appear
to act as if they were driven by uncontrollable external forces, rather
than their own free will. The analogy with the "automatic" aspects of the
obsessive compulsive disorder and the psychopathic behaviour described by
Babylonians is astonishing. The idea of ancient Greeks and Babylonians
without self-consciousness can seem bizarre at first sight. However, it is
likely that concepts which are for us of ordinary use - that is, mind,
self, consciousness, self-awareness, identity, etc. - went through a
process of development and transformation in the course of Western
civilisation (5).
This last hypothesis might provide an answer to both questions mentioned
above. Lacking a sophisticated concept of a unitary subjective Self,
Babylonians could not distinguish between self- and nonself-conscious
behaviour. Consequently, neutral and objective accounts were their only
ways of describing obsessive compulsive disorders and psychopathic
behaviours. Finally, they might have not resorted to a supernatural
explanation for psychiatric disorders simply because they had no
conception as yet of a conscious mind susceptible to be affected by divine
entities.
References
1. Jaynes J. The Origin of Consciousness in the Breakdown of the
Bicameral Mind. Boston, MA; Houghton Mifflin, 1976.
2. Kuijsten M. (ed.) Reflections on the Dawn of Consciousness: Julian
Jaynes's Bicameral Mind Theory Revisited. Julian Jaynes Society Henderson,
NV, 2006.
3. Cavanna A.E., Trimble M., Cinti F., Monaco F. The "bicameral mind" 30
years on: a critical reappraisal of Julian Jaynes' hypothesis. Functional
Neurology 2007; 22(1): 11-15.
4. Taylor C. Sources of the Self. Cambridge; Cambridge University Press,
1989.
5. Crivellato E., Ribatti D. Soul, Mind, Brain: Greek philosophy and the
birth of neuroscience. Brian Research Bulletin 2007; 71: 327-336.
Dear Editor,
I read with great interest the article by Do D et al. regarding the treatment of paroxysmal sympathetic storm with labetalol.
I'll lilke to thank the authors for such a concise and clinically relevant piece on not only the typical presentation and early recognition of sympathetic storming, but also an evidence based (the case report mentioned in the original letter) method for managing these patients.
This is a very e...
Dear Editor,
I read with great interest the article by Do D et al. regarding the treatment of paroxysmal sympathetic storm with labetalol.
I'll lilke to thank the authors for such a concise and clinically relevant piece on not only the typical presentation and early recognition of sympathetic storming, but also an evidence based (the case report mentioned in the original letter) method for managing these patients.
This is a very educational and useful article, especially for a junior doctor working on a Neurology/neurosurgery high dependecy ward/intensive care unit.
The main reason for this letter is to point out what i think is a genuine mistake in the management section of the original piece. I refer to the 2nd line of paragraph 6, the statement: '...and specific alpha-2 adrenoceptor antagonists, such as clonidine and methyldopa...', describing methods/ways to directly inhibiting the sympathetic overactivity causing most of the signs/symptoms associated with paroxysmal sympathetic storm.
Clonidine and Methyldopa are both specific presynaptic alpha-2 adrenoreceptor AGONISTS that decrease overall sympathetic activity by binding to alpha-2 receptors on noradrenergic nerve terminals located centrally, causing the inhibition of adenylyl cyclase, resulting in a decrease in cyclic adenosine monophosphate (cAMP) concentrations, and causing the closure of calcium ion channels. This dampens the release of more neurotransmitter, noradrenaline in this case, therefore reducing overall sympathetic tone and the associated effects of hyperpyrexia, hypertenion, tachycardia, e.t.c. Note that methyldopa is initially converted to alpha-methylnorepinephrine in the adrenergic nerve endings, before it can have this effect on the alpha-2 adrenergic receptors.
In summary, the original letter is a well written piece that briefly explains the recognition and management of paroxysmal sympathetic storm, but with a key error made in the description of the medications used in managing this medical syndrome.
References
1. D Do, VL Sheen, E Bromfield.Treatment of paroxysmal sympathetic storm with labetalol.J Neurol Neurosurg Psychiatry 2000;69:832-833 doi:10.1136/jnnp.69.6.832
2. Shen, Howard (2008). Illustrated Pharmacology Memory Cards: PharMnemonics. Minireview. pp. 12. ISBN 1-59541-101-1.
3. Oh SJ, Hong YK, Song EK.Paroxysmal autonomic dysregulation with fever that was controlled by propranolol in a brain neoplasm patient.Korean J Intern Med. 2007 Mar;22(1):51-4.
Focal onset of ALS is attractive; it superficially mirrors what is
encountered clinically, initial weakness in an arm, leg or bulbar muscles
and is an explanation for phenotypic variation in terms of site of onset
and rate of progression (Ravits and La Spada 2009). I congratulate
Fujimura-Kimono and colleagues in their efforts to define patterns of
spread through the ALS motor system and finding that the interval between...
Focal onset of ALS is attractive; it superficially mirrors what is
encountered clinically, initial weakness in an arm, leg or bulbar muscles
and is an explanation for phenotypic variation in terms of site of onset
and rate of progression (Ravits and La Spada 2009). I congratulate
Fujimura-Kimono and colleagues in their efforts to define patterns of
spread through the ALS motor system and finding that the interval between
the onset and subsequent region is an important prognostic indicator is of
considerable value.
However, there are at least two issues that should raise concern and
question the focal onset of ALS. Firstly even though onset may appear to
arise rather focally, for example one limb or bulbar, this does not
necessarily reflect reality. Even when weakness and wasting appears to be
restricted to a limb or the bulbar region, fasciculation which, is an
essential feature of ALS is frequently quite diffuse. This may not be
evident clinically and often requires needle electromyography to confirm
(Eisen 2009). For ALS specialist who is also an electromyographer, it is
clear that acute and/or chronic denervation (fibrillation and/or complex
unstable motor units) are seen much more diffusely than suggested by the
"focal" clinical onset deficit. This was the underlying philosophy of the
new Awaji criteria (Carvalho and Swash 2009). Fujimura-Kimo et al do
recognize that absence of electrophysiology is a limitation of their
study. In addition subtle but diffuse upper motor neuron signs frequently
accompany focal muscle weakness and wasting.
The second issue relates to the time of onset of ALS. If ALS is
similar to other neurodegenerative disorders (Alzheimer's and Parkinson's)
which is currently accepted, there is a lengthy, albeit, underdetermined
pre-clinical period during which complex, poorly understood, dysfunction
of the motor system occurs which is insufficient to translate into
clinical deficit. It is this that eventually results in relative focal
failure of motor function involving different neuronal populations and non
-neuronal cells. So the important question is what is it that triggers a
diffuse propensity of non-clinical neuronal dysfunction into one with a
focal neurological deficit?
Fujimura-Kiyono, C, Kimura, F, Ishida, S et al (2011). "Onset and
spreading patterns of
lower motor neuron involvements predict survival in sporadic amyotrophic
lateral sclerosis" J Neurol Neurosurg Psychiatry 82(10)
Carvalho, M. D. and M. Swash (2009). "Awaji diagnostic algorithm increases
sensitivity of El Escorial criteria for ALS diagnosis." Amyotrophic
lateral sclerosis : official publication of the World Federation of
Neurology Research Group on Motor Neuron Diseases 10(1): 53-57.
Eisen, A. (2009). "Amyotrophic lateral sclerosis: A 40-year personal
perspective." Journal of clinical neuroscience : official journal of the
Neurosurgical Society of Australasia 16(4): 505-512.
Ravits, J. M. and A. R. La Spada (2009). "ALS motor phenotype
heterogeneity, focality, and spread: deconstructing motor neuron
degeneration." Neurology 73(10): 805-811.
We thank Drs DiFrancesco et al for their comments on our recent paper
in which we proposed diagnostic criteria for cerebral amyloid related
inflammation (CAA-I). The report by this group of an increase in anti-
amyloid beta autoantibodies in a 68 year old man with probable CAA-I is of
interest and may well help further our understanding of the pathogenesis
of CAA-I. However, we agree that this finding must be confirmed in a...
We thank Drs DiFrancesco et al for their comments on our recent paper
in which we proposed diagnostic criteria for cerebral amyloid related
inflammation (CAA-I). The report by this group of an increase in anti-
amyloid beta autoantibodies in a 68 year old man with probable CAA-I is of
interest and may well help further our understanding of the pathogenesis
of CAA-I. However, we agree that this finding must be confirmed in a
larger cohort of patients before further comment on pathogenesis and
likely diagnostic utility of the presence or absence of anti-amyloid beta
autoantibodies can be considered. CAA-I is such a rare condition that this
is unlikely to be possible without collaboration between different centres
and we would encourage such collaboration.
1. Chung KK, Anderson NE, Hutchinson D, et al. Cerebral amyloid angiopathy
related inflammation: three case reports and a review. J Neurol Neurosurg
Psychiatry. 2011 Jan;82(1):20-6.
2. DiFrancesco JC, Brioschi M, Brighina L, et al. Anti-A? autoantibodies
in the CSF of a patient with CAA-related inflammation: a case report.
Neurology. 2011 Mar 1;76(9):842-4.
In their recent paper Chung and colleagues[1] describe 3 cases of cerebral amyloid angiopathy related inflammation (CAA-I) all confirmed by brain biopsy and review the scientific literature, proposing the criteria for probable and definite diagnosis.
CAA-I is a rare and treatable encephalopathy affecting a subgroup of CAA patients, in which a predisposing condition is represented by the APOE ?4/?4 genotype in the majority of pati...
In their recent paper Chung and colleagues[1] describe 3 cases of cerebral amyloid angiopathy related inflammation (CAA-I) all confirmed by brain biopsy and review the scientific literature, proposing the criteria for probable and definite diagnosis.
CAA-I is a rare and treatable encephalopathy affecting a subgroup of CAA patients, in which a predisposing condition is represented by the APOE ?4/?4 genotype in the majority of patients. CAA-I generally presents with subacute headaches, cognitive and behavioral changes, seizures and focal neurological deficits[2]. Radiological features of CAA-I are mainly represented by bilateral, generally asymmetric, swollen white matter lesions in the cerebral hemispheres, hyperintense in T2-weighted images, possibly exerting mass effect, usually without contrast enhancement. Appropriate MR Gradient Echo sequences may show multiple microhemorrhages that strongly suggest CAA.
The pathogenesis of CAA-I is still unknown, but it is probably due to an autoimmune reaction against amyloid-beta (A?) deposits in the wall of blood vessels, leading to an acute inflammatory response known as vasogenic edema (VE). The recognition of this rare condition is important, in order to rapidly initiate a treatment with high-dose steroid and immunosuppressive agents, with a significant clinical improvement in the majority of patients.
We have recently described one patient with probable CAA-I, according to Kinnecom diagnostic criteria[3], in whom we showed a specific increase of anti-A? 1-40 and 1-42 autoantibodies in the CSF of the patient before steroid treatment, and their reduction to normal levels following dexamethasone 24 mg/day IV for 20 days[4].
These results, even if assessed on a single case, seem to be of striking importance in order to understand the pathogenetic mechanism of CAA-I[5]. Anti-A? autoantibodies may in fact represent the mediators of the autoimmune reaction against A? protein located in brain vessels, leading to the inflammatory reaction occurring in CAA-I.
We believe that these results should also be confirmed in other cases of CAA-I and the role of anti-A? autoantibodies in the pathogenesis of the disease should be clarified. At present, there is no clinical/radiological investigation, other than brain and leptomeningeal biopsy, that could be considered specific for the diagnosis of CAA-I. If the role of the anti-A? autoantibodies will be confirmed in the pathogenesis of CAA-I, their dosage in the CSF of supposed CAA-I patients could be proposed as one of the diagnostic criteria for the disease.
Finally, a better understanding of the role of anti-A? autoantibodies might have possible implications also in the field of Alzheimer's disease immunotherapy. In fact, VE has been consistently documented as one major side effect of passive immunotherapy (especially in ?4 carriers)[6], and early active A? vaccination trials had to be stopped because of severe meningoencephalitis strictly resembling CAA-I, as pointed out by Chung and colleagues[1].
REFERENCES
1. Chung KK, Anderson NE, Hutchinson D, et al. Cerebral amyloid angiopathy related inflammation: three case reports and a review. J Neurol Neurosurg Psychiatry. 2011 Jan;82(1):20-6.
2. Eng JA, Frosch MP, Choi K, et al. Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol 2004;55: 250 -256.
3. Kinnecom C, Lev MH, Wendell L, et al. Course of cerebral amyloid angiopathy-related inflammation. Neurology 2007;68:1411-1416.
4. DiFrancesco JC, Brioschi M, Brighina L, et al. Anti-A? autoantibodies in the CSF of a patient with CAA-related inflammation: a case report. Neurology. 2011 Mar 1;76(9):842-4.
5. Greenberg SM, Frosch MP. Life imitates art: anti-amyloid antibodies and inflammatory cerebral amyloid angiopathy. Neurology. 2011 Mar 1;76(9):772-3.
6. Panza F, Frisardi V, Imbimbo BP, et al. Anti-?-Amyloid Immunotherapy for Alzheimer's Disease: Focus on Bapineuzumab. Curr Alzheimer Res. 2011 May 18. [Epub ahead of print]
Dementia and depression are frequently comorbid among older adult
patients. Depression is related to cognitive decrement and can even
represent the first signs of a neurodegenerative process. It can be
difficult to distinguish depressed patients exhibiting the first signs of
dementia from those whose cognition will improve with treatment. Studies
from the neuropsychological reported that there is relationship between
de...
Dementia and depression are frequently comorbid among older adult
patients. Depression is related to cognitive decrement and can even
represent the first signs of a neurodegenerative process. It can be
difficult to distinguish depressed patients exhibiting the first signs of
dementia from those whose cognition will improve with treatment. Studies
from the neuropsychological reported that there is relationship between
depression and dementia shown by examining potential neurobiological
mechanisms that may potentiate both syndromes in the context of the
ongoing debate on depression as a prodrome and/or a risk factor for
dementia. Other article concluded with suggestions for clinicians when
deciding who to refer for neuropsychological assessment and with ideas for
further research that might promote a better understanding of the complex
association between depression and dementia during old age. In series of
research studies it was found that Geriatric depression has been
associated with cognitive impairments, but whether suboptimal effort
contributes to these deficits is unknown. One study investigated
differences in cognitive functioning between depressed and nondepressed
elderly veterans, before and after excluding patients who provided
suboptimal effort on testing at a memory disorders clinic. Patients
diagnosed with a depressive disorder performed more poorly than non
depressed patients on almost all Repeatable Battery for the Assessment of
Neuropsychological Status indices, but these differences became
nonstatistically significant after excluding patients who provided
suboptimal effort. However, when patients were classified as normal,
mildly, or severely depressed based on Geriatric Depression Scale scores,
these groups were not significantly different on Repeatable Battery for
the Assessment of Neuropsychological Status indices, regardless of whether
patients who provided suboptimal effort were included or excluded from
analyses. The findings suggest that cognitive deficits in depression
reported in previous research may be attributable to suboptimal effort and
that identifying depression via clinical diagnosis or psychometric data
may affect this trend.
General speaking ,low mood and dementia even in early cognitive
impairments remains a prominent co morbid factors among older adult
patients more researchers are in need to explore more about other co
morbid factors associated with early and progressive dementia process
Espay and colleagues report a detailed clinical and pathological
study of two unrelated individuals with rapidly progressive atypical
parkinsonism (similar to progressive supranuclear palsy, PSP), and
additional frontotemporal and motor neuron involvement, in whom TDP-43
inclusion pathology was demonstrated. (1) Sequencing of PGRN and TARDBP
gene coding regions was negative, and therefore no genetic cause...
Espay and colleagues report a detailed clinical and pathological
study of two unrelated individuals with rapidly progressive atypical
parkinsonism (similar to progressive supranuclear palsy, PSP), and
additional frontotemporal and motor neuron involvement, in whom TDP-43
inclusion pathology was demonstrated. (1) Sequencing of PGRN and TARDBP
gene coding regions was negative, and therefore no genetic cause was
identified. An additional gene that needs to be considered, however, in
light of important very recent evidence, is ATXN2, in which pure CAG
expansions (range 34-59 repeats) lead to spinocerebellar ataxia (SCA2).
The encoded protein ataxin-2 was shown to interact with TDP-43, which
plays a key role in motor neuron disease (MND), and modulate its toxicity,
with intermediate CAG expansions in ATXN2 (27-33 repeats) appearing to be
risk factors for MND. (2) This has already been confirmed in other
studies, 3-4 and importantly a clear association with PSP was also shown,
(3) with the risk highest for both MND and PSP for repeats >30. Rather
than the pure CAG repeats which occur in the typical SCA2 phenotype, CAA
interruptions of the CAG expansion repeats are found in motor neuron
disease and PSP. (3-4)
It is therefore plausible that the unexplained PSP / MND overlap
phenotype with TDP-43 inclusions may have been associated with interrupted
intermediate size expansions in ATXN2, and confirmation of this would
advance understanding of the pathology of this novel type of
neurodegeneration. Testing of DNA from different tissues and brain regions
available would also allow the investigation of possible mosaicism, which
has been previously reported in SCA2 (5) and could help explain the
phenotypic variation of this type of ATXN2 mutation.
1. Espay AJ, Spina S, Houghton DJ, Murrell JR, de Courten-Myers GM,
Ghetti B, et al. Rapidly progressive atypical parkinsonism associated with
frontotemporal lobar degeneration and motor neuron disease. J Neurol
Neurosurg Psychiatry 2011;82:751-3.
2. Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, et al.
Ataxin-2 intermediate-length polyglutamine expansions are associated with
increased risk for ALS. Nature 2010;466:1069-75.
3. Ross OA, Rutherford NJ, Baker M, Soto-Ortolaza AI, Carrasquillo MM,
Dejesus-Hernandez M, et al. Ataxin-2 repeat-length variation and
neurodegeneration. Hum Mol Genet 2011. doi:10.1093/hmg/ddr227
4. Yu Z, Zhu Y, Chen-Plotkin AS, Clay-Falcone D, McCluskey L, Elman L, et
al. PolyQ repeat expansions in ATXN2 associated with ALS are CAA
interrupted repeats. PLoS One 2011;6:e17951.
5. Matsuura T, Sasaki H, Yabe I, Hamada K, Hamada T, Shitara M, et al.
Mosaicism of unstable CAG repeats in the brain of spinocerebellar ataxia
type 2. J Neurol 1999;246:835-9.
We read with interest the article "Dangers of bone graft substitutes:
lessons from using Genex" (Saadoun, MacDonald, Bell and Papadopoulos, JNNP
published online March 8, 2011), notably as it purported the potential for
Genex putty to "cause soft tissue inflammation and destruction".
All three patients in the article were reported to have wound related
adverse reactions. Since initial certification, in excess of 5,0...
We read with interest the article "Dangers of bone graft substitutes:
lessons from using Genex" (Saadoun, MacDonald, Bell and Papadopoulos, JNNP
published online March 8, 2011), notably as it purported the potential for
Genex putty to "cause soft tissue inflammation and destruction".
All three patients in the article were reported to have wound related
adverse reactions. Since initial certification, in excess of 5,000 packs
of Genex have been distributed worldwide and, as a percentage of Genex
released in 2010, there were fewer than 0.4% reported complaints. None of
the reports were related to soft tissue damage.
The article presents a hypothesis that Genex putty "produces sterile
pus which destroys adjacent soft tissues"; a mouse study is used to test
this hypothesis.
All manufacturers of bone graft substitutes are required to conduct
extensive testing of both the raw materials used in the manufacture of
their products and the finished device itself in order to show that their
devices are biocompatible with respect to the intended application and
duration of contact.
Testing to ISO 10993 Biological evaluation of medical devices is
advised, not only to ensure patient safety, but also to comply with the
demanding international regulatory requirements that apply to the medical
device industry.
It should be noted that allograft, such as cadaver tissue and
demineralised bone matrix, is not regulated as a medical device either in
Europe or the USA. As such it is not subject to the same strict regulatory
demands as synthetic bone void fillers.
All bone void fillers (often referred to as bone graft substitutes)
are indicated for use in bony voids or gaps in the skeletal system that
are not intrinsic to the stability of the bony structure and should not be
used where infection is present. They should not be used to overfill or
pressurise the defect site.
Any implanted material has the potential to elicit a foreign-body
reaction. This reaction depends upon the property of the material itself
and also upon the patient and the site of implantation.
As part of the essential requirements for the regulatory approval of
Genex putty an implantation study was performed utilizing the Boden
model.[1] This involves an intertransverse process spinal fusion procedure
in a rabbit. The graft material is placed adjacent to the decorticated
vertebral body and between the transverse processes. Macroscopic,
radiographic and histologic appearance of the fusion was performed at 4, 8
and 12 weeks following surgery, 6 animals per time point (total 18
rabbits).
In this model, Genex was shown to be safe and efficacious and
promoted increasing fusion with implantation time. At no time point (4
weeks minimum) was there evidence of neutrophil infiltrate, either in the
graft bed or within adjacent tissue.
Although it is appreciated that this model does not specifically
assess an acute soft tissue response, no adverse events or tissue
reactions were reported in this study.
The article mentions bone morphogenic proteins. It is now well known
that BMP usage in the cervical spine has been associated with soft tissue
inflammation and significant adverse events, but has not shown these
reactions when used in other sites. This serves to indicate that adverse
events can be indication (and patient) specific.
Medical devices in Europe must be CE marked in accordance with the
Medical Devices Directive 93/42/EEC (as amended). This signifies
compliance to the Essential Requirements (Annex I), including safety and
biocompatibility requirements. All approved bone graft substitutes,
including Genex (Biocomposites, UK), have been certified as meeting the
requirements for class III resorbable devices in the EEC.
Similarly, Genex has been cleared as a Class II medical device by the
US Food & Drug Administration (FDA) and is recognised internationally
by other regulatory agencies as a medical device.
Finally, being classified as a medical device does not make adverse
incident reporting difficult. On the contrary, the homepage of the
Medicines and Healthcare products Regulatory Agency (MHRA website:
www.mhra.gov.uk), has a clear selection button to "Report Medical Device
Adverse Incidents" taking the user directly to the online reporting
system.
Synthetic bone void fillers have a long and safe history of clinical
use, when used appropriately. The first reported use of calcium sulphate
as a bone void filler was by Dreesmann in 1892.[2] The use of tricalcium
phosphate as a bone void filler was first reported by Albee in 1920.[3]
Their advantages over autograft and allograft tissue have been well
documented.
Based on our knowledge of global use, Genex is a safe and effective
bone void filler when used in accordance with the Instructions for Use.
References
1. Boden S, Schimandle J, Hutton W. An experimental lumbar
intertransverse process spinal fusion model. Radiographic, histologic and
biomechanical healing characteristics. Spine 1995;20:412-20.
2. Dreesmann H, Ueber Knochenplombierung. Beitr Klin Chir 1892;9:804-810.
3. Albee FH, Studies in bone growth: Triple calcium phosphate as a
stimulus to osteogenesis. Ann Surg 1920;71:32.
Conflict of Interest:
Simon Fitzer and John Cooper are both employees of Biocomposites Ltd (JS is Technical Research Director)
Vivekananda et al(1)report that when controlled for sex, cases of
sporadic amyotrophic lateral sclerosis (ALS) have a lower mean finger
length ratio R [where R = (2D / 4D) and 2D and 4D are the lengths of the
2nd and 4th digits respectively] than healthy controls. These authors
interpret their finding as indicating prenatal involvement of high
concentrations of intrauterine testosterone, T. However, their
interpretation...
Vivekananda et al(1)report that when controlled for sex, cases of
sporadic amyotrophic lateral sclerosis (ALS) have a lower mean finger
length ratio R [where R = (2D / 4D) and 2D and 4D are the lengths of the
2nd and 4th digits respectively] than healthy controls. These authors
interpret their finding as indicating prenatal involvement of high
concentrations of intrauterine testosterone, T. However, their
interpretation is not the only one : another possibility arises from the
reported variation of R with adult sex hormone levels(2). So (some cases
of) ALS may arise either as a consequence of high maternal T levels, or of
high levels of the patient's own postnatal T (or both). Here I offer a
means of discriminating between these two hypotheses.
I have adduced substantial quantities of data to support the
hypothesis that mammalian (including human) offspring sex ratios at birth
are partially controlled by parental hormone levels around the time of
conception(3-5). Ex hypothesi, high levels of T are associated with the
subsequent births of sons. So if my hypothesis and that of Vivekananda et
al(1) were both correct, that would explain why probands with ALS contain
an excess of males(6,7). Moreover, if both hypotheses were correct, then
ALS probands should have a statistical excess of brothers. The point
should be tested.
An illustrative use of this form of argument provided support for
Baron-Cohen's hypothesis(8) that one cause of autism is high intrauterine
T concentrations. If his hypothesis and mine were both correct, then
autistic probands should have an excess of brothers. This has been
reported(9) and twice replicated(10,11), giving strong support to Baron-
Cohen's hypothesis. So it would be interesting to see data on the sib sex
ratio of ALS probands.
Another approach to the present problem may be via the variable of
parity or birth order. First-borns, as contrasted with later-borns, are
reportedly exposed to higher levels of testosterone in early(12), and
late(13) pregnancy. So if the hypothesis of Vivekananda et al(1) were
correct, there should be a statistical excess of first-borns among ALS
probands. This point has been tested, also by Vivekananda and co-
workers(14), and they reported a non-significant result. However this
latter conclusion may be indecisive : there are pitfalls in the
interpretation of birth order studies.
1. In the first place, Vivekananda et al(14) were testing for a
positive birth order effect (viz one in which the risk correlates
positively with birth order). So they omitted a substantial quantity of
their data viz : all their affected sibships of size less than 4 because
these sibships might have been incomplete and thus be uninformative about
the effect. However the purpose at present is to test for a negative birth
order effect : viz one in which the risk correlates negatively with birth
order and which may therefore be manifest in incomplete sibships of size
2+. So I suggest that these workers should test their complete material
without omitting the shorter sibships.
2. In the second place, these workers give no explanation for their
choice of statistical test : in particular, and in the absence of a
control group, it is not clear that it is as powerful as other more
conventional tests e.g. that of Haldane and Smith(15). So I suggest that
their entire material should be submitted to that test. If a significant
birth order effect is indicated, that will give strong support to the
hypothesis of Vivekananda et al(1) that one cause of amyotrophic lateral
sclerosis is high intrauterine levels of testosterone.
References
1. Vivekananda U, Manjalay ZR, Garesalingam J et al. Low index to
ring finger length in sporadic ALS supports prenatally defined motor
neuronal vulnerability. J Neurol Neurosurg Psychiatr 2011;82:635-637
2. Manning JT, Scutt D, Wilson J et al. The ratio of 2nd to 4th digit
lengths : a prediction of sperm numbers and concentrations of
testosterone, luteinizing hormone and oestrogen. Hum Reprod 1998;13:3000-
3004
3. James WH. Evidence that mammalian sex ratios at birth are
partially controlled by parental hormone levels at the time of conception.
J Theor Biol 1996;180:271-286
4. James WH. Further evidence that mammalian sex ratios are partially
controlled by parental hormone levels around the time of conception. Hum
Reprod 2004;19:1250-1256
5. James WH. Evidence that mammalian sex ratios at birth are
partially controlled by parental hormone levels around the time of
conception. J Endocrinol 2008;198:3-15
6. McCombe PA, Henderson RD. Effects of gender in amyotrophic lateral
sclerosis. Gender Med 2010;7:557-570
7. Logroscino G. Incidence of amyotrophic laternal sclerosis in
Europe. J Neurol Neurosurg Psychiatr 2010;81:385-390
8. Baron-Cohen S. The extreme male brain theory of autism. Trends
Cogn Sci 2002;6:248-254
9. James WH. Further evidence that some male-based neurodevelopmental
disorders are associated with high intrauterine testosterone
concentrations. Dev Med Child Neurol 2008;50:15-18
10. Mouridsen SE, Hauschild KM. The sex ratio of siblings of
individuals with a history of developmental language disorder. Logoped
Phoniatr Vocol 2010;35:144-148
11. Mouridsen SE, Rich B, Isager T. Sibling sex ratio of individuals
diagnosed with autism spectrum disorder as children. Dev Med Child Neurol
2010;52:289-292
12. Troisi E, Hoover RN, Thadhani R. et al. Maternal, prenatal and
perinatal characteristics and first trimester maternal serum hormone
concentrations. Br J Cancer 2008;99:1161-1164
13. Maccoby EE, Doering CH, Jacklin CN et al. Concentration of sex
hormones in umbilical cord blood and their relation to sex and birth order
of infants. Child Dev 1979;50:632-642
14. Vivekananda U, Johnston C, McKenna-Yasek D et al. Birth order and
the genetics of amyotrophic lateral sclerosis. J Neurol 2008;255:99-102
15. Haldane JBS, Smith CAB. A simple exact test for birth order
effect. Ann Eugen (Lond)1947;14: 117-124
Regarding your Cochrane review "Antidepressants for neuropathic pain"
which was published in J Neurol Neurosurg Psychiatry. 2010 Dec;81(12):1372
-3, we would like to point out an inconsistency.
Our comment refers to the statement made on page 11: : "Six placebo-
controlled studies were found in postherpetic neuralgia. All demonstrated
superiority of a...
Regarding your Cochrane review "Antidepressants for neuropathic pain"
which was published in J Neurol Neurosurg Psychiatry. 2010 Dec;81(12):1372
-3, we would like to point out an inconsistency.
Our comment refers to the statement made on page 11: : "Six placebo-
controlled studies were found in postherpetic neuralgia. All demonstrated
superiority of antidepressants over placebo. Four of them included data of
global improvementor pain relief with risk ratio of effectiveness NNT 2.7
(95% CI 2to 4), RR 2.3 (95%CI 1.7 to 3.2) (Bowsher 1997;Kishore-Kumar
1990; Max 1988; Watson 1982).
Our comment also refers to the figure "Analysis 3.1 Comparison 3
Postherpetic neuralgia- number of patients with moderate pain relief or
better, Outcome 1 Antidepressant vs placebo."
We feel that the trial by Bowsher in 1997, which contributes 72% of
the weight in the point-estimate calculation, in fact examines a
preventive rather than therapeutic effect, in patients with acute herpes
zoster rather than postherpetic neuralgia.
This trial's population does therefore not consist of patients with
postherpetic neuralgia, but rather of patients with acute herpes zoster.
They are treated with a 90-day course of amitryptilline in order to
prevent postherpetic neuralgia in the future. In contrast, the other
trials mentioned in the review examine the therapeutic effect of
amitryptilline as a pain killer once post-herpetic neuralgia has
developed.
These are essentially distinct study-populations, with essentialy distinct
treatment goals. In the first case the goal is to prevent postherpetic
pain, while in the latter the goal is to treat it.
In our opinion, this distinction should be made explicit in the
Cochrane review and these trials should not be meta-analyzed in one pooled
point-estimate.
Yours sincerely,
JMI Vos, MD, internist-hematologist in training
Prof. Dr. S. Middeldorp, internist
Corresponding author
JMI Vos
Dept. of Hematology, F4-224
Academic Medical Center
Meibergdreef 9
1105 AZ Amsterdam
The Netherlands
Tel. (31)205665785
j.m.vos@amc.uva.nl
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Amsterdam, 4th May 2011
Dear dr. Saarto,
Regarding your Cochrane review "Antidepressants for neuropathic pain" which was published in J Neurol Neurosurg Psychiatry. 2010 Dec;81(12):1372 -3, we would like to point out an inconsistency.
Our comment refers to the statement made on page 11: : "Six placebo- controlled studies were found in postherpetic neuralgia. All demonstrated superiority of a...
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