Could you state the recommended method of collecting swabs for RSV?
From your brief synopsis, I gathered that the anterior nares only was
swabbed for culture and was found to be effective and less painful. Is
that correct?
With great interest we have read the article of Kakkar & Garg [1].
They mentioned the presence of cytoplasmic fragments or so called
pseudoplatelets that may interfere with the platelet count when using
automated haematology analysers.
In 2003 we reported the presence of pseudoplatelets in a number of
patients, which causes spurious platelet counts to such an extent that the
risk of serious ble...
With great interest we have read the article of Kakkar & Garg [1].
They mentioned the presence of cytoplasmic fragments or so called
pseudoplatelets that may interfere with the platelet count when using
automated haematology analysers.
In 2003 we reported the presence of pseudoplatelets in a number of
patients, which causes spurious platelet counts to such an extent that the
risk of serious bleeding would not be anticipated [2]. We found that in 25% of newly diagnosed acute leukemias pseudoplatelets could be observed.
This led in 5% of these patients to a reclassification of their bleeding
risk.
Kakkar & Garg emphasized that of every new patient with acute
leukaemia a blood smear should be investigated for the presence of
pseudoplatelets. We support their view. An elegant alternative is counting
of platelets labelled with the specific platelet marker CD61 with a
flowcytometer [3].
Wim van der Meer
Radboud University Hospital
564 Department of Clinical Chemistry
P.O.Box 9101
6500 HB Nijmegen, The Netherlands
w.vandermeer@akc.umcn.nl
Ries de Keijzer
Laboratory of Clinical Pathology
Ziekenhuis Rivierenland
P.O.Box 6024
4000 HA Tiel, The Netherlands
1. Kakkar N, Garg G. Cytoplasmic fragments of leukaemic cells
masquerading as platelets in an automated haematology analyser J Clin
Pathol 2005;58:224.
2. Van der Meer W, MacKenzie MA, Dinnissen JWB et al. Pseudoplatelets: a
retrospective study of their incidence and interference with platelet
counting. J Clin Pathol 2003;56:772-774.
3. Segal HC, Briggs C, Kunka S et al. Accuracy of platelt counting
haematology analysers in severe thrombocytopenia and potetial impact on
platelet transfusion. Br J Haematol 2005;128:520-525.
Setting up standards when interpreting mtDNA CR sequence data from
tumors.
We agree with Parr et al.[1] on the importance to compare the mtDNA
sequence data of our recent case report [2] (a divergence of 7
homoplasmic nucleotide positions within the 16024-16365 segment of the
HV1 region between two morphologically different tissue sections found on
the same slide) with the available...
Setting up standards when interpreting mtDNA CR sequence data from
tumors.
We agree with Parr et al.[1] on the importance to compare the mtDNA
sequence data of our recent case report [2] (a divergence of 7
homoplasmic nucleotide positions within the 16024-16365 segment of the
HV1 region between two morphologically different tissue sections found on
the same slide) with the available scientific data on mtDNA somatic
mutations in tumors to better understand the significance of our
findings. Indeed we performed such a comparison during case results
interpretation and we found a rate and a pattern of mtDNA instability in
different type of tumours similar to that reported by Tan et al. [3] (to
use a paper cited by Parr et al. to challenge the hypothesis of Alonso et
al.). Tan et al. reported 8 frozen tumor tissue samples (from a total of
19) displaying just one (7 samples) or two (1 sample) somatic mutations
within the HV1 segment (16024-16365) analysed by Alonso et al. [2]. This
discrete pattern of mtDNA instability is certainly not enough to explain
the high divergence between two tissue sections obtained by Alonso et al.
The results obtained by Chen et al. [4] are also cited by Parr et
al. [1] to challenge the conclusions of Alonso et al. [2]. Chen et al.
reported 3 prostate tumor samples (from a total of 16) with one (1
sample), five (1 sample), or eight (1 sample, all heteroplasmic
positions) somatic mutations within the HV1 segment analysed by Alonso et
al. Again the pattern of instability detected by Chen et al. with high
incidence of heteroplasmy is different from the homoplasmic divergence
reported by Alonso et al. Furthermore, Chen et al. used 45 PCR cycles (9
PCR cycles more than the standard used in forensic laboratories (5)) to
amplify fragments around 600 bp from a reduced number of tumour cells
obtained by laser microcapture from formalin-fixed tissue sections. Under
these analytical conditions it is very difficult to guarantee (or to
validate) the reproducibility of each single PCR reaction against
background contamination and other artefacts. Especially if DNA
degradation produced by formalin makes tumour DNA partially refractory to
amplify 600 bp fragment sizes producing a situation of low copy number
(LCN) [6,7] that could compromise seriously the reliability of the
results. Specific DNA quantification is a recommended procedure of special
interest when dealing with such a LCN DNA specimens[8]. Budowle et al. [9, 10] demonstrated high incidence of artifactual heteroplasmic results
when using high number of PCR cycles to analyse the mtDNA CR sequence from
hair samples.
We do not share the arguments of Parr et al. to explain the
significance of the mtDNA mutations reported by Alonso et al. First,
because all the nucleotide positions reported by Alonso et al. (including
16293G) are polymorphic nucleotide positions in human populations (you can
see that at http://www.genpat.uu.se/mtDB/ and http://www.fbi.gov/hq/lab/fsc/backissu/april2002/miller1.htm). Second,
because the haplotypes detected by Alonso et al. were assigned to
different haplogroups (haplogroups k & U5a1a) according to
phylogenetic criteria. The lack of match after database searching was not
only observed for the tumor haplotype (16256T, 16270T, 16293G) but also
for the constitutional haplotype (16224C, 16234T, 16311C, 16356C) obtained
from normal tissue. This is just reflecting that the human mtDNA diversity
is still not fully represented in the reduced sample size of current mtDNA
population databases.
Finally, we would like to state that the conclusions of Alonso et al. [2] are based upon three different lines of evidence: (a) the lack of
correspondence between the histological analysis of two different (a pre-
and a post-surgical) biopsies, (b) the presence in the pre-surgical slide
of two different (morphologically and histological) tissue sections that
also present a different position pattern on the same slide (see Figure
1), and (c) the distinctive mtDNA sequence data (with phylogenetic
consistency) obtained from each tissue section that showed a clear
divergence on 7 nucleotide homoplasmic positions.
Anyway, the debate opened by Parr et al. is valid. A compilation of
reliable data on cancer mtDNA instability would be desirable and very
useful for both scientific communities. But if we like to perform an
objective comparison of mtDNA sequence data across different labs we need
to be sure of using comparable methods and interpretation standards. A
certain degree of methodological standardization is crucial for this
purpose. An important part of the standardization progress made in
forensic mtDNA typing was accomplished by continuous inter-laboratory
collaborative exercises organized by different scientific groups and
societies (SWGDAM, EDNAP, ISFG-working groups…). A similar standardization
progress is suggested for molecular oncology labs dealing with mtDNA
instability in cancer.
References
(1) Ryan L. Parr, Gabriel D. Dakubo, Jennifer Maki MtDNA haplotyping of
pathology specimens. JCP Online, eletter 31 Jan 2005.
(2) Alonso, A. et al. Mitochondrial DNA haplotyping revealed the presence
of mixed up benign and neoplastic tissue sections from two individuals on
the same prostatic biopsy slide. J Clin Pathol 2005; 58, 83 -6.
(3) Tan, D.J., Bai, R.K. & Wong, L.J. Comprehensive scanning of
somatic mitochondrial DNA mutations in breast cancer. Cancer Res 2002; 62,
972-6.
(4) Chen, J.Z., Gokden, N., Greene, G.F., Mukunyadzi, P. & Kadlubar,
F.F. Extensive somatic mitochondrial mutations in primary prostate cancer
using laser capture microdissection. Cancer Res 2002; 62, 6470-4.
(5) Wilson, M.R., DiZinno, J.A., Polanskey, D., Replogle, J. and Budowle B
(1995) Validation of mitochondrial DNA sequencing for forensic casework
analysis. Int. J. Leg. Med., 10, 68-74.
(6) Gill, P. Application of low copy number DNA profiling. Croat Med
J 2001; 42, 229-232.
(7) Budowle B, Hobson D, Smerick J, Smith J. Low copy number:
consideration and caution. Proceedings from the Twelfth International
Symposium on Human Identification 2001 (available at www.promega.com).
(8) Alonso A, Martin P, Albarran C, Garcia P, Primorac D, Garcia O,
Fernandez de Simon L, Garcia-Hirschfeld J, Sancho M, Fernandez-Piqueras J.
Specific quantification of human genomes from low copy number DNA samples
in forensic and ancient DNA studies. Croat Med J. 2003 Jun;44(3):273-80.
(9) Budowle B, Allard MW, Wilson MR, Chakraborty R. Forensics and
mitochondrial DNA: applications, debates, and foundations. Annu Rev
Genomics Hum Genet. 2003;4:119-41. Review.
(10) Budowle B, Allard MW, Wilson MR. Critique of interpretation of
high levels of heteroplasmy in the human mitochondrial DNA hypervariable
region I from hair. Forensic Sci Int. 2002 Mar 28;126(1):30-3.
Alonso et al [1] recommend the use of mitochondrial genetic typing to
exclude the possibility of tissue carryover artifacts in situations where
low DNA content and high degradation may compromise conventional short
tandem repeat typing. They studied archived presurgical hematoxylin and
eosin stained needle biopsy sections from the same slide to ascertain the
authentic source of the malignant and...
Alonso et al [1] recommend the use of mitochondrial genetic typing to
exclude the possibility of tissue carryover artifacts in situations where
low DNA content and high degradation may compromise conventional short
tandem repeat typing. They studied archived presurgical hematoxylin and
eosin stained needle biopsy sections from the same slide to ascertain the
authentic source of the malignant and benign biopsy specimen on the slide.
To this end, they amplified the hypervariable region I (HVI) of the
mitochondrial genome from DNA extracts from the malignant and normal
prostate biopsy specimens, and available blood sample from the presumptive
patient. Due to the high HVI sequence divergence between the malignant and
normal samples, and the absence of heteroplasmy, they concluded that the
samples were from two different individuals, and could not be explained by
somatic mtDNA instability. Since the haplotype of the normal tissue
section and blood were identical, the malignant biopsy on the slide was
considered to be a contaminant from an unknown individual. Contending that
in this particular case the tissue biopsy specimens were truly from two
individuals, the general recommendation made by Alonso et al.[1] to use
mtDNA sequence analysis for tissue typing will likely be fraught with
erroneous conclusions in some cases.
Based on our findings we would like to propose an alternative
explanation to that of Alonso et al.[1] Specifically, the mutations that
were observed are not due to contamination but are in fact symptomatic of
the malignancy. The mechanism by which somatic mutations accumulate
during the pathogenesis of prostate adenocarcinoma is poorly understood.
However, it is possible a burst of multiple mtDNA mutations occur in
response to extreme cellular oxidative stress [2]. The displacement loop
(which includes HVI) is a mutation hot spot and accumulates more mutations
than the rest of the mitochondrial genome. Indeed the mitochondrial
genetic signature of malignant tissues and in particular prostate
adenocarcinoma is frequently different from the corresponding benign
epithelial glands and blood [3]. Somatic mitochondrial mutations in
cancers at polymorphic sites are not uncommon, and this can alter the
haplotype of malignant tissues from the corresponding blood. We conducted
a comprehensive study of prostate cancer mitochondrial genetics by having
a certified pathologist laser capture pure malignant cells from biopsy
specimens from several patients, and the D-loop sequences were compared
with the corresponding blood. Several sequence variations (both
homoplasmic and heteroplasmic somatic mutations) between blood and tumor
specimens were observed. Mitochondrial DNA analysis of glioblastoma by
Kirches et al.[4] revealed a D-loop sequence divergence between blood and
matched tumors in 41% of the samples. Somatic mutations were identified in
74% of breast cancer samples with 81.5% of these being restricted to the D
-loop [5]. Interestingly, one of the markers (16293G) detected in the
prostate cancer specimen by Alonso et al.[1] is likely a disease specific
marker of glioblastoma, breast cancer [4,5] and prostate cancer (our
observation). Also the absence of heteroplasmic mutation in a specimen (as
observed by Alonso et al.[1]) is not inconsistent with the malignant
phenotype as homoplasmic mtDNA substitution mutations have been observed
in many cancers including prostate adenocarcinoma [3]. Given that prostate
needle biopsies of an individual are from different parts of the prostate
gland, and that prostate cancer can be multi-focal, the data of Alonso et
al.[1] can be consistent with all samples originating from the same
individual. In this case the haplotype of the blood and normal samples
will cluster (“wild type haplotype”) and may differ from the
adenocarcinoma (“mutant haplotype”) as they observed. Indeed Alonso et
al.[1] could not find any match when they searched two databases for these
haplotypes. The lack of a population match suggests a somatic mutation
process as attested to in the literature [6,7].
The use of mtDNA sequences for unambiguous identification of tissue
samples is highly reliable when using non-malignant samples, however
malignant tissues contain mutations in mtDNA that may confound such
determinations but never the less are not indications of sample cross-
contamination.
References
(1) Alonso, A. et al. Mitochondrial DNA haplotyping revealed the
presence of mixed up benign and neoplastic tissue sections from two
individuals on the same prostatic biopsy slide. J Clin Pathol 2005; 58, 83
-6.
(2) Chen, J.Z., Gokden, N., Greene, G.F., Green, B. & Kadlubar,
F.F. Simultaneous generation of multiple mitochondrial DNA mutations in
human prostate tumors suggests mitochondrial hyper-mutagenesis.
Carcinogenesis 2003; 24, 1481-7
(3) Chen, J.Z., Gokden, N., Greene, G.F., Mukunyadzi, P. &
Kadlubar, F.F. Extensive somatic mitochondrial mutations in primary
prostate cancer using laser capture microdissection. Cancer Res 2002; 62,
6470-4.
(4) Kirches, E. et al. High frequency of mitochondrial DNA mutations
in glioblastoma multiforme identified by direct sequence comparison to
blood samples. Int J Cancer 2001; 93, 534-8.
(5) Tan, D.J., Bai, R.K. & Wong, L.J. Comprehensive scanning of
somatic mitochondrial DNA mutations in breast cancer. Cancer Res 2002; 62,
972-6.
(6) Carew, J.S. & Huang, P. Mitochondrial defects in cancer. Mol
Cancer 2002; 1, 9.
(7) Abnet, C.C. et al. Control region mutations and the 'common
deletion' are frequent in the mitochondrial DNA of patients with
esophageal squamous cell carcinoma. BMC Cancer 2004; 4, 30.
In response to Dr Kruger, we provide extra minor details that had been omitted for reasons of word count.
As described, dyspnoea had been present and worsening for 6 weeks. The blood gas results cited were from 5 days after the date of hospital admission but were not significantly different from gases taken on 2 earlier occasions during the admission. The results cited were the ones tha...
In response to Dr Kruger, we provide extra minor details that had been omitted for reasons of word count.
As described, dyspnoea had been present and worsening for 6 weeks. The blood gas results cited were from 5 days after the date of hospital admission but were not significantly different from gases taken on 2 earlier occasions during the admission. The results cited were the ones that lead to consideration of the possibility that the statin was the culprit. We regarded the mixed acid-base disturbance as a metabolic acidosis compensated by respiratory alkalosis.
We would agree that there were other unmeasured components in the acidosis but can exclude the suggested salicylate and paracetamol on the basis of the six weeks preceding medical history and the five days known medication intake, by virtue of the in-patient stay. Beta-hydroxy-butyrate assay was not available but we agree this may have contributed. CK on admission was 99 U/L (ref range 0-160 U/L).
The patient was receiving nebulised salbutamol 5mg qds. This was continued after discontinuation of the statin, at which time the acidosis resolved. Salbutamol may of course have been a third element contributing to the acidosis.
Immediate is a relative term. Symptomatic relief began on the day after the first missed dose. However, Atorvastatin has a long half life and a blood gas taken 6 days after statin cessation was pH 7.44, pCO2 3.9kPa, pO2 10.8 kPa, HCO3 22.3 mmol/L, base excess –3.9 mmol/L; indicating near complete normalisation of results.
The blood gas analyser output for the sample indicates that HCO3(s) was 13.8 mmol/L as correctly stated in the report; tCO2 however was 5.7 mmol/L, which is consistent with Dr Kruger's estimate.
The inspired pO2 recorded for the blood gas sample reported is 21%. However, this is also the default in the event of a non-entry so we concur that supplemental oxygen was probably in use at the time of sampling.
Finally, we would like to point out that we did not specifically suggest that we were adding to the body of evidence linking statins to lactic acidosis; we suggested that the combination of statin with thiamine deficiency may be important; i.e. the proximate cause of the acidosis was the thiamine deficiency but the symptomatic presentation was precipitated by the statin. On this point, it is significant that after some months of thiamine therapy (and after publication of the report), the patient was restarted on Atorvastatin because of new ischaemic vascular symptoms with no recurrence of acidosis. We therefore conclude that the combination of the two factors was critical.
We read with interest the recent article by Alikhan et al , in which
they reviewed necropsy reports to find out the number of deaths due to
fatal pulmonary embolism in hospitalised patients.[1] There seem to be a
number of confusions in this paper.
1. Acute infection was the most common medical illness found in
patients who had died from pulmonary embolism, in particular respiratory
in...
We read with interest the recent article by Alikhan et al , in which
they reviewed necropsy reports to find out the number of deaths due to
fatal pulmonary embolism in hospitalised patients.[1] There seem to be a
number of confusions in this paper.
1. Acute infection was the most common medical illness found in
patients who had died from pulmonary embolism, in particular respiratory
infections. The authors state that the pathophysiology of venous
thromboembolism in the presence of acute infection remains to be fully
defined and then quote recent evidence that respiratory viruses are
capable of infecting endothelial cells and causing a shift from anti-
coagulant to pro-coagulant activity.[2] Such a proposed mechanism would
presumably increase the likelihood of pulmonary thrombosis, not
thromboembolism from deep venous thromboses.
2. The authors recognise that without denominator numbers for the
surgical and medical patient groups, no interpretation is possible
regarding the actual incidence of fatal pulmonary embolism. However, they
themselves then go on to make a number of comparisons between surgical and
“non-surgical” groups.
3. Pulmonary emboli were recorded as the cause of death when the
necropsy report stated that embolism was the main or contributing cause of
death. Many things get written down as contributing towards death, as any
pathologist knows. The authors also state that it is difficult to
distinguish between fatal, contributory, and incidental emboli when the
definitions and interpretations are based on pathologists’ opinions over a
long time period. One obvious way to address this difficulty would be for
the authors to ask a pathologist to help them interpret the necropsy
reports.
References
1. Alikhan R, Peters F, Wilmott R, et al. Fatal pulmonary emboli
in hospitalised patients: a necropsy review. J Clin Pathol 2004;57:1254-7.
2. Visseren FL, Bouwman JJ, Bouter KP, et al. Procoagulant
activity of endothelial cells after infection with respiratory viruses.
Thromb Haemost 2000;84:319-24.
When a patient has an infection, doctors often send a
sample of infected blood or tissue to a lab where
they can grow the bacteria and see which antibiotics
are most effective (called Bacterial Culture and
Sensitivity Testing). Chemosensitivity testing is an
attempt to do something similar for cancer; fresh
samples of the patient's tumor from surgery or a
biopsy are grown in test tubes and tested wit...
When a patient has an infection, doctors often send a
sample of infected blood or tissue to a lab where
they can grow the bacteria and see which antibiotics
are most effective (called Bacterial Culture and
Sensitivity Testing). Chemosensitivity testing is an
attempt to do something similar for cancer; fresh
samples of the patient's tumor from surgery or a
biopsy are grown in test tubes and tested with
various drugs. Drugs that are most effective in
killing the cultured cells are recommended for
treatment. It is highly desirable to know what drugs
are effective against your particular cancer cells
before highly-toxic agents are systemically
administered to your body.
One approach to individualizing patient therapy is
chemosensitivity testing. Chemosensitivity assay is a
laboratory test that determines how effective
specific chemotherapy agents are against an
individual patient's cancer cells. Often, results are
obtained before the patient begins treatment. This
kind of testing can assist in individualizing cancer
therapy by providing information about the likely
response of an individual patient's tumor to proposed
therapy. Chemosensitivity testing may have utility at
the time of initial therapy, and in instances of
severe drug hypersensitivity, failed therapy,
recurrent disease, and metastatic disease, by
providing assistance in selecting optimal
chemotherapy regimens.
All available chemosensitivity assays are able to
report drug "resistance" information. Resistance
implies that when a patient's cancer cells are
exposed to a particular chemotherapy agent in the
laboratory, the cancer cells will continue to live
and grow. Some chemosensitivity assays also are able
to report drug "sensitivity" information. Sensitivity
implies that when a patient's cancer cells are
treated with a particular chemotherapy agent in the
laboratory, that agent will kill the cancer cells or
inhibit their proliferation.
The goal of all chemosensitivity tests is to
determine the response of a patient's cancer cells to
proposed chemotherapy agents. Knowing which
chemotherapy agents the patient's cancer cells are
resistant to is important. Then, these options can be
eliminated, thereby avoiding the toxicity of
ineffective agents. In addition, some
chemosensitivity assays predict tumor cell
sensitivity, or which agent would be most effective.
Choosing the most effective agent can help patients
to avoid the physical, emotional, and financial costs
of failed therapy and experience an increased quality
of life.
Fresh samples of the patient's tumor from surgery or
a biopsy are grown in test tubes and tested with
various drugs. Drugs that are most effective in
killing the cultured cells are recommended for
treatment. Chemosensitivity testing does have
predictive value, especially in predicting
what "won't" work. Patients who have been through
several chemotherapy regimens and are running out of
options might want to consider chemosensitivity
testing. It might help you find the best option or
save you from fruitless additional treatment. Today,
chemosensitivity testing has progressed to the point
where it is 85% - 90% effective.
Chemosensitivity testing might help you find the best
option, or save you from fruitless additional
treatment. Another situation where chemosensitivity
testing might make particularly good sense is in rare
cancers where there may not be enough experience or
previous ideas of which drugs might be most
effective.
Finally, there has been a veritable deluge of new
approvals of cytotoxic drugs in recent years as the
tortuous FDA process has been speeded and
liberalized. In many cases a new drug has been
approved on the basis of a single very very narrow
indication. But these drugs may have many useful
applications - and it's going to take years to find
out. Chemosensitivity testing offers a way of seeing
if any of these new drugs might apply to your
specific cancer.
We read with interest the report on postulated atorvastatin
induced lactic acidosis [1]. In our view, the arguments outlined by its
authors do not support this hypothesis at all, for the reasons outlined
below:
a) The patient clearly had a mixed acid-base disturbance (combined
respiratory alkalosis and metabolic acidosis, as evidenced by the normal
pH of 7.39 coupled with severe hypocapnia)....
We read with interest the report on postulated atorvastatin
induced lactic acidosis [1]. In our view, the arguments outlined by its
authors do not support this hypothesis at all, for the reasons outlined
below:
a) The patient clearly had a mixed acid-base disturbance (combined
respiratory alkalosis and metabolic acidosis, as evidenced by the normal
pH of 7.39 coupled with severe hypocapnia).
b) Both the delta anion gap (24.2 –16= 8 mEq/L) and the decrease in
standard base excess (which we use in preference to whole blood base
excess and calculate to be -17.9 mEq/L) are much larger than the delta
lactate, which is only approximately 1.5 mmol/L. This clearly indicates
that the metabolic acidosis is multifactorial, and that another
pathological process rather than hyperlactaemia is the major contributor
to the raised anion gap. This should lead to a search for other causes of
a raised anion gap. For example, one would need to measure serum
salicylates, the osmolar gap and plasma beta-hydroxybutyrate. With
concerns of statin myopathy, a serum CK would be useful. With a history of
paracetamol ingestion, pyroglutamic acidosis is a likely possibility and
could be diagnosed using a urinary organic acid screen [2].
c) The authors’ discussion of potential causes of an elevated plasma
lactate concentration is incomplete. For example, they have failed to
discuss the possible contribution of salbutamol to the hyperlactaemia.
Furthermore, covert tissue hypoxia is a possibility despite normal
arterial oxygenation, which can lead to hyperlactaemia.
d) If it were to be a mitochondrial paralysis from statin therapy, it
is hard to imagine an immediate clinical improvement upon cessation of the
medication.
Other significant and fundamental errors in the report detract from
its validity. They include the following:
a) The [HCO3-] is said to be 13.8 mmol/L, whereas at the quoted pH (7.39)
and PCO2 (1.2 kPa) it would be much lower at 5.3 mmol/L.
b) The quoted PO2 of 19.3 kPa on room air implies a negative A-a gradient
of nearly 1 kPa. This is clearly impossible in any patient, let alone an
82 year old woman. Presumably supplemental oxygen was being administered.
c) The mention of unmeasured cations instead of anions in the abstract when
discussing a raised anion gap is a cause for confusion.
We recognise that simvastatin has been reported to induce lactic
acidosis through mitochondrial failure [3]. However, this report describes
a mixed acid-base disorder not primarily due to lactate. Hence, the
authors cannot claim that it adds to the body of evidence supporting the
link between statin therapy and lactic acidosis.
(2) Dempsey GA, Lyall HJ, Corke CF, Scheinkestel CD. Pyroglutamic acidemia:
a cause of high anion gap metabolic acidosis. Crit Care Med
2000;28(6):1803-7.
(3) Goli AK, Goli SA, Byrd RP, Jr., Roy TM. Simvastatin-induced lactic
acidosis: a rare adverse reaction? Clin Pharmacol Ther 2002;72(4):461-4.
In his letter of the letter 18th August 2004, Dr Chandler makes some
interesting comments on our paper “Increased neutrophil apoptosis in
chronic fatigue syndrome” [1]. He states that “a more likely explanation
for the group's findings are that CFS patients have a primary
psychological disorder with the secondary expected immune dysfunction”. We
strongly disagree with this statement.
In his letter of the letter 18th August 2004, Dr Chandler makes some
interesting comments on our paper “Increased neutrophil apoptosis in
chronic fatigue syndrome” [1]. He states that “a more likely explanation
for the group's findings are that CFS patients have a primary
psychological disorder with the secondary expected immune dysfunction”. We
strongly disagree with this statement.
It is noteworthy that many research findings that support a physical
basis to CFS are constantly under attack and are commonly reduced to the
lowest common denominator i.e. that CFS is “psychological in origin”. Dr
Chandler comments that, “there is a wealth of data suggesting that primary
depressive illnesses are associated with immune function defects”. That
may be true, however, we are not aware of a study which shows that
neutrophils are significantly apoptotic in depressed patients and that
this is associated with an increase in the pro-inflammatory cytokine,
transforming growth factor â-1. Furthermore, the CFS patients in our study
were not depressed or excessively anxious and we have already reported on
their psychological status in a separate report [2]. Indeed, three groups
of CFS patients are mentioned in that report [2]: those with self-reported
symptoms which developed sporadically (CFS, n =48); after Gulf War service
(GW, n =24); and following exposure to organophosphate insecticides (OP, n
=25). All of these patients underwent a clinical examination which
included psychiatric status, they all completed the MOS SF-36 quality of
life and Hospital Anxiety and Depression scales, and fulfilled major and
minor criteria for CDC-1994 CFS. The GW and OP cohorts had significant
impairments to both emotional and mental health measures (GW > OP) when
compared to their own controls and to the sporadic CFS patients. We have
not yet reported on the neutrophil apoptosis data on the GW and OP
patients (or in other studies of their lymphocyte function) but neither
cohort had any difference in the percentage of neutrophils undergoing
apoptosis when compared with their respective controls. We additionally
found that the GW and OP cohorts had no difference in the percentages of
tumour necrosis factor receptor-1 death receptor molecules expressed on
their neutrophils or levels of platelet poor plasma activated transforming
growth factor â-1. This data is at variance with Dr Chandlers comment that
“a more likely explanation for the group's findings are that CFS patients
have a primary psychological disorder”.
What is clear is that the term CFS is heterogeneous and lacks
specificity as others have reported [3, 4]. The CFS patients in our study
should more accurately be described as those having myalgic
encephalomyelitis (ME) as defined by Ramsay [5] which has recently been
reported to be operationally distinct from those with chronic fatigue and
chronic fatigue syndrome [6] especially in the neurological and
neuropsychiatric areas reported in our recent study [2]. Fatigue is a
symptom and not a disease and, ultimately, “an operational CFS case
definition will need to be based on empirical studies designed to
delineate the possibly distinct biological pathways that result in
illness” [3]: such a case definition already exists [7]. Our paper on
increased neutrophil apoptosis in a specific subset of patients within the
CFS construct goes some way to assisting in this process of
classification.
References
(1) Kennedy G, Spence V, Underwood C. Increased neutrophil apoptosis
in chronic fatigue syndrome. J Clinical Pathology 2004; 57: 891-3
(2) Kennedy G, Abbot NC, Spence V, Underwood C, Belch JJF. The
specificity of the CDC-1994 criteria for chronic fatigue syndrome: a
comparison of health status in three groups of patients who fulfill the
criteria. Annals of Epidemiology 2004; 14: 95-100
(3) Reeves WC, Lloyd A, Vernon SD et al. Identification of
ambiguities in the 1994 chronic fatigue syndrome research case definition
and recommendations for resolution. BMC Health Services Research 2003,
3:25
(4) Jason LA, King CP, Richman JA, et al. US case definition of
Chronic Fatigue Syndrome: Diagnostic and theoretical issues. J Chronic
Fatigue Syndrome 1999; 5: 3–33.
(5) Ramsay, M. A. (1988). Myalgic encephalomyelitis and post-viral
fatigue states: The saga of Royal Free disease (2nd ed.). Hampshire, UK:
Gower.
(6) Jason LA, Helgerson J, Torres-Harding SR et al. Variability in
diagnostic criteria for chronic fatigue syndrome may result in substantial
differences in patterns of symptoms and disability. Evaluation & the
Health Professions 2003; 26: 3-22
(7) Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG,
Lerner AM, et al. Myalgic encephalomyelitis/chronic fatigue syndrome:
Clinical working case definition, diagnostic and treatment protocols. J
Chronic Fatigue Syndrome 2003; 11: 7–116.
I welcome the latest research on neutrophil
apoptosis from a educated, experienced, and motivated M.E. expert.
I am very concerned, and thoroughly disappointed again, that, despite
the concerns raised, by hundreds of well educated people, involved with
M.E. worldwide, for many years, someone who ha...
I welcome the latest research on neutrophil
apoptosis from a educated, experienced, and motivated M.E. expert.
I am very concerned, and thoroughly disappointed again, that, despite
the concerns raised, by hundreds of well educated people, involved with
M.E. worldwide, for many years, someone who has admitted to being "quite
new" to a SHO post, on a Chronic Fatigue ward, has assumed, that he has
the authority and education, to criticise the outcome of this research, at
this stage, when most people admit they are not 100% sure about the
aetiology M.E.
This seems to be a pre-determined blinkered
attitude, that screams out "l know all there is to know". I will not tolerate,
on behalf of the members of the M.E.Association, the approach
perpetrated by information solely provided by the Psychiatrists, who have
continually reported, that M.E. is an illness belief, that one has a real
illness that must not be encouraged, by validating, or providing medical
testing, for a non-illness.
The Department of Health have on many occasions, declared
that they are duty bound, to take account of all national and international
information and evidence, from all sources so as to provide as broad a spectrum of ideas and treatment plans as
is reasonable. And to provide the least damaging and most helpful, practical
treatment or advice for all. The Canadian Guidelines have the potential to be adapted for world
wide use, but l have been told the government appears to use international advice only, when it suits
them, and ignore it when it suits patients.
Has the DOH considered fully, the possible financial implications,
for us all, if there is no research into the physical, epidemiological and
biological cause of M.E.?
This has resulted in many cases of long term physical damage,<see 25%
Report 2002-2004> which has resulted in the death of hundreds of people
every year.
A high proportion are those have been young adults, who have been
constantly, denied referrals, to the independent, M.E. specialists that we
have in our files.
Could you state the recommended method of collecting swabs for RSV? From your brief synopsis, I gathered that the anterior nares only was swabbed for culture and was found to be effective and less painful. Is that correct?
Terrie Will
Dear Editor,
With great interest we have read the article of Kakkar & Garg [1]. They mentioned the presence of cytoplasmic fragments or so called pseudoplatelets that may interfere with the platelet count when using automated haematology analysers. In 2003 we reported the presence of pseudoplatelets in a number of patients, which causes spurious platelet counts to such an extent that the risk of serious ble...
Dear Editor,
Setting up standards when interpreting mtDNA CR sequence data from tumors.
We agree with Parr et al.[1] on the importance to compare the mtDNA sequence data of our recent case report [2] (a divergence of 7 homoplasmic nucleotide positions within the 16024-16365 segment of the HV1 region between two morphologically different tissue sections found on the same slide) with the available...
Dear Editor
Alonso et al [1] recommend the use of mitochondrial genetic typing to exclude the possibility of tissue carryover artifacts in situations where low DNA content and high degradation may compromise conventional short tandem repeat typing. They studied archived presurgical hematoxylin and eosin stained needle biopsy sections from the same slide to ascertain the authentic source of the malignant and...
Dear Editor
In response to Dr Kruger, we provide extra minor details that had been omitted for reasons of word count.
Dear Editor
We read with interest the recent article by Alikhan et al , in which they reviewed necropsy reports to find out the number of deaths due to fatal pulmonary embolism in hospitalised patients.[1] There seem to be a number of confusions in this paper.
1. Acute infection was the most common medical illness found in patients who had died from pulmonary embolism, in particular respiratory in...
Dear Editor
When a patient has an infection, doctors often send a sample of infected blood or tissue to a lab where they can grow the bacteria and see which antibiotics are most effective (called Bacterial Culture and Sensitivity Testing). Chemosensitivity testing is an attempt to do something similar for cancer; fresh samples of the patient's tumor from surgery or a biopsy are grown in test tubes and tested wit...
Dear Editor
We read with interest the report on postulated atorvastatin induced lactic acidosis [1]. In our view, the arguments outlined by its authors do not support this hypothesis at all, for the reasons outlined below:
a) The patient clearly had a mixed acid-base disturbance (combined respiratory alkalosis and metabolic acidosis, as evidenced by the normal pH of 7.39 coupled with severe hypocapnia)....
Dear Editor
In his letter of the letter 18th August 2004, Dr Chandler makes some interesting comments on our paper “Increased neutrophil apoptosis in chronic fatigue syndrome” [1]. He states that “a more likely explanation for the group's findings are that CFS patients have a primary psychological disorder with the secondary expected immune dysfunction”. We strongly disagree with this statement.
It is n...
Dear Editor
I welcome the latest research on neutrophil apoptosis from a educated, experienced, and motivated M.E. expert.
I am very concerned, and thoroughly disappointed again, that, despite the concerns raised, by hundreds of well educated people, involved with M.E. worldwide, for many years, someone who ha...
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