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Digital mammography represents a potential new and exciting
development in the interface between computers and health care. Your paper
highlights some of the emerging issues which might be expected with new
technology. You have noted the increase in incidence of breast cancer,
together with a large increase in recall rates. Reports from the
radiologists also indicate that between 6% and 10% of tumors are
identified clini...
Digital mammography represents a potential new and exciting
development in the interface between computers and health care. Your paper
highlights some of the emerging issues which might be expected with new
technology. You have noted the increase in incidence of breast cancer,
together with a large increase in recall rates. Reports from the
radiologists also indicate that between 6% and 10% of tumors are
identified clinically following mammography.
The protocol presented by those involved in the screening program
differs in a number of significant aspects from conventional screen film
mammography.
The instructions provided to women attending for screening do not include
any advice regarding using talcum powder. This advice had always
previously been given both in writing and orally to those attending for
mammograms.
All X-rays are reported and scored by two specialist radiologists.
However, the reports, when issued, do not identify the radiologists, nor
is the panel from which they are selected apparent. The Quality Assurance
manual indicates that targets are set for the incidence of breast cancer.
A Standarised Detection Ratio (S.D.R.)is the preferred method for
correcting unit performance. This raises the possibility that the computer
can over-ride the results from the individual radiologists. Such a
mechanism might again contribute to an increase in detection of breast
cancer.
The new digital equipment relies much less on X-ray exposure and has
substituted pressure to compensate for the reduction in the X-ray content.
Is it possible that the increase in pressure on breast tissue might
contribute to the increase in incidence of second round breast cancers
from 4.4 to 5.7/1,000 when the older SFM machine is compared to the newer
FFDM machine, reported by Hambly et al in the American Journal of
Radiology, October 2009.
Is the observed interval tumor rate a result of the reduced
penetration in the new machine, with consequent diminution in accuracy of
detecting mass lesions? Alternatively, is the increased pressure in the
new machine causally related to the number of women who present with mass
lesions following mammography?
Ref:Immunohistochemical assessment for Cdx2 expression in the Barrett metaplasia-dysplasia-adenocarcinoma sequence;
This original study confirms to its cited and previous reports on Cdx2 expression in BO related intestinal metaplasia and its downregulation with the evolution of lesion to dysplasia and adenocarcinoma.[1] A well documented research communication about authors' confirmation and conclusion that the Cdx2 down regulatio...
Ref:Immunohistochemical assessment for Cdx2 expression in the Barrett metaplasia-dysplasia-adenocarcinoma sequence;
This original study confirms to its cited and previous reports on Cdx2 expression in BO related intestinal metaplasia and its downregulation with the evolution of lesion to dysplasia and adenocarcinoma.[1] A well documented research communication about authors' confirmation and conclusion that the Cdx2 down regulation was linear and significant from BO metaplasia to dysplasia to adenocarcinoma, and that the Cdx2 evaluation hence, was a reliable parameter for diagnosing and distinguishing the three entities from one another by IHC score using normal colonic mucosa as control. However, the normal colonic mucosa control mentioned by authors in last paragraph of methods was neither depicted with the tests IHC images which was essential in view of novelty of the study, nor this sole novel aspect of the study was mentioned in their effective conclusion, to say that any case of BO related metaplasia, dysplasia, adenocarcinoma was Cdx2 score-able using normal colonic mucosa as control and finally diagnosable on the basis of IHC score despite inconclusive histopathological evidence.
References:
1. Fitzgerald RC. Molecular basis of Barrett's oesophagus and oesophageal adenocarcinoma Gut 2006;55:1810-1820
This study from multiple centers of repute from UK and Spain
demonstrated cytoplasmic and nuclear expressions of NF-kB/p65, and
established that in good number-ratio of 1:4 or 1:3 cytoexpression was
followed/accompanied by the nuclear expression, besides there were cases
of breast carcinoma negative for nuclear as well as cyto expression of NF-
kB; could imply that p65 expression was consequence rather than being an
esse...
This study from multiple centers of repute from UK and Spain
demonstrated cytoplasmic and nuclear expressions of NF-kB/p65, and
established that in good number-ratio of 1:4 or 1:3 cytoexpression was
followed/accompanied by the nuclear expression, besides there were cases
of breast carcinoma negative for nuclear as well as cyto expression of NF-
kB; could imply that p65 expression was consequence rather than being an
essential component of the etiopathogenic pathway sequence of the breast
carcinogenesis. Further it appeared that this study identified NF-kB
negative ER +ve, NF-kB +ve ER -ve, NF-kb +ve ER +ve, NF-kB -ve ER -ve
subgroups; it could be indicative of remotely coordination of NF-kb and ER
receptors expressions and regulation by EGFR. It may also explain
unexpected result relating to therapy, but only the authors may be in
position to explain what may be the factual position.
Kapoor et al. (1) investigated pseudohyperkalemia in outpatients and
attributed many of the cases to hematological abnormalities or delay in
specimen centrifugation or clotting. Plasma is often recommended as the
preferred specimen in patients with leukocytosis, erythrocytosis or
thrombosis (2). Potassium released from ruptured cells during the clotting
process of serum specimens may result in false...
Kapoor et al. (1) investigated pseudohyperkalemia in outpatients and
attributed many of the cases to hematological abnormalities or delay in
specimen centrifugation or clotting. Plasma is often recommended as the
preferred specimen in patients with leukocytosis, erythrocytosis or
thrombosis (2). Potassium released from ruptured cells during the clotting
process of serum specimens may result in false-positive reporting and
unnecessary therapy (3). Others have reported on a phenomenon known as
reverse pseudohyperkalemia in patients with leukocytosis where potassium
concentrations in plasma specimens exceeded concentrations in serum (4).
We describe a similar case of reverse psuedohyperkalemia. A 87-year-
old man with chronic lymphocytic leukemia (CLL) was treated for the past 2
years as an outpatient. He received cyclophosphamide, vincristine, and
rituximab chemotherapeutic agents as part of his treatment plan. Blood was
collected in serum separator (SST) and EDTA tubes for routine metabolic
and hematology studies. The potassium concentration averaged 3.7 mmol/L on
a Beckman DXC chemistry analyzer (n=11). His white blood cell (WBC) and
platelet counts averaged 306 x 109 cells/L (94-97% lymphocytes) and 95 x
109 platelets/L over this time period. Recently, he was admitted to the
ED. Specimens were collected for metabolic (lithium-heparin specimen with
separator gel) and hematology (EDTA plasma) analyses. The specimens were
transported by pneumatic tube, and time from collection to analysis was
<60 min. The potassium concentration was 7.5 mmol/L; similar results
were obtained on a second analyzer. No hemolysis was observed. The
hematology results supported a known diagnosis of CLL but all other
laboratory data was within normal limits. Pseudohyperkalemia was
investigated. Additional venous blood specimens were collected in lithium-
heparin with a separator gel and a SST tubes. The specimens were
immediately transported to the lab by pneumatic tube (<5 min transport
time), promptly centrifuged (5 min at 3500 rpm) or allowed to clot (30
min; then centrifuged for 5 min at 3500 rpm) and analyzed. The plasma
specimen exhibited significantly higher potassium (7.4 mmol/L)
concentration compared with the serum specimen (3.9 mmol/L). A significant
layer of WBC was evident on the packed erythrocyte layer in the lithium-
heparin tube. No WBC layer was observed in the serum specimen. Four days
later, a similar occurrence (lithium-heparin potassium = 6.4; serum
potassium = 4.2 mmol/L) was observed on the same in-patient.
Some cells, especially malignant ones are susceptible to in-vitro
heparin-induced cell membrane damage during specimen processing resulting
in diffusion of potassium into the supernatant from ruptured leukocytes.
Similar cases in other leukemia patients have been observed in our
laboratory. Both laboratorians and clinicians should be aware of this
phenomenon to minimize false-positive reporting and unnecessary therapy.
1. A K Kapoor, AK, Ravi A, Twomey PJ. Investigation of outpatients
referred to a chemical pathologist with potential pseudohyperkalaemia. J
Clin Pathol 2009; 62:920-923.
2. Ifudu O, Markell MS, Friedman EA. Unrecognized pseudohyperkalemia
as a cause of elevated potassium in patients with renal disease. Am J
Nephrol. 1992;12(1-2):102-4.
3. Sevastos N, Theodossiades G, Savvas SP, Tsilidis K, Efstathiou S,
Archimandritis AJ. Pseudohyperkalemia in patients with increased cellular
components of blood. Am J Med Sci. 2006 Jan;331(1):17-21
4. Abraham B, Fakhar I, Tikaria A, Hocutt L, Marshall J, Swaminathan
S, Bornhorst JA. Reverse pseudohyperkalemia in a leukemic patient. Clin
Chem. 2008 Feb;54(2):449-51.
Editor - The article "Alcohol and unnatural death in the West of
Ireland: a 5-year review" emphasized the need for effective interventions
to reduce mortality due to the alcohol-related road traffic collision
(RTC)[1]. Recently in Ireland, allowable blood alcohol concentration (BAC)
limit of drivers was decreased from 0.8mg/ml to 0.5mg/ml. According to
Ingoldsby and Callagy concluded in their manuscript that legislative...
Editor - The article "Alcohol and unnatural death in the West of
Ireland: a 5-year review" emphasized the need for effective interventions
to reduce mortality due to the alcohol-related road traffic collision
(RTC)[1]. Recently in Ireland, allowable blood alcohol concentration (BAC)
limit of drivers was decreased from 0.8mg/ml to 0.5mg/ml. According to
Ingoldsby and Callagy concluded in their manuscript that legislative
change might not be effective in reducing fatalities because the BACs in
most of fatal drivers exceeded 0.8mg/ml[1]. However, the conclusion seems
to be doubtful.
In Japan, legal limit of BAC in drivers decreased and its effect have been
scientifically validated by us. In 1970, the Japanese government
introduced a law setting the maximum allowable breath alcohol
concentration at 0.25mg/L (BAC of 0.5mg/ml). This law was revised in 1978
to increase penalties for drivers in violation of this law. We analyzed
the BAC of drivers involved in fatal MVCs that occurred between 1986 and
2001[2]. Approximately 10.0 to 13.7% of offenders were drunk drivers with
BAC levels of 0.5mg/ml or more. However, 3.8 to 6.1% of offenders were
drunk drivers with BAC levels below the legal limit (between 0 and
0.5mg/ml). Furthermore, we determined the relative risks of fatal MVCs due
to alcohol-impaired (BAC level greater than 0.25mg/L) driving in Japan[3].
The relative risk of fatality was 5.5 in 1986 and gradually increased to
8.0 by 2001 for alcohol-impaired driving of a four-wheeled vehicle. The
increase in the relative risk indicates that a large number of deaths
could be prevented if drivers refrained from drinking. In June 2002, the
Japanese Government strengthened the Road Traffic Law and decreased the
allowable breath alcohol concentration from 0.25 to 0.15 mg/L (BAC: from
0.5 to 0.3mg/ml). In 2002, the number of drunk driving collisions was
markedly decreased from the previous year (25,440 to 20,328, a 20.1%
decrease). Also, the number of fatal drunk driving collisions was 997 in
2002, a 16.3% decrease from the previous year. In 2002, 8,326 persons died
in MVCs in Japan, the lowest number in the preceding 35 years and a 5.0%
decrease from the previous year. These data reflected the deterrent effect
of the revised law. With the strength of allowable BAC limit, the
awareness in which drunk driving should be prohibited also improved,
subsequently, the number of drunk driving might be decreased. Therefore,
the effect of the revision of the law of drunk driving in Ireland should
be accurately validated with the nationwide statistics of the accidents
and fatalities by drunken-driving.
We agree the proposal that interventions other than driving limit
reduction should be considered to reduce mortality. In Japan, in addition
to reduce the allowable BAC limit of drivers, stricter countermeasures for
drunk driving also contributed to the decrease of alcohol related vehicle
accidents and fatalities. The police responded by implementing the revised
Traffic Law to include stricter regulations and penalties targeting drunk
driving and any environments that enable drunk driving (enacted in 2007).
Furthermore, the police force continues to promote strict regulations.
When a person is arrested for drunk driving, an in-depth investigation is
conducted not only on the driver but also on the other vehicle passengers
and/or persons who provided the alcohol to the driver. It was decided that
the revised Road Traffic Law would also promote the application of the
penal code to fellow passengers who had enabled the drunk driving actions,
or to persons who had provided alcohol to the driver. Recently, the number
of traffic collisions caused by drunk driving has decreased as a result of
the expansion and consolidation of two sets of penal codes, along with the
revision of the Road Traffic Act and establishment of a new penal code. In
2008, there were 6,219 cases of drunk driving-related collisions, less
than one-third of those in 2002[4]. We showed the effective measures to
prevent alcohol-related traffic fatalities in Japan.
We forensic pathologists have to not only determine the actual cause of
death, but contribute to the primary prevention of unnatural deaths.
Further effort might be needed for us to lesser the common alcohol-
associated unnatural deaths.
References
1. Ingolsby H, Callagy G. Alcohol and unnatural deaths in the West of
Ireland: a 5-year review. J clin Pathol 2010;63:900-903.
2. Hitosugi M, Maegawa M, Kido M, et al. Trends in fatal traffic accidents
due to alcohol-impaired driving in Japan, relative to breath alcohol
levels of drivers. Jpn J Occup Med Traumatol 2007;55:234-238, in Japanese
with English abstract.
3. Hitosugi M, Sorimachi Y, Kurosu A, et al. Risk of death due to alcohol-
impaired driving in Japan. Lancet 2003;361:1132.
4. Ministry of Land, Infrastructure, Transport and Tourism in Japan. White
Papers on Ministry of Land, Infrastructure, Transport and Tourism, 2008.
Ministry of Land, Infrastructure, Transport and Tourism in Japan, Tokyo,
2009, in Japanese.
Masahito Hitosugi, MD, PhD, Shogo Tokudome, MD, PhD,
Department of Legal Medicine, Dokkyo Medical University School of Medicine
Mibu, Tochigi 321-0293, Japan
hitosugi@dokkyomed.ac.jp
Dear Drs Kaushik, Fear, Richards, McDermott, Nuwaysir, Kellam,
Harrison, Wilkinson, Tyrrell, Holgate, Kerr, and Editors at JCP,
I hope this note finds you
well. Congratulations to the Physicians and Researchers who completed such
admirable work regarding the possible etiology of the CFS (Chronic Fatigue
Syndrome), as they made the observations that were "consistent with a
complex pathogenesis involving T...
Dear Drs Kaushik, Fear, Richards, McDermott, Nuwaysir, Kellam,
Harrison, Wilkinson, Tyrrell, Holgate, Kerr, and Editors at JCP,
I hope this note finds you
well. Congratulations to the Physicians and Researchers who completed such
admirable work regarding the possible etiology of the CFS (Chronic Fatigue
Syndrome), as they made the observations that were "consistent with a
complex pathogenesis involving T cell activation and abnormalities of
neuronal and
mitochondrial function, possibly as a result of virus infection or
organophosphate exposures."
While the Chronic Fatigue Syndrome (CFS) is considered to be a
multifactoral disease affecting several organ systems, there are many who
believe that
the mitochondria should provide answers to its etiology.
The results of Dr Kaushik et al, to the effect of,
"The involvement of genes from several disparate pathways suggests a
complex pathogenesis involving T cell activation and abnormalities of
neuronal and mitochondrial function"
and "These results suggest possible molecular bases for the
recognized contributions of organophosphate exposure and virus infection"
remind me of another study of Patients, some with malabsorption
syndromes, who seemed to have the most reduced levels of Interferron. If
Interferon levels are severely reduced, then perhaps that would explain a
smoldering virus which wasn't very aggressive, but persistent.
A malabsorption syndrome would very possibly cause reduced Thiamine,
Niacin and other Nutrient levels. I've always thought that one must fill
the Nutritional Tank before much should be expected from the usual and
corrective Metabolic
Pathways.
I was most surprised to recently find what could be described as a
mitochondrial specific toxin found almost everywhere, which is synthesized
by the
Streptomyces griseus strain of bacteria.
Writing in the January 2000, Infection and Immunity, p165, V68, Drs
Paananen and Timonen found that "human blood lymphocytes treated with
small doses
(30 ng/ml ) of pure valinomycin, or high-pressure liquid chromatorgraphy-
pure valinomycin from S. griseus quickly show mitochondrial swelling and
reduced NK cell activity. Larger doses (>100 ng/ml1) induced NK cell
apoptosis within 2 days. Within 2 h, the toxin at 100 ng/ml dramatically
inhibited interleukin-15 (IL-15)- and IL-18-induced granulocyte-
macrophage" and "Here we report that pure commercial valinomycin and high-
pressure liquid chromatography (HPLC)-pure valinomycin from S. griseus
inhibit human NK activity and cytokine production and induce apoptosis of
NK cells at doses 10 to 500 times lower than those previously used. Thus,
a toxin derived from bacteria that are abundant in the environment has the
potential to cause immune suppression."
Since S griseus is ubiquitous, found in both soil and household dust,
the possibility exists that the toxin, valinomycin, could cause or worsen
a CFS
by disrupting mitochondrial function. The Respiratory chain inhibitor,
valinomycin, is a Thiamine triphosphate inhibitor in the mitochondria.
My impression is that fatigue:depression::dementia:psychosis.
Significant deficiencies or blockage of the Thiamine and/or Niacin
Metabolic Pathways
cause severe fatigue and dementia, which is possibly misdiagnosed as
depression and psychosis.
The fact that valinomycin disrupts the mitochondrial Thiamine Pathway
is significant.
Overseas, the CFS is known as the systolic hypotensive syndrome,
which could be how a different toxin, reserpine, presents itself. During
the 1950's,
reserpine was added to chicken and turkey feed to improve productivity,
and could have then entered the Human Food Chain.
In the Article titled "Thiamine Triphosphate Synthesis In Rat Brain
Occurs In Mitochondria, And Is Coupled To The Respiratory Chain," the
Authors Dr
Gangolf et al, comment on how "In animals, thiamine deficiency causes
specific brain lesions, generally attributed to decreased levels of
thiamine
diphosphate (, an essential cofactor in brain energy metabolism.
However, another derivative, thiamine triphosphate , may have a
neuronal
function" and "ThTP synthesis is severely inhibited by respiratory chain
inhibitors such as myxothiazol-" and "ThTP synthesis is impaired by
disruption of
the mitochondria or depolarization of the inner membrane (by protonophores
or valinomycin)-." (Journal of Biological Chemistry, Published on November
11,
2009 as Manuscript M109.054379)
Dr Gangolf et al's Discussion ends with- "Such a mechanism could help
to better understand the events involved in the onset of neurodegenerative
diseases. It is therefore interesting to note that thiamine deficiency has
been shown to exacerbate the pathology of
Alzheimer disease and that there are
dysfunctions of thiamine metabolism in neurodegenerative diseases."
I would suggest that while competitive inhibition of the Thiamine
Pathway could be overcome with higher levels of Thiamine, the valinomycin
toxin mechanism which inhibits ThTP synthesis needs further study
Perhaps the mitochondrial genome needs to be studied separately for
gene expression, since it is always derived from a maternal source.
Best wishes always. Keep up the Good Work.
Cordially,
Joseph W Arabasz MD
Past Division Chairman, Anesthesiology, Cook County Hospital,
Chicago, Illinois
Past Chairman, Respiratory Therapy, Cook County Hospital, Chicago,
Illinois
Diplomate ABA
Mensa
Sigma Xi, The Professional Science Research Society
Of all the prospective candidates for thyroid replacement therapy(1),
even when due account is taken of the improvent in left ventricular
diastolic function attributable to this treatment modality in patients of
mean age 39.9 with subclinical hypothyroidism(SCH)(2), the over 65s with
SCH are probably the ones least likely to be at cardiovascular
disadvantage if they do not receive thyroid replacement t...
Of all the prospective candidates for thyroid replacement therapy(1),
even when due account is taken of the improvent in left ventricular
diastolic function attributable to this treatment modality in patients of
mean age 39.9 with subclinical hypothyroidism(SCH)(2), the over 65s with
SCH are probably the ones least likely to be at cardiovascular
disadvantage if they do not receive thyroid replacement therapy(3)(4). In
a longitudinal study of risk factors for development of cardiovascular
disease(CVD) in 3233 adults aged 65 or more with baseline serum
thyrotropin(TSH) levels(including 496 with SCH characterised by serum TSH
>4.5 mU/l but < 20.0 mU/l) no difference was documented between SCH
and euthyroidism for incident coronary heart disease and CVD death(3).
Likewise, among 427 subjects of mean age 73 with SCH(characterised by mean
TSH 8.1 mU/l) and coexisting type 2 diabetes, there was no relationship
between baseline TSH and cardiovascular mortality(4). Furthermore, on
follow-up of SCH for 5 or more years, this disorder was not additive to
the relatively higher cardiovascular risk attributable solely to type 2
diabetes(4). Finally, in a prospective longitudinal study evaluating
disability in daily life, depressive symptoms, cognitive function, and
mortality in 558 subjects aged 85(including 67 with TSH in the range 4.8
mU/l to 33 mU/l, some of whom were subclinically hypothyroid, and others
overtly hypothyroid), who were followed up for 4 years, all measures of
performance significantly deteriorated with time, but increasing baseline
levels of TSH were not associated with accelerated increase in disability
in activities of daily living, depressive symptoms, or cognitive decline
during follow-up. If anything, "increasing TSH levels at baseline were
associated with a significant(p=0.03) decelerated increase in disability
in instrumental ADLs(activities of daily living". Furthermore, increasing
baseline TSH levels were associated with lower mortality on 4 year follow-
up(5). Accordingly, especially in subjects aged 85 or more with SCH
characterised by TSH < 33 mU/l, there should be no "rush" to initiate
thyroid replacement therapy, because it appears to confer no improvement
in quality of life, and definitely neither cardiovascular benefit nor
survival benefit.
(2) Yazici M., Gorgulu S., Sertbas Y et al
Effects of thyroxin therapy on cardiac function in patients with
subclinical hypothyroidism: index of myocardial performance in the
evaluation of left ventricular function
International Journal of Cardiology 2004;95:135-143
(3)Cappola AR., Fried LP., Arnold AM et al
Thyroid status, cardiovascular risk, and mortality in older adults
JAMA 2006;295:1033-1041
(4)Sathyapalan T., Manuchehri AM., Atkin SL
Subclinical hypothyroidism is associated with reduced all-cause mortality
in patients with type 2 diabetes
Diabetes Care 2010;33:e37
(5)Gussekloo J., van Exel E., de Craen AJM et al
Throid status, disability and cognitive function, and survival in old age
JAMA 2004;292:2591-9
We are astonished by Wiwanitkit's inaccurate remarks regarding the
number of subjects studied and analytical methodology in our study [1].
The data set was of more than sufficient size to be subjected to rigorous
statistical analyses. If Wiwanitkit had bothered to even casually read the
articles he cites [1,2], he should have immediately realised that firstly
the thrust of Lenters-Westra's and Sling...
We are astonished by Wiwanitkit's inaccurate remarks regarding the
number of subjects studied and analytical methodology in our study [1].
The data set was of more than sufficient size to be subjected to rigorous
statistical analyses. If Wiwanitkit had bothered to even casually read the
articles he cites [1,2], he should have immediately realised that firstly
the thrust of Lenters-Westra's and Slingerland's paper was to
highlight poor analytical performance of some HbA1c point-of- care (not
laboratory based) instruments and secondly that laboratory HbA1c analyser
used in our study (Tosoh G7, cation-exchange HPLC) was a reference method
for measurement of HbA1c in study of Lenters-Westra and Slingerland [1,2].
In addition our HbA1c assay, and indeed all our assays, are subject to
stringent internal quality control procedures and external quality
assurance. We had hoped our article would stimulate meaningful debate
rather than inane comment.
Dr Taruna Likhari,
Professor Rousseau Gama
References
1. Likhari T, Gama R. Ethnic differences in glycated haemoglobin
between white subjects and those of South Asian origin with normal glucose
tolerance. J Clin Pathol 2010; 63:278-280
2. Lenters-Westra E, Slingerland RJ. Six of eight hemoglobin A1c point-of-
care instruments do not meet the general accepted analytical performance
criteria. Clin Chem 2010;56:44-52
I read the recent publication by Likhari et al with a great
interest [1]. Likhari et al concluded that "In subjects with similar
fasting and postprandial glycaemia on OGTT, those of South Asian origin
have higher HbA(1c) levels than white subjects. It is speculated that the
higher glycaemia-independent HBA1c levels in people of South Asian origin
could possibly contribute to their increase cardiovas...
I read the recent publication by Likhari et al with a great
interest [1]. Likhari et al concluded that "In subjects with similar
fasting and postprandial glycaemia on OGTT, those of South Asian origin
have higher HbA(1c) levels than white subjects. It is speculated that the
higher glycaemia-independent HBA1c levels in people of South Asian origin
could possibly contribute to their increase cardiovascular risk [1]." I
have some additional concerns on this work. First, the rather few subjects
in this work reduce the value of the research. It is questionable whether
the number of subjects in this work is statisticall acceptable or not.
Second, the concern on the performance of the analyzers for HBA1C should
be raised. In a recent publication, only a few analyzers are acceptable
for precision and accuracy [2].
References
1. Likhari T, Gama R. Ethnic differences in glycated haemoglobin between
white subjects and those of South Asian origin with normal glucose
tolerance. J Clin Pathol 2010; 63:278-280
2. Lenters-Westra E, Slingerland RJ. Six of eight hemoglobin A1c point-of-
care instruments do not meet the general accepted analytical performance
criteria. Clin Chem 2010;56:44-52
Elizabeth H Blackburn and Jack Szostak discovered that a unique DNA
sequence in the telomeres protects chromosomes from degradation. Carol
Greider and Elizabeth Blackburn identified telomerase, the enzyme that
makes telomere DNA. These discoveries explained how the ends of the
chromosomes are protected by the telomeres and that they are built by
telomerase. If the telomeres are shortened, cells age....
Elizabeth H Blackburn and Jack Szostak discovered that a unique DNA
sequence in the telomeres protects chromosomes from degradation. Carol
Greider and Elizabeth Blackburn identified telomerase, the enzyme that
makes telomere DNA. These discoveries explained how the ends of the
chromosomes are protected by the telomeres and that they are built by
telomerase. If the telomeres are shortened, cells age. Conversely, if
telomerase activity is high, telomere length is maintained, and cellular
senescence is delayed. This is the case in cancer cells, which can be
considered to have eternal life [1]. Cancer cells have the ability to
divide infinitely and yet preserve their telomeres. How do they escape
cellular senescence? One explanation became apparent with the finding that
cancer cells often have increased telomerase activity [1] Telomeres,
repeated sequences of DNA at the end of chromosomes, prevent degradation
of genetic material. Each time chromosomes replicate a small amount of
the DNA at both ends is lost, by an uncertain mechanism. Because human
telomeres shorten at a much faster rate than many lower organisms, we do
speculate that this telomere shortening probably has a beneficial effect
for humans, namely mortality. The telomere hypothesis of aging postulates
that as the telomeres naturally shorten during the lifetime of an
individual, a signal or set of signals is given to the cells to cause the
cells to cease growing (senesce). At birth, human telomeres are about
10,000 base pairs long, but by 100 years of age this telomere reduces to
about 5,000 base pairs. Scientists discovered an important enzyme that can
turn the telomere production on the DNA molecule "on" and "off." It's
called telomerase. It seems that as we get older, the amount of telomerase
in our cells decreases. Naturally, the exploration of this enzyme is now
the focus of much investigation, but unfortunately the research is aimed
at understanding how to turn telomeres "off" to limit the spread of
"immortal" cancer cells. Telomerase is actually an enzyme (a catalytic
protein) that is able to arrest or reverse this shortening process.
Normally, telomerase is only used to increase the length of telomeres
during the formation of sperm and perhaps eggs, thus ensuring that our
offspring inherit long "young" telomeres to propagate the species. The
telomere hypothesis of cancer is that the function of telomere shortening
is to cause cells that have lost normal control over growth to senesce
(i.e. stop growing) before being able to replicate enough times to become
a tumor, thus decreasing the frequency of cancer. Immortal cells like
cancer have an unfair advantage over normal human cells which are designed
to senesce. But nature seems to have planned this human telomere
shortening perhaps to prolong life by hindering the otherwise unchecked
growth of non-immortal or benign tumors. Malignant, or immortal tumors can
simply outlive the rest of the organism. Malignant cancer cells are being
studied because they appear to have altered the shortening of telomeres by
turning "on" the telomerase. Thus it appears that some cancers and aging
are both connected with the biology of telomeres. So telomerase-inhibiting
drugs would probably kill the cancer cells before much damage is done to
normal cell
Today reduction in mortality in breast cancer is due to early
detection through screening by mammography. However at least 25%
reduction in mortality could have been achieved due this screening
procedure [early-stage pre menopausal breast cancer, for example, 10-year
survival rates is today 68% for African Americans versus 77% for
Caucasians]. Besides these there played other factors also and these are
1) systemic or improved systemic treatment with chemotherapy 2) adjuduvant
therapies after surgery to eliminate micro metastasis like Her2 Nue
antagonist Herpentine and to prevent recurrences. Women with steroid
hormone receptor[ER+ or PR+] positive and negative cases are benefited by
Cyclopshomide & methotraxate & 5 FU chemotherapeutic agents. More
effective adjuduvant endocrine treatments are with variuous aromatase
inhibitors like letrozole or anastrozole.
Cases of breast cancers occur even when there is no family history or only
a few cases in elderly relatives are known as sporadic breast cancer.
Hereditary breast cancer is different from those of sporadic breast cancer
.The increased risk of breast cancer for those with a family history may
be caused by inherited factors (genes) like BRCA1 and BRCA2,[both the
genes protects breast cells from developing cancer. Certain mutations in
BRCA1 stop the gene working properly and therefore make it more likely
that breast cancer will develop],or a combination of inherited factors and
lifestyle like no breast feeding or unmarried women. Having an increased
genetic risk by mutation of these two genes can lead to breast cancer
developing even at an earlier age. BRCA1 and TP53 genes are of high
penetrance genes for breast Cancers. Mutations in the rare high
penetrance breast cancer predisposing genes are BRCA1 and BRCA2 and they
account for 16 to 25% of the inherited component of breast cancers in the
world scenario.This, in turn, can have an impact on raising your family.
So is it today possible to do BRCA1 gene test for people that know they
carry a specific mutation that predisposes them to suffer from breast
cancer. It is a real fact that most Breast cancers develop sporadically
and not related with a familial history or hereditary BRCA genes. It is
thought that less than 5% of people those develop breast or bowel cancer
do so because of an inherited fault. Unless there is a strong family
history of breast cancer in you it is unlikely that your child will
inherit a gene that increases the risk of developing cancer. So splicing
off BRCA1 gene before embryo may be an advancement for medical technology
[2]. Mutations in TP53, which at same time may cause the Li Fraumeni
syndrome, STK11 gene causing Peutz Jeghers syndrome, and PTEN causing
Cowden syndrome are however very uncommon sporadic causes of breast
cancers of NOS type, as are mutations in CDH1, although these mutations
may be highly penetrant for breast cancer The intermediate penetrance
breast cancer susceptibility genes are mutations in ATM, CHEK2, BRIP1,
BARD1, and PALB2. They can cause an increased odds ratio for breast cancer
of 2 to 4. These genes are all involved in the same DNA repair pathways,
but it is curious that they do not confer the high risk of breast cancer
seen in women who carry mutations in BRCA1 and BRCA2. Also of great
interest is that biallelic mutations in BRCA2, BRIP1, and PALB2 cause
Fanconi anaemia subtypes FANC D, J, and N respectively, further indicating
overlap in the functions of these genes. There are also good evidences now
that there are up to eight polymorphisms, which are reproducibly found to
influence breast cancer risk, particularly the FGFR2 gene. Carriers of two
low risk rs2981582 alleles at the FGFR2 locus (frequency 38% of the
population) have a relative risk of breast cancer of 0.83 compared with
the general population, carriers of one high-risk and one low-risk allele
(47%) have a relative risk of 1.05, and carriers of two high-risk alleles
(14%) have a relative risk of 1.26
Telomere crisis is also an important early event in the development
of breast cancer. In the breast, cells in a milk-collecting duct
occasionally proliferate excessively due to development of a regulatory
defect and results usual ductal hyperplasia." The chromosomes in these
growing cells lose a hundred or so base pairs of DNA every time they
divide," ,because the usual DNA replication processes don't copy DNA all
the way out to the ends of the chromosomes. This erodes the DNA sequences
that interact with proteins to form structures called telomeres, which
protect the chromosome ends. Eventually the DNA ends erode so much they
can no longer protect the chromosomes. When this happens the chromosomes
become unstable, and damage-control mechanisms kick in that kill the
unstable cells. This process, known as "telomere crisis Cells in which telomerase is activated can then proliferate indefinitely to form the next stage of cancer, known as 'ductal carcinoma in situ.' The mean telomere length is found decreased from normal tissue to carcinoma in situ, and decreased even more in invasive cancers of breast.
It was therefore proposed that breast cancer might be treated by eradicating telomerase. Several studies are underway in this area, including clinical trials evaluating vaccines directed against cells with elevated telomerase activity[1] "
Authors
Professor Pranab kumar Bhattacharya MD(cal), FIC path(Ind.)
Mr. Ritwik Bhattacharya, B.Com(cal)
Mr. Rupak Bhattacharya BSc
Mrs Dahlia Mukherjee BA (hons)
Miss Upasana Bhattacharya of Mahamyatala,
Dr. Debashis Bhattacharya Ms(cal) FRCS(Edin)
Dr. Diptendra Narayan Sarkar
Dr. Tarun Biswas MBBS(cal)-
Dr. Satyaki Mitra MD(PGT)
Dr. Avisnata Das MBBS(cal),
References
1] Press Release on the 5 October 2009 “The Nobel Prize in Physiology or
Medicine 2009� by The Nobel Assembly, consisting of at Karolinska
Institutet, Sweden
2] Response by Professor Pranab Kumar Bhattacharya Published by BMJ
on 4th feb 20009 .for the BMJ case reports Blog unnatural selection by
author Dean Jankens, published on 9th Jan 2009
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