Professor Brian Andrews NEJM Recommendations for Medical Students and
Tutors
Week of the 11th February 2016 (#29)
University of Notre Dame Australia
(Fremantle Campus)
Occasional Editorial Comment
As you are aware, I have had difficulty with
the mechanics of constructing this blog and if it were not for the help that I
had received from Frank Bate, the newly appointed Director of MEDSU, I would
still be floundering. My thanks go to Frank for his help and encouragement.
The articles that
interested the students the most this week were:
i)
Review of Urinary Tract Infections in Older
Men
ii)
The Perspective and Framingham study data on
the Decline of Dementia in specific populations
iii)
The perspective on Polio
You will see that I was particularly carried
away by the two articles on the Nanobody for use in TTP and epitope binding by
monoclonal antibodies in MGUS and myeloma: however, neither of these articles
were assessed as relevant by the medical students, unfortunately.
Must Read Articles
CLINICAL
PRACTICE
Urinary Tract Infections in Older Men
http://www.nejm.org/doi/full/10.1056/NEJMcp1503950
Effective treatment of urinary tract
infection in men requires determining whether the infection site is the kidney,
bladder, or prostate; the duration and choice of therapy vary with
presentation. Chronic bacterial prostatitis requires prolonged antimicrobial
therapy
This
is an excellent review article on UTIs in older men. In general practice,
urology and nursing home patients this is a significant problem. The review
discusses the causes, types, frequency, asymptomatic bacteriuria, therapeutic
options of which most can be applied generally to the population, and also acute
and chronic prostatitis. The hyperlink for this review should be saved in your
database.
Articles Recommended for Medical Students
Perspective
HISTORY
OF MEDICINE
Is Dementia in Decline? Historical Trends and
Future Trajectories
http://www.nejm.org/doi/full/10.1056/NEJMp1514434
The potential decline of dementia, seen in
light of the rise and fall of other major diseases, raises a tantalizing
prospect: Can we control our burden of disease? The history of the debate on
CAD decline carries important lessons for emerging reports of dementia's
decline
ORIGINAL
ARTICLE
Incidence of Dementia over Three Decades in the
Framingham Heart Study
In the Framingham Heart Study, the incidence
of dementia among participants 60 years of age or older has declined over three
decades; the 5-year cumulative hazard rate declined from 3.6 per 100 persons in
the 1970s and 1980s to 2.0 per 100 persons in the 2000s and 2010s.
The Perspective and the Original Article focus on the apparent decline in the incidence of
dementia overall in the Framingham study over a thirty year period. From the
data, the decline is most significant in vascular dementia (P value <0.004). In the Framingham population, Alzheimer’s
dementia is approximately three times more common than vascular dementia,
though there still appears to be a reduction in incidence of AD over thirty
years ( P value of 0.052) although not as marked as with vascular dementia. At
a minimum, the data indicate that there is no increase in the incidence of
Alzheimer’s dementia in this selected population. They indicate that the
frequency of dementia is lower in the population who graduate from high school
compared to those who do not and stress that this data only applies to
high-income countries e.g. Europe, US, and Australia.
The article describes
the Framingham Heart Study which is a unique community-based longitudinal
cohort study which began in 1971. The cohort is overwhelmingly of European
ancestry and thus the findings cannot be interpreted for other races and ethnic
backgrounds. The neurological and dementia assessment is as thorough as could
be done. In the Discussion section which should be carefully read, the authors
discuss the strengths and limitations of their study and also stress that still
the worldwide burden of dementia will continue to increase rapidly as the
average life expectancy continues to increase. They indicate that although many
vascular risk factors are improving, the incidence of diabetes mellitus and
obesity are markedly increasing and that the specific factor(s) resulting in
this decline are not all apparent. Stay tuned for further studies.
Perspective
A World Free of Polio — The Final Steps
Because oral polio vaccine has been associated with cases of paralysis, it is essential to discontinue its use after polio eradication has been certified. The first step is a shift from a trivalent OPV to a bivalent one, which requires a multipronged global strategy.
This was an eye-opener
for the students and me regarding the use of the oral polio vaccine in the
global eradication of polio: we all thought that the oral vaccine with the herd
immunity it produced was a cure-all. Not so! The story is much more complicated
and information can be gleamed by reading the article, particularly the
difficulties changing from the trivalent to the divalent vaccine oral polio
vaccine in large populations and the reasons why this is necessary.
IMAGES
IN CLINICAL MEDICINE
Scalp
Necrosis Associated with Giant-Cell Arteritis
http://www.nejm.org/doi/full/10.1056/NEJMicm1505378
A 74-year-old man presented with headache,
jaw claudication, and worsening scalp ulceration. Examination revealed areas of
scalp necrosis. He received a diagnosis of scalp necrosis as a complication of
giant-cell arteritis
This
is a well described but rare complication of giant cell arteritis.
MEDICINE
AND SOCIETy
Falling Together — Empathetic Care for the
Dying
http://www.nejm.org/doi/full/10.1056/NEJMms1516444
How does one live knowing one will soon die?
How can a physician ease this transition between life and death? What is the
relationship between empathy and hope? Neurosurgeon Paul Kalanithi explores
these questions in the posthumously published When Breath Becomes Air
I was pleasantly surprised by the number of students
who found this to be a very illuminating and reflective article. It is probably
a must-read article as it focuses on what empathy is and discusses how much the
physician should give of themselves (“falling together”) to exhibit true empathy
with their dying patient.
I was taken aback this week when a final year
student came up to me and told me of one of his palliative care patients who
was close to death with metastatic pancreatic cancer. The patient asked him to
sit down and then asked him “Doctor, what is it like to die?” I was very
impressed by the maturity, compassion, understanding, and, yes, empathy that
this student exhibited with this patient. I also felt very proud of our medical school and what we appear
to be achieving if this is any reflection.
Important Articles Related to
Mechanisms of Disease and Translational Research
ORIGINAL
ARTICLE
BRIEF
REPORT
Clonal Immunoglobulin against Lysolipids in the
Origin of Myeloma
http://www.nejm.org/doi/full/10.1056/NEJMoa1508808
Monoclonal gammopathies developing during the
course of Gaucher's disease are reactive against lyso-glucosylceramide (LGL1),
which is elevated as a consequence of the metabolic defect. Binding to this
antigen was noted in one third of sporadic human monoclonal gammopathies.
This
is a fascinating Brief Report for
anybody interested in MGUS (monoclonal gammopathy of unknown significance)
and/or multiple myeloma. In most cases of monoclonal gammopathy the binding
antigen (epitope) for the specific monoclonal protein is unknown. In an
occasional patient with myeloma or primary amyloidosis, the antigen may be
clotting factor VIII. More recently (see introduction) several newer antigens
have been identified as inherited risk factors for plasma-cell dyscrasias.
It
is known, by some, that patients with i) Gaucher’s disease (an autosomal
recessive, inborn error of metabolism associated with a missing enzyme glucocerebrosidase which leads to an
accumulation of the proximal substrate lyso-glucosylceramide
or LGL1 – this leads to an accumulation of macrophages full of LGL1 in the bone
marrow and in the liver and spleen resulting in marked hepatosplenomegaly –
there are also two murine experimental models associated with this enzyme
deficiency) and now ii) obesity patients, all of whom exhibit a higher
frequency of myeloma.
This
study has found, that in approximately 33% of sporadic, unselected patients
with human monoclonal gammopathies that the monoclonal protein binds to LGL1 or
another lyso-lipid lysophosphatidlycholine.
What
is even more interesting in the murine model, is that if the level of LGL1 is
reduced with therapy, the level of anti-LGL1 antibodies as well as the
frequency of monoclonal antibodies is reduced. It is also known that with
substrate-reduction therapy in another experimental model that the risks of
B-cell lymphomas is also reduced.
Substrate
reduction can also be achieved in human by either enzyme replacement or gene therapy. Can these results be replicated in humans?
If specific antigens can be demonstrated to be involved in
antigen-driven selection of monoclonal protein proliferation and these can be
identified in a specific patient with myeloma, what could be the possible
future role of reducing or eliminating the antigen in the potential treatment
of myeloma? This is why I have written so much on the fascinating article.
Other articles which should be of interest to medical students
ORIGINAL ARTICLE
Caplacizumab for Acquired Thrombotic
Thrombocytopenic Purpura
Thrombotic
thrombocytopenic purpura is often caused by an autoantibody to ADAMTS13,
resulting in ultralarge von Willebrand factor, which induces platelet
aggregation. Caplacizumab blocks platelet aggregation and speeds recovery when
combined with plasma exchange.
EDITORIAL
Von Willebrand Factor — A New Target for TTP
Treatment?
Thrombotic
thrombocytopenic purpura (TTP), a rare thrombotic microangiopathy, is defined
by a mechanical hemolytic anemia, severe thrombocytopenia, and visceral
ischemia due to systemic platelet-rich microthrombi. Specifically in TTP
microthrombi, von Willebrand factor, not fibrinogen, is the protein that binds
to platelets.
When you are interns, or if you are a very
inquiring medical student, you may come across an occasional patient in the ICU
with the very uncommon entity thrombotic thrombocytopenic purpura (TTP), which
still has a mortality rate around 20% with current optimal treatment.
As the name implies there is increased thrombosis, related to aggregation of
platelets by interacting with ultralarge von Willebrand multimers; thrombocytopenia, due to platelet
consumption in these large aggregates which occlude smaller vessels in the
heart, brain and kidney leading to ischemia and purpura, bleeding particularly in mucosal sites due to thrombocytopenia.
Here, the name describes the pathology.
But here’s where it gets more interesting.
Under normal physiological circumstances, the formation of ultralarge von Willebrand multimers is
inhibited by a circulating proteolytic enzyme ADAMTS13 (for unexplained reasons,
once students or interns learn this, many remember it just like dysdiadokokinesis)
which breaks down the multimers inhibiting thrombosis. In TTP, there is an
inhibitory autoantibody directed against ADAMTS13 leading to large platelet-von
Willebrand complexes which block the blood vessels. The principles of current
therapy are plasmaphoresis-plasma exchange which removes both the large
complexes and the autoantibody and replaces the functional ADAMST13 enzyme in
the normal plasma. In addition, autoantibody production is inhibited by the
monoclonal antibody Rituximab which binds to the B-cell receptor CD20 and
immunosuppressive agents if necessary.
This study introduces two new concepts:
i)
If you can produce
a protein small enough (with antibody activity) and which can bind to a
specific epitope, it may be able to bind specifically to a catalytic site on an
enzyme or, in this case, bind to the A1 domain on von Willebrand factor stopping
it interacting with its platelet receptor and inhibiting multimers formation –
this is achieved in this single-blind, parallel-design, randomized,
placebo-controlled study at 56 sites on 75 patients by the use of a unique protein called caplacizumab, and
ii)
The concept
of single-variable-domain immunoglobulin with a MW of 12-15 kDa called a
Nanobody by the manufacturer. This protein does not cross-link binding sites on
von Willebrand factor. You might ask, “So what?” This is just the start, so
stay tuned and remember this is where many of you heard it first. Trials are
currently underway using this nanobody in patients with acute coronary syndrome
(ACS) to stop platelet aggregation, but how effective will this be? However,
researchers are now able to order their own designer specific nanobody which is
easily biologically engineered, provided you have the funding and you have the
antigen.
CASE
RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
