Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of 21st July 2016 (#52)
University
of Notre Dame Australia (Fremantle Campus)
Occasional Editorial Comment
This is the one year anniversary of my blog. In the survey
I recently sent out, 25% of medical students responded. All indicated that this was a valuable
learning resource and agreed that I should continue with the blog. I wish to
thank all readers for your support.
Must Read or Save Articles
REVIEW ARTICLE
Medical
Considerations before International Travel
The
scope of illnesses that may befall international travelers is broad. A guide to
preparing for the preventable causes of illness is provided. Physicians may
find it useful in counseling their patients who travel internationally.
This is an in-depth review of many of the medical
consideration you may have regarding international travel. I recommend
reviewing the Supplemental Appendix where you will find numerous web addresses including
Travel Health Online (http://www.tripprep.com/ ). After you register, type in the place you
want to visit and nearly all the information you require will be presented. Unfortunately
it is not up to date as I typed in Puerto Rico and no mention was made of ZIKA virus
infection. More current information is provided in the text of the article with
hyperlinks.
I recommend that you store this article and review as
needed.
Recommended
learning: MED300 and MED400 should review the medical cases on
travel and infectious diseases (Fever and Polyarthritis, Fever in a Traveller
and Traveller’s Diarrhoea).
Articles Recommended for Medical Students
IMAGES IN CLINICAL MEDICINE
Thyroid
Ophthalmopathy, Dermopathy, and Acropachy
A
56-year-old man was referred to a dermatologist for assessment of the
progression of his thyroid dermopathy. Three years earlier, he had received a
diagnosis of Graves’ disease with thyroid-associated ophthalmopathy and
dermopathy.
The clinical photographs demonstrate the autoimmune
manifestations of Graves’ disease – ophthalmopathy, pretibial myxoedema, and
thyroid acropachy which are all associated with high levels of TSH-receptor
stimulating antibody. Acropachy is rare with periostitis also involving the
lower radius and ulna. The periostitis is described as “wool on a sheep’s back”
(also seen in the hands in psoriatic arthritis) in contrast to the linear
periostitis seen at the lower radius and ulna in hypertrophic pulmonary osteoarthropathy
(HPO).
Recommended
learning: Review causes of thyrotoxicosis and Graves’ disease,
particularly from the weekly MED300 medical cases.
IMAGES IN CLINICAL MEDICINE
Nodular
Lymphoid Hyperplasia
An
18-year-old woman presented with recurrent episodes of diarrhea associated with
epigastric discomfort and bloating. Examination of the stool revealed
trophozoites of the species Giardia lamblia. Gastroduodenoscopy revealed
multiple nodules in the duodenum.
Nodular lymphoid hyperplasia can occur throughout the
GI tract but is most frequent within the small intestine. It may, as in this
case, or may not be associated with an immunodeficiency state (most often IgA
deficiency or common variable immunodeficiency). For those needing more
information, I recommend the following NIH review (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231492/ ).
Recommended
learning: Review immunodeficiency which was covered in MED100,
particularly IgA deficiency.
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case
22-2016 — A 65-Year-Old Man with Syncope, Dyspnea, and Leg Edema
A
65-year-old man presented with syncope. One month earlier, cough, dyspnea, and
leg edema had developed. Imaging studies of the chest revealed lymphadenopathy,
and an echocardiogram showed hypertrophic obstructive cardiomyopathy. A
diagnostic procedure was performed.
This patient
presents with syncope and symptoms and signs of pulmonary hypertension. There
is an interesting discussion of the primary disease.
Important Articles Related to Mechanisms of Disease and
Translational Research
ORIGINAL ARTICLE
BRIEF REPORT
Proopiomelanocortin
Deficiency Treated with a Melanocortin-4 Receptor Agonist
Absence
of proopiomelanocortin results in early-onset obesity, hyperphagia,
hypopigmentation, and hypocortisolism. Two affected patients received
setmelanotide, a new melanocortin-4 receptor agonist, which led to sustainable
reduction of hunger and substantial weight loss.
EDITORIAL
Hormone-Replacement
Therapy for Melanocyte-Stimulating Hormone Deficiency
This Brief
Report is my choice of article of the week but was not reviewed by any of the
medical students.
It describes two patients with neonatal hypoadrenalism
and extreme obesity associated with hyperphagy.
It relates these biological effects to a mutation in the gene encoding
proopiomelanocortin (POMC) and describes the therapeutic benefit of a drug
which activates MSH receptors within the hypothalamus leading to reduced food
intake and weight loss. One patient has a heterozygous mutation in POMC, while the
other has a homozygous mutation, both resulting in a similar phenotype.
POMC is produced in the pituitary, is a long precursor polypeptide,
and is catalysed to MSH, ACTH, b-endorphin
and b-lipotropin.
I learned the following about melanocortin receptors:
1. MSH
binds to four of the five melanocortin receptors (1,3,4,5), while ACTH binds to
the melanocortin-2 receptor (MC2R) in the zona fasciculata of the adrenal
gland.
2. Lack
of activation of the MC1R results in depigmentation and red hair.
3. Lack
of activation of the MC4R and the MC3R lead to hyperphagy and extreme obesity.
4. Lack
of activation of the MC5R activation lead to decreased sebum production and lesser
effects on RBC differentiation, thermoregulation, fatty acid oxidation in
skeletal muscle and lipolysis in fat cells, and the inflammatory response.
Thus the phenotype of functional deficiency of POMC is
hypoadrenalism in the newborn, depigmentation and red hairs, hyperphagy and
extreme obesity.
The authors describe the anti-obesity effect of a drug,
setmelanotide, which binds to and activates the MC4- and MC3-receptors,
resulting in decreased food intake and weight loss.
The Editorial summarises the results of the article, discussing
the possible role of setmelanotide, leptin therapy, and the role of MCR4R
agonists in treating obesity. This is an example of patient to bench and back
to the patient.
Recommended
learning:
1. Review
the epidemiology, causes and effects of obesity.
2. Review
the management of obesity, including the place for bariatric surgery.
3. Consider
the physiological roles of leptin and ghrelin.
CLINICAL IMPLICATIONS OF BASIC RESEARCH
Defining
Metastatic Cell Latency
A
study modeling lung-cancer and breast-cancer metastasis in the mouse showed how
tumor cells, once seeded to a site distant from that of the primary tumor, may
maintain a state of dormancy until they are “reawakened.”
Pathological analyses suggest that tumor
cells can seed to and be maintained in many different organs. How do they
escape immune attack and survive? How is their dormant state maintained, and
what stimulates their escape from dormancy?
These questions, which are posed by the author, are the
subject of a research article by Malladi
et al. which partially addresses some of these issues. The study involved mice injected via the tail
vein with human cell lines derived from metastatic lung and breast cancer
patients. These cells are defined as latency-competent cells which have the
potential to seed distant sites and remain dormant for months before exhibiting
their metastatic potential.
From the review and from previously described works,
with the limitations of the murine models studied, I learned the following which
are well illustrated in Figure 1:
1. Once
metastatic tumour cells cross the endothelial barrier and enter the tissue, two
types of circulating monocytes are activated: one type is a patrolling, non-classical
monocyte which recruits NK cells to destroy the majority of the tumour cells expressing
an NK-activating receptor, while the other, a classical monocyte provides
proliferation and survival signals to surviving tumour cells causing them to
proliferate and express NK-cell-inhibitory receptors.
2. The
low number of latency-competent tumour cells which survive have properties of
stem cells with expression of cell specific transcription factors. These cells
maintain their dormancy by down-regulation of Wnt signalling due to increased
expression of Dkk1. They also evade NK-mediated destruction by continued expression
of NK-cell-inhibitory receptors.
3. At
a time in the future, the dormant cell comes to life as a metastatic lethal
lesion following activation of the Wnt pathway, presumably via the intercession
of a monocyte or macrophage.
The author of
the Editorial addresses possible ways
in the future that these results may be translated into identifying these
metastatic cell clusters and destroy them before they proliferate.
Recommended
learning: Review the pathology and immunological mechanisms
involved with metastatic disease.
Other Articles which should interest medical students
ORIGINAL ARTICLE
Extending
Aromatase-Inhibitor Adjuvant Therapy to 10 Years
An
additional 5 years of adjuvant aromatase-inhibitor therapy in women with early
hormone-receptor–positive breast cancer resulted in longer disease-free
survival and a lower incidence of contralateral breast cancer than placebo, but
not in longer overall survival.
EDITORIAL
Changing
Adjuvant Breast-Cancer Therapy with a Signal for Prevention
This is a double-blind, placebo controlled trial
involving 1918 post-menopausal women with previously treated hormone receptor
positive breast cancer which compares an aromatase inhibitor (letrozole) with
placebo over an extended 5 year period.
This study commenced at a median time from initial
diagnosis of 10.6 years (which is the time over which most metastatic lesions
would have become apparent). 79% of women had been treated initially with
tamoxifen (70% from between 4.5 - 6 years) followed by an aromatase inhibitor
for a additional median duration of 5 years. These patients were then entered
in the study.
The results of the study indicated:
1. A
significant reduction in the annual incidence rate of contralateral breast
cancer (letrozole= 0.21% versus placebo 0.49%, P=0.007) (see Figure 2)
2. No
significant difference in overall survival rate between the letrazole and
placebo treated groups, as expected.
3. A
disease free survival greater for the letrozole treated group which was defined
as either disease recurrence or new disease in the contralateral breast. This result was predicted.
4. A higher
incidence of bone pain, fractures and new-onset osteoporosis in the letrozole
group, which would be expected, as no early treatment with bisphosphonates was
initiated.
5. The
influence of letrozole on hot flashes, arthralgia, myalgia and quality of life
was not as pronounced as that seen in earlier studies.
6. That
there were no signals to date for increased cardiovascular risks
There was a discussion in the Editorial regarding the use of aromatase inhibitors in primary
prevention of breast cancer, comparing this with cardiologists and their use of
drugs in primary prevention of cardiovascular disease.
ORIGINAL ARTICLE
HIV
Infection Linked to Injection Use of Oxymorphone in Indiana, 2014–2015
A
rapid spread of HIV type 1 was identified in a community in Indiana and was
found to be related to injection use of oxymorphone.
The article describes 11 new diagnoses of HIV infection
in a small community in Indiana associated with IV injection of oxymorphone.
The messages I
got from this article were:
1. Within
one month of initiating a needle exchange program, there was a dramatic fall in
the number of new HIV cases reported (what’s new?), and
2. Who
else but Donald Trump would choose a vice-presidential running mate (Mike Pence)
who is the current unpopular governor of the ultraconservative Republican state
of Indiana and who, because of his evangelical “principles,” opposed needle
exchange until public pressure forced him to agree to change his “principles.” Even in a right wing state like Indiana, it is
obvious that the citizens have a higher regard for the health of others than
their highly unpopular governor.
