Wednesday 12 April 2017

NEJM Week of 9th March 2017 (# 85)

Professor Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week of March 9, 2017 (#85)
University of Notre Dame Australia (Fremantle Campus)



Occasional Editorial Comment



This will be the last episode of my NEJM blog. I thank you for your readership and hope that I have stimulated some medical students to regularly review a medical journal of their choice, at least weekly, and to learn to critically review the articles.



Must Read Articles


SOUNDING BOARD

Realizing the Potential of Cancer Prevention — The Role of Implementation Science


Accumulating evidence shows that there are simple methods of reducing the incidence of cancer and cancer-related mortality in people at average and high risk. Further study is needed to better understand how these lifesaving, cost-effective measures can be put to greater use.

This is a short, must read article from the US that discusses the scientific basis for cancer prevention and how the scientific, evidence-based knowledge already acquired can be optimized and standardized to prevent cancer. This is not to say that new research must not be acquired in cancer biology, therapy and prevention, but that the current knowledge should also be used optimally.

The first paragraph provides an excellent overview and should be read by all. Table1 reviews the risk modifiers in cancer prevention and a CDC analysis of the data from each US state. It is interesting, although predictable, that California has the highest per-capita consumption of fruit and vegetables of any state, but of more significance is that Massachusetts, the only US state with universal health care, has the highest percentage of its population screened for colon, breast and cervical cancer. This is a statistic that will fall on the deaf ears of the Trump administration.


REVIEW ARTICLE

Psoriatic Arthritis


Psoriatic arthritis occurs in up to 30% of people with psoriasis and can have serious debilitating effects on the peripheral joints, spine, tendon insertions, and fingers. Management has improved, but complete disease control is not yet achievable.

While most students will not read this review article in its entirety, the Figures and Tables should at a minimum be reviewed. The sections on Coexisting Conditions, Causes and Pathophysiological Features and Therapy make for interesting reading.  This should be read by MEDI6400 students prior to their musculoskeletal rotation.

Recommended learning:  HLA-B27 associated spondyloarthropathies.




Articles Recommended for Medical Students



Perspective

Anesthesia and Developing Brains — Implications of the FDA Warning


The FDA has issued a warning regarding use of general anesthetic and sedation drugs in children under 3 years of age and in pregnant women in their third trimester — a warning that will change practice and raise questions that currently have no clear answer.

The genesis of this concern is predicated upon in vitro and animal studies on species ranging from roundworms to nonhuman primates where all of the anaesthetic agents tested resulted in acute neuroanatomical consequences and associated long-lasting functional effects.

 Without human data, on December 14, 2016, the FDA issued a “Drug Safety Communication” (www.fda.gov/Drugs/DrugSafety/ucm532356.htm) warning that general anesthesia and sedation drugs used in children less than 3 years of age or in pregnant women in their third trimester who were undergoing anesthesia for more than 3 hours or repeated use of anesthetics “may affect the development of children’s brains.” This warning will result in a labelling change for 11 common general anesthetics and sedative agents that bind to GABA or NMDA receptors, including all anesthetic gases such as sevoflurane, and the intravenous agents propofol, ketamine, barbiturates, and benzodiazepines.

While the duration of most anaesthetics is less than three hours, this warning will still send a chill through most parents whose child needs an anaesthetic but hopefully will not lead to postponing necessary surgery. Studies are currently underway to address this possible concern in humans and hopefully the results will be obtained soon.


Perspective

At Risk for Serious Mental Illness — Screening Children of Patients with Mood Disorders or Schizophrenia


The lack of attention paid to the millions of children born to a parent with schizophrenia, bipolar disorder, or recurrent major depression is out of phase with the massive need in primary care and the available scientific evidence.

This Perspective highlights the need for the general practitioner, in particular, to consider the potential risks to the child or adolescent of developing a mental illness if one of their parents is affected by schizophrenia, bipolar disorder, or recurrent major depression.  The recent population prevalence was estimated at 4% in a large European cohort.  The risk to the child or adolescent of a parent with mental illness developing a mental illness is estimated at 15 -20 times more than where none of the parents have mental illness.

The article discusses four major system based problems and provides possible solutions. I consider this is a very important article to read.


ORIGINAL ARTICLE

Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia


After nearly 11 years of follow-up, long-term administration of imatinib was shown to be associated with prolonged control of chronic myeloid leukemia and no cumulative or late toxic effects have emerged.


EDITORIAL

Imatinib Changed Everything


Early published work in 1990 demonstrated that the insertion of the bcr/abl gene of the Philadelphia chromosome into murine haematopoietic stem cells resulted in chronic myelogenous leukaemia (CML) in the mice.
 Subsequent to the development of a selective inhibitor of the abl tyrosine kinase, Brian Drucker, one of the authors of the present study, in 1996 used this drug to inhibit the growth of bcr/abl positive cultured haematopoietic cells.  In 2001, he extended this work and published the positive results of the safety and efficacy of this drug (imatinib) in the treatment of human CML.

In the current study, he and colleagues present the 10 year follow-up data on the use of imatinib in the treatment of CML. While there are many nuances in the study and subgroup analyses, overall this drug has proved to be extremely effective in treating CML.  Its use produced few significant adverse effects and patients frequently died of unrelated comorbidities.

Prior to the introduction of imatinib into clinical medicine, medical schools had no difficulty in finding CML patients with large spleens for OSCI examinations. Sustained splenic enlargement in CML is now a rare occurrence.

Imatinib basically changed the face of therapeutics in the field of oncology with the development and use of a “designer drug” for the first time. The Editorial provides a very informative historical review of this area as well as a glimpse into the future.


IMAGES IN CLINICAL MEDICINE

Grouped Pustules on an Erythematous Base


A 27-year-old woman presented with painful lesions on her left arm. A diagnosis was made with the use of a Tzanck smear.
This is a classic skin picture of HSV infection and a positive Tzanck test, useful in diagnosing HSV or VZV infection if immunofluorescence and PCR are not available.


IMAGES IN CLINICAL MEDICINE

Glucagonoma-Associated Rash


A 65-year-old man with type 2 diabetes presented with weight loss and other symptoms that occurred after a rash had developed on his arms, genitals, buttocks, and legs. Imaging showed a pancreatic lesion.



Important Articles Related to Mechanisms of Disease and Translational Research



None



Other Articles which should interest medical students



ORIGINAL ARTICLE

Chimpanzee Adenovirus Vector Ebola Vaccine


This update of a preliminary report from November 2014 presents safety, immunogenicity, and long-term durability data from a trial of an Ebola vaccine in humans that is based on a chimpanzee adenovirus type 3 construct with the Ebola Zaire and Sudan glycoprotein inserts.



EDITORIAL

One Step Closer to an Ebola Virus Vaccine


This article and accompanying editorial describe a replication-defective recombinant chimpanzee adenovirus type 3–vectored ebolavirus vaccine (cAd3-EBO) which is used to induce immunity against the Ebola virus. The vaccine immunogen encodes the glycoprotein from Zaire and Sudan species.  This phase 1, dose-escalation, open-label trial of the vaccine was administered to 20 healthy adults, 10 receiving a lower (2x1010 particle-unit dose) and 10 a higher dose (2x1011 particle-unit dose).  T cell responses were assessed over an eight week period with optimal CD4 and CD8 responses obtained from the higher dose.  Durability of the antibody response was best preserved at 48 weeks with the higher dose. Efficacy and phase 2 studies are currently underway.



CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

Case 7-2017 — A 73-Year-Old Man with Confusion and Recurrent Epistaxis


A 73-year-old man with a history of heart failure, pulmonary hypertension, and a hepatic venovenous malformation presented with confusion. CT of the abdomen revealed pneumatosis of the ascending colon to the level of the hepatic flexure. Diagnostic tests were performed.

This is a classic clinical diagnosis of a case of hereditary haemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) which was confirmed by genetic analysis. The most interesting aspect of this case was the clinical presentation with hepatic encephalopathy produced by a large portal-systemic shunt within an hepatic AV malformation. I was also unaware of an ENT procedure (Young’s procedure) used to obliterate the nostrils to avoid serious blood loss from recurrent epistaxis.

The genes associated with HHT are involved with the TGFb – BMP signalling pathway.  The specific gene mutation associated with this patient involved the ACVRL1 (ALK1, HHT2) gene associated with later age onset, recurrent nose bleeds, AV malformations in the liver, and spine and pulmonary hypertension without shunting.



New and Novel Therapies



None



Articles Some Medical Students Found Interesting



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Tuesday 4 April 2017

NEJM Week of March 2nd 2017 (# 84)

Professor Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week of March 2, 2017 (#84)
University of Notre Dame Australia (Fremantle Campus)



Occasional Editorial Comment


This week there are three articles that reflect the importance of the title in enticing the readers (medical students) to investigate the article.

The first is a Perspective article, “The Interpreter,” which I found to be very informative and which addressed some difficulties interpreters have in reality dealing with patients with malignancy and severe disease with whom they empathize. Because of the blandness of the title, students did not read the article.  If it had been titled e.g. Interpreter’s Challenges, students all agreed that they would have at least glanced at the article.

The second article “Histology Rings True” under Clinical Problem Solving was read by only one of 27 students. This is an example of the authors “trying too hard” with the title which only means something to the readers once they have read the CPC. The title should be such that it provides the potential reader with some idea about the contents of the article in order to interest the reader to look further at the article e.g. hepatic granulomata.
 
In contrast is a third article, an editorial, entitled “Ditching the Itch with Anti-Type 2 Cytokine Therapies for Atopic Dermatitis.” This title is catchy while at the same time describing the broad contents of the editorial.



Must Read Articles


Perspective

The Interpreter


When an interpreter hesitates before translating bad news for a patient, an oncologist realizes how little consideration most health care professionals give to these invaluable conduits who are also human beings, emotionally affected by the news they help to break.


Articles Recommended for Medical Students



Perspective

HISTORY OF MEDICINE

Sickle Cell Disease — A History of Progress and Peril


Given sickle cell disease’s prevalence among black Americans, questions of race and stigma have shadowed the history of its medical treatment. Recent developments in treating pain crises and gene therapy are part of a history of slow progress tinged with constant peril.

This Perspective provides the reader with a recent history of sickle cell disease (SSD) in the US.  The author discusses the racial overtones associated with SSD as well as current advances in therapy.  In 1971, Richard Nixon introduced his “war on cancer” initiative and in 1972 signed into law the “Sickle Cell Anemia Control Act” recognising a disease that involved the African American population and that had been neglected in medical research until that time.


ORIGINAL ARTICLE

Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy


Two placebo-controlled trials involving pregnant women with subclinical hypothyroidism or hypothyroxinemia showed that levothyroxine beginning between 8 and 20 weeks of gestation did not significantly improve cognitive outcomes in children through 5 years of age.


EDITORIAL

Subclinical Hypothyroidism and Hypothyroxinemia in Pregnancy — Still No Answers


Most students read the article and the editorial because of both the title and the association with pregnancy. This provides the student the opportunity to review thyroid function during pregnancy.
 
The study involved two parallel placebo-controlled trials which included patients with either i) subclinical hypothyroidism, defined as a TSH level of 4.0 mU/L or more (the upper limit of normal falls in pregnancy) together with a normal free T4 level (mean gestational age of 16.7 weeks), or ii) patients with hypothyroxinemia, defined as a low free T4 level associated with a normal TSH level (mean gestational age of 17.8 weeks). The question was whether treating these patient groups with levothyroxine to maintain a TSH level in the former group between 0.1 -2.5 mU/l and a free T4 level in the latter group between 0.86 – 1.9 ng/dl. The results of placebo components of the trials showed that levothyroxine replacement resulted in no differences in cognitive function in any of the four groups at five years.  Further, the presence or absence of antibodies against TPO made no difference to the outcomes of the studies.

The editorial indicates however that as the majority of women in the US and Australia have their first prenatal visit before 12 weeks, earlier treatment with levothyroxine is more likely if there appears to be any evidence of thyroid dysfunction.  In all likelihood replacement levothyroxine will be commenced as it is cheap and unlikely to be harmful.

Recommended learning: Review the endocrine changes that occur during pregnancy.



Important Articles Related to Mechanisms of Disease and Translational Research


ORIGINAL ARTICLE

Anti–Interleukin-31 Receptor A Antibody for Atopic Dermatitis


In a phase 2, placebo-controlled trial, nemolizumab, an antibody against interleukin-31 receptor A, reduced pruritus in patients with moderate-to-severe atopic dermatitis. These findings support the role of interleukin-31 in the pathophysiology of atopic dermatitis.


EDITORIAL

Ditching the Itch with Anti–Type 2 Cytokine Therapies for Atopic Dermatitis


I found the results of this study very interesting. Atopic dermatitis is associated with a predominantly Th2 mediated immune response with local release of TSLP (thymic stromal lymphopoietin, a major promoter of atopy), 1L-4, IL-13 and IL-31. Both TSLP and IL-31 bind to neuronal receptors which may explain the role these cytokines play in activating sensory neurons in the dermis producing the pruritus associated with atopic dermatitis. 

This is a 12-week, double-blinded, placebo controlled trial in 264 adult patients with moderate to severe atopic dermatitis studying the effect of a monoclonal antibody against the IL-31 receptor A (nemolizumab) on pruritus control as the primary outcome. Nemolizumab produced a significant improvement in pruritus in patients compared with controls (63.1% at the highest dose versus 20.9% in controls).

Recommended learning: Review the diagnosis and management of atopic dermatitis.


CLINICAL IMPLICATIONS OF BASIC RESEARCH

Parsing the Pancreas


High-resolution analysis of gene expression in individual pancreatic cells is providing new insights into cell subpopulations and candidate genes relevant to the causes and progression of pancreatic disorders.

The authors have reviewed four published studies using isolated single cells from murine and human pancreas (references 1-4) both from normal patients and from patients with type 2 diabetes. Single cells were isolated from the pancreas using specific techniques (Figure 1) and a cDNA library was established for each cell type by reverse transcription. Using next generation sequencing, the transcriptome was identified for each islet cell type (a, b, d, e, g) as well as stellate cells, endothelial cells, Schwann cells, immune cells from diabetic patients, and acinar cells from small and large pancreatic ducts. Using complex specific computer algorithms on DNA sequences, each cell type was sorted by a common transcript and studied.

 Information such as new cell surface markers, specific molecular pathways, cell heterogeneity, beta cell genes from diabetic and normal controls, and studies on “non-malignant” acinar cells from small and large ducts from patients with adenocarcinoma of the pancreas is now able to be obtained.

The revolution in single-cell assays is in the process of incorporating epigenetic and proteomic analyses. It is allowing researchers to answer questions that could not hitherto be addressed and raises prospects for a better understanding of that most complex of organs, the human brain.



Other Articles which should interest medical students


IMAGES IN CLINICAL MEDICINE

Iodide-Associated Sialadenitis


A 67-year-old man who had previously had heart transplantation and had chronic kidney disease underwent coronary angiography. He had received pretreatment owing to a reported history of iodine allergy but reported neck swelling several hours later.

This case represents an unusual, self-limiting, non-allergic complication of iodine contrast resulting in submandibular gland enlargement without thyroid enlargement in a patient with chronic kidney disease.


IMAGES IN CLINICAL MEDICINE

Cholesteryl Ester Crystals in Lysosomal Acid Lipase Deficiency


An 18-year-old woman had elevated aminotransferase levels and a workup negative for infectious and autoimmune disease. Liver biopsy revealed birefringent cholesteryl ester crystals consistent with lysosomal acid lipase deficiency.

This patient presented with massive hepatosplenomegaly with the CT scan demonstrating steatosis.  A liver biopsy revealed lipid deposition predominantly within Kupffer cells.  When frozen tissue was examined by polarizing microscopy, the diagnosis was made.

Recommended learning: Review the causes of hepatosplenomegaly.


CLINICAL PROBLEM-SOLVING

Histology Rings True


A 58-year-old man with rheumatoid arthritis who was being treated with etanercept and methotrexate presented to the emergency department with fevers, night sweats, yellowing of his eyes, and dark urine.

This CPC involves an immunosuppressed patient presenting with symptoms suggesting infection and evidence of hepatitis associated with granulomata in the liver.   Very interesting differential diagnoses are provided but with the histopathology suggesting the correct diagnosis.
              
Recommended learning: Review the causes of hepatic granulomata.



New and Novel Therapies


ORIGINAL ARTICLE

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia


Among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia, treatment with the bispecific anti-CD19 and anti-CD3 monoclonal antibody blinatumomab resulted in longer overall survival and higher remission rates than did chemotherapy.

This study utilizes a monoclonal antibody which binds to two epitopes.  These are CD19 (a B cell marker) on the surface of leukaemic B lymphocytes and CD3 on the surface of T lymphocytes.  The antibody brings the cytotoxic T cell in close proximity to the malignant B cell which is then destroyed.
 Patients with relapsed or refractory B-cell precursor ALL were treated with either the monoclonal antibody (blinatumomab) or chemotherapy. In those receiving the monoclonal antibody, the survival rate was extended from 4.0 months to 7.1 months. Another major aim of the study was to improve the overall clinical status of the patients with the monoclonal antibody thereby allowing 25% of patients to be eligible for an allogeneic haematopoietic stem cell transplant.


ORIGINAL ARTICLE

BRIEF REPORT

Gene Therapy in a Patient with Sickle Cell Disease


A boy with hydroxyurea-refractory sickle cell anemia underwent bone marrow transplantation with autologous hematopoietic stem cells transduced by a lentivirus to express an antisickling β-globin variant. No sickle cell crises occurred in the following 15 months.

This is a single case study of a patient with severe sickle cell disease who underwent an autologous haematopoietic stem cell transplant using a lentivirus vector to transfer an anti-sickling b-globin variant.  This is the first of many such studies to come.



Articles Some Medical Students Found Interesting



REVIEW ARTICLE

THE CHANGING FACE OF CLINICAL TRIALS

Informed Consent


An investigator obtaining informed consent traditionally asks participants to sign a written consent document — an approach that is becoming outdated. This multipart review examines electronic and video informed consent and consent in app-based and Internet-based trials, with videos showing examples.


This review of informed consent in clinical trials outlines the changes that have occurred in this area over time.  The review involves such areas as electronic informed consent and internet-based trials, mobile health research – app-based trials, and video informed consent

Monday 27 March 2017

NEJM Week of 23rd February 2017 (#83)

Professor Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week of 23rd February 2017 (#83)
University of Notre Dame Australia (Fremantle Campus)



Occasional Editorial Comment


None


Must Read Articles


ORIGINAL ARTICLE

Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator


A total of 1500 nonthoracic MRI examinations were performed on patients with a non–MRI-conditional pacemaker or ICD, after programming of the devices in accordance with a standardized protocol. No patient whose device was appropriately programmed had device or lead failure.

Over the past twenty years, pacemakers and implantable cardioverter-defibrillators (ICDs) have been designed to reduce the risks associated with MRI when used per defined protocol.

It is estimated that there are approximately eight million devices world-wide that are non-MRI-conditional or potentially not “MRI safe.” It is also estimated that approximately half of the patients with these devices will require an MRI in their lifetime.

1500 patients with non-MRI conditional devices were studied and received standard MRIs (77% for either the brain, cervical spine or lumbar spine). No MRIs were obtained of the thoracic cavity.  MRI machines with a magnetic field strength of 1.5 tesla were used.  Devices were programmed as per protocol before and after the MRI (MRIs were not performed on patients whose ICDs were pacing-dependent). During the study, there was no significant magnetic field-induced cardiac lead heating, although one patient experienced ICD failure, with the device needing to be replaced as protocol had not been followed with appropriate pre-MRI programming of the device. Otherwise no significant adverse events occurred. 



CLINICAL PRACTICE

Screening for Chlamydia trachomatis Infections in Women


Chlamydial infection may result in pelvic inflammatory disease, infertility, and ectopic pregnancy. Chlamydia screening is recommended in sexually active women younger than 25 years of age and other women at increased risk and can be performed on vaginal swabs or urine samples.

This is an excellent case-based review on chlamydial infections in women. The epidemiology, pathology and clinical presentations are defined followed by a discussion of screening strategies (see box insert for Key Clinical Points on screening). Treatment strategies and areas of uncertainty are outlined. This should be read by all medical students.

Recommended learning: Genital infections due to Chlamydia trachomatis.


IMAGES IN CLINICAL MEDICINE

Empyema Necessitatis


A 40-year-old man presented with fever, weight loss, dyspnea, and cough. Physical examination revealed a tender, bulging anterior thoracic mass.

This is an unusual complication of an empyema which, due to tuberculosis, tracks through the parietal pleura into the chest wall. There is an interesting clinical picture and CT scans.

Recommended learning: Review the pulmonary pathology of tuberculosis.



Articles Recommended for Medical Students



Perspective

Recreational Cannabis — Minimizing the Health Risks from Legalization


Twenty percent of the U.S. population now lives in states that have passed ballot initiatives to allow cannabis to be sold for recreational use. The net effect of cannabis legalization on public health is uncertain, and much will depend on how the laws are implemented.

This interesting Perspective summarises what is known and unknown regarding recreational cannabis use with respect to health effects, legalization, and public health policies. After reading this, I realized how much evidence based information needs to be gathered.




Important Articles Related to Mechanisms of Disease and Translational Research



None



Other Articles which should interest medical students



ORIGINAL ARTICLE

Tight Glycemic Control in Critically Ill Children


Tight glycemic control has not improved outcomes in studies involving critically ill adults or children after cardiac surgery. A controlled study involving hyperglycemic critically ill children who had not undergone cardiac surgery showed no benefit of tight glycemic control.

After this study involving tight glycaemic control in critically ill children (lower-target group at 4.4 – 6.1 mmol/L and higher-target group at 8.3 – 10.0 mmol/L), it now appears that in most studies to date on critically ill adults and children that clinical outcomes are not improved with tight glycaemic control.  As this study demonstrates, patients in the lower-target group (tight control) had more health care-associated infections and more episodes of severe hypoglycaemia.



IMAGES IN CLINICAL MEDICINE

Gastric Gyri — Pediatric Ménétrier’s Disease


A 5-year-old boy presented with nausea, vomiting, and intermittent abdominal pain. Images showed giant cerebriform enlargement of rugal folds in the fundus and the body, which were suggestive of Ménétrier’s disease.

When considering the gastrointestinal causes of hypoalbuminemia, one of the rarer causes, Menetrier’s disease, may need to be considered.

Recommended learning: Review the mechanisms, clinical entities associated with and approach to the management of hypoalbuminemia.


CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

Case 6-2017 — A 57-Year-Old Woman with Fatigue, Sweats, Weight Loss, Headache, and Skin Lesions


A 57-year-old woman presented with fatigue, night sweats, weight loss, headache, abdominal pain, and skin lesions. Laboratory testing revealed hypergammaglobulinemia and hypocomplementemia. Diagnostic tests were performed.
This CPC provides an excellent differential diagnosis of a patient presenting with fatigue, night sweats, weight loss, headache, abdominal pain, and skin lesions.  This patient is also found to have lacrimal gland enlargement, hypergammaglobulinemia, hypocomplementemia and increased plasma cells on a biopsy. I would not have even considered giant cell arteritis in my DD. The diagnosis is an IgG4-related disease, the group of which also includes disorders such as autoimmune pancreatitis and idiopathic retroperitoneal fibrosis.
IgG4 related disorders have been previously discussed in issues # 64, http://www.nejm.org/doi/full/10.1056/NEJMcpc1610097  and #14 http://www.nejm.org/doi/full/10.1056/NEJMra1104650.


New and Novel Therapies



ORIGINAL ARTICLE

Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis


In patients with hereditary angioedema with C1 inhibitor deficiency, swelling episodes are related to the release of bradykinin from high-molecular-weight kininogen from kallikrein action. Lanadelumab, which inhibits kallikrein action, reduced the rate of attacks of angioedema.

EDITORIAL

Kallikrein Inhibition for Hereditary Angioedema


Hereditary angioedema (HA), due to a functional deficiency in C1 (esterase) inhibitor (types I and II), is a rare disorder and is usually autosomal dominant in inheritance.  Deficient function of C1INH results in ongoing activation of the classical complement system with reduced C4 levels, activation of the coagulation system and activation of the kallikrein-kinin system (Fletcher factor deficiency is a rare congenital absence of prekallikrein which does not produce any significant clinical manifestations). Kallikrein generation from prekallikrein leads to excessive proteolysis of high MW kininogen and formation of bradykinin which results in vasodilation, vascular leakage, oedema and pain.  80% of patients with HA exhibit reduced production of C1INH, while 20% have functional inhibition of C1INH usually due to autoantibodies (SLE and B cell lymphomas).

The clinical manifestations of HA result from intermittent subcutaneous oedema of the hands, feet, face and abdominal wall and from submucosal oedema of the mouth, airways, GIT and genitourinary system.  There is no urticaria or pruritus associated with this condition. Patients usually present with recurrent painful swelling of lips, tongue, and airways compromising breathing and abdominal pain.

This study employs the prophylactic use of a monoclonal antibody (lanadelumab) against kallikrein, resulting in reduced cleavage of high MW kininogen and reduced plasma levels of bradykinin, which leads to fewer episodes of clinical angioedema.

The prophylactic use of this monoclonal antibody was effective and produced no significant adverse events in this brief six week, phase 1b study.  This is really an “appetiser study” responsible in part for some of the literature pollution that occurs. If this study had not been performed at the MGH in Boston, it would not have been published in the Journal. As the authors indicate in their discussion, the full phase 3 six-month (24 week) study is under way and had undoubtedly been completed at the time of submission and subsequent publication of this study. Maybe the results of another agent for treating HA are soon to be published in the Journal.



Articles Some Medical Students Found Interesting




Perspective

HISTORY OF MEDICINE

The Death of Animals in Medical School

Although live animals had been used in medical education for millennia, with recent changes at Johns Hopkins and the University of Tennessee, every core U.S. medical school curriculum has now ceased this practice. It is worth considering the causes and implications of this milestone.

This is an interesting historical review of the use of live animals in medical education in the US.


ORIGINAL ARTICLE

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome


A third of patients with the DiGeorge syndrome have congenital kidney and urinary tract anomalies. This study provides evidence that haploinsufficiency of CRKL is associated with such anomalies in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies.

I found this to be a fascinating study, though none of the medical students in my groups felt the same, until we discussed the article in some detail.

This is a truly an extensive and elegant study involving 2080 patients with congenital kidney and urinary tract abnormalities and 22,094 controls. The authors performed a genome wide search for structural variants in 22q11.2 in the above two cohorts.

This article illustrates the following:

1.     30% of patients with DiGeorge syndrome have congenital renal and urinary tract abnormalities.  They also exhibit the more well-characterized thymic aplasia with profound T cell immunodeficiency, hypoparathyroidism leading to hypocalcaemia, congenital cardiac malformations frequently requiring early surgery and facial and neck abnormalities.

2.     Most non-renal manifestations of the DiGeorge syndrome are associated with small deletions in chromosome 22, resulting in loss of function in TBX1 (the tbx1 gene translates the T-box 1 protein).

3.     The T-box 1 protein appears to be necessary for the normal development of large arteries that carry blood out of the heartmuscles and bones of the face and neck, and glands such as the thymus and parathyroid (Wikipedia).

4.     The hypothesis was generated that if renal abnormalities in DiGeorge syndrome were not attributable to deletions involving the tbx1 gene on 22q11.2, could another deletion in a nearby area of 22q11.2 on chromosome 22 be responsible?

5.     The authors identified a heterozygous 370 kB deletion in 22q11.2 containing a series of nine genes that when absent were associated with the renal defects in the DiGeorge syndrome. Further characterization of these genes identified the three important responsible genes, snap29, aifm3 and crkl.  However, absence of the crkl gene alone resulted in renal agenesis or hypodysplasia.

6.     CRKL encodes an adapter protein that regulates intracellular signalling transduction from multiple growth factors, including the fibroblast growth factors, which are key regulators of kidney and urinary tract development (article).

7.     In zebra fish embryos, the authors produced a crkl loss of function mutation which resulted in renal defects. In a mouse model, inactivation of crkl resulted in similar renal abnormalities to those in humans.

8.     In 1.1% of the 2080 humans with congenital renal abnormalities and in 0.01% of the population controls, heterozygous deletions of 22q11.2 were identified.

9.     The authors have identified a gene crkl that is responsible for the congenital renal abnormalities of the DiGeorge syndrome and a small number of patients with sporadic congenital renal and urinary tract abnormalities.