Friday, November 28, 2008
Monday, November 24, 2008
With that update, I now present my "Best of the Month" post for August '08:
On Wednesday [Aug 6 '08], I wrote about the fact that the brains of gorillas weigh only about 40% as much as human brains. There is, however, one way in which our brains are similar to simians: the presence of the von Economo neuron (VEN).
Constantin von Economo demonstrated in the 1920’s that these neurons are present only in the anterior cingulate and insular cortices (layer Vb). It was later determined that VENs are only present in hominids (humans and great apes), and that they are more numerous on the right side of the brain. Also referred to as spindle neurons because of their spindle-shaped cell bodies, VENs are larger than pyramidal neurons and tend to cluster parallel to small arterioles (pictured on right as compared to pyramidal neuron). More recently, it was found that VENs are also present in various species of whales and in elephants. The common theme here is that VENs are present in social animals with large brains. Since the VEN-populated areas of the brain are preferentially affected in frontotemporal dementia (FTD), it is thought that perhaps loss of these neurons may be related to the aberrant social functioning seen in FTD patients.
Thursday, November 20, 2008
It remarkable that Kennedy hasn't simply retired, given his grave diagnosis. His example is truly a profile in courage.
The VOA report goes on to say that "the Massachusetts senator, who was first elected in 1962, underwent surgery in June for a malignant brain tumor. He made a brief appearance in the Senate in July, and delivered a speech supporting Mr. Obama at the Democratic National Convention in August."
Monday, November 17, 2008
Thursday, November 13, 2008
In a recent post about poliomyelitis, the illustrious Dr. John Donahue of
“I have the same problem you and everyone else seems to have -- I've never seen one myself and cannot find any photos of one either in my own file or anywhere in books or on the web. I remember reading a description a long time ago - I think it might have been from the old AFIP neuropath teaching slide set - that they were supposed to be small eosinophilic (?) nuclear inclusions that were sometimes seen in neurons in poliomyelitis. I don't remember actually seeing them in the slide in that teaching set. From the description, I had the impression they might have resembled Marinesco bodies or maybe even normal but prominent nucleoli... or perhaps those small inclusions seen in some neurodegenerative dementias. They don't seem to be as 'specific' as Cowdry A inclusions and perhaps they don't even exist? Frankly I think Cowdry B inclusions have reached the point where they should be relegated to the trashbin of neuropathology.” (Emphasis added.)
I recently photographed a Marinesco body (see picture, arrow points to the eosinophilic body) within the
nucleus (outlined) of a pigmented neuron in the substantia nigra.
“Well, I doubt that it was a hoax but I think some of those folks were quite prone to seeing things that just the passage of time (and new information) has proved to be ‘not real’. Another case in point - how many Alzheimer type 1 astrocytes have you
I then wrote back to the individual who got me started on this hunt for the illusory Cowdry B in the first place: John E Donahue, MD. Here’s what Dr. Donahue had to say about the issue:
“I think these descriptions are very old and go back to the day where everything was described visually, without knowing etiology. (Remember, there are eight structures of Scherer from the original 1938 article, only three of which are really relevant anymore, and maybe even the gliosarcoma being a tertiary structure may be going the way of the dinosaur since I've heard recently that the gliosarcoma arises from a single precursor cell)…”
Fuller and Goodman, in Practical Review of Neuropathology (Lippincott, 2001), define a Cowdry B purely on morphological grounds -- with no implication as to the cause (polio or otherwise) -- as being small, eosinophilic, intranuclear inclusions with no halo and causing no nuclear effacement. I quote page 20: “[T]he quotidian Marinesco bodies that are routinely observed in the neurons of the pigmented brainstem nuclei are sterling examples of the Cowdry type B beau ideal.”
Perhaps the Marinesco body, rather than a “sterling example”, may in fact be the only example of a Cowdry B inclusion! Come to think of it, I think I’ll offer a $10 reward for anyone who can send me a photomicrograph of a polio-related Cowdry B inclusion. Email me the photo at email@example.com. I hope you have better luck finding one than I did!
Saturday, November 8, 2008
Friday, November 7, 2008
Campbell and colleagues address the phenomenon of exaggerated muscle fatigue after exercise, a finding present in many neuromuscular disorders. Using mouse models, the Campbell lab showed that sarcolemma-localized signalling by nNOS in skeletal muscle is required to maintain activity after mild exercise. To quote the abstract: "We show that nNOS-null mice do not have muscle pathology and have no loss of muscle-specific force after exercise but do display this exaggerated fatigue response to mild exercise.... Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction-induced signalling from sarcolemma-localized nNOS, which decreases cGMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise-induced signalling." It is interesting that there was no histomorphological pathology in the nNOS-null mice, suggesting that nNOS histochemical staining of patient biopsies might reveal an underlying disease process in otherwise non-specific biopsy findings. Or, as Steve Moore put it, nNOS can function as the "canary in the mine" for detecting myopathies.
Wednesday, November 5, 2008
From time to time, I feature an installment of my “Best Post Of The Month” series. The next month up for review is July '08, and I feel that this was the best item posted that month:
WHAT IS nNOS? AND WHY IS nNOS HISTOCHEMISTRY USEFUL IN MUSCLE BIOPSIES?
I recently sent a specimen out for histochemistry to see if the muscle had diminished dystrophin and/or dystrophin-associated proteins. One of the histochemical stains in the panel was neuronal nitric oxide synthase (nNOS). I honestly didn’t know what the deal was with that particular protein, so I thought I’d share with you what I found out.
In normal muscle, histochemistry for nNOS shows uniform sarcolemmal labeling. Internal sarcoplasmal labeling can also be present. Blood vessel walls are also positive. In Duchenne or Becker muscular dystrophy, nNOS is absent or reduced in the sarcolemma. Immature fibers will also lack nNOS histochemical staining.
An article by Ehmsen et al in the Journal of Cell Science states the following: “The production of nitric oxide (NO) by nNOS is important for increasing local blood flow to match the increased metabolic load of contracting muscles, such as during exercise… [P]atients with DMD [Duchenne muscular dystrophy] show abnormal blood vessel constriction presumably due to lack of nNOS at the sarcolemma… However, abolishing nNOS expression alone in mice does not cause overt dystrophy.”
So if it doesn’t cause overt dystrophy, what’s the point of doing this particular histochemical stain?
Dr. Steve Moore (pictured), muscle pathology guru at the University of Iowa, emailed me the following response when I queried him on the subject: “[nNOS] is quite sensitive to dystrophin mutations, meaning that it is virtually always absent in DMD and reduced to absent in BMD. In milder cases of BMD, nNOS sometimes can be the "canary in the mine" for detecting a dystrophinopathy. In the setting of a possible dystrophin mutation carrier, it provides one more marker for the muscle cells expressing either normal or mutant dystrophin. Dystrophin-negative fibers are also nNOS negative. This contrasts with the dystrophin-negative fibers being utrophin positive (utrophin is frequently expressed at the sarcolemma when dystrophin is missing or abnormal). Bottom line - using nNOS increases my confidence in the interpretation of the other immunostains in selected cases.”
Dubowitz V and Sewry CA. Muscle Biopsy: A Practical Approach, 3rd edition (2007) p 261 and 279.
Ehmsen J et al., The dystrophin-associated protein complex. Journal of Cell Science 115 (14) p. 2801-3.
Sunday, November 2, 2008
Karen Everingham -- formerly of the Illinois Association of Museums and now of the Historic Sites Division of the Illinois Historic Preservation Agency -- told me about an unusual medical museum sponsored by the College of Physicians of Philadelphia called the Mutter Museum. Among the medical curios and artifacts housed at the Mutter is a unique set of sliced sections of the human head prepared for the museum in 1910. What's special about this series of sections is that it demonstrates the human brain in situ within the context of the entire head. The first section in the series (pictured) shows the face of the subject sectioned. The next time I'm in Philadephia, I will surely visit the Mutter. Thanks, Karen!