1 July 07 - Beached jellyfish, and autonomic nervous system evolution
Last week I found myself swimming in Boston Harbor with jellyfish --shriek! The next
day, walking along Carson Beach, I saw thousands of them washed up on the sand.
The last time I remember seeing jellyfish was at Duxbury Beach, and I included this
sighting as a prologue to the Course Guide for the TOPS-20 Monitor Internals course
I wrote when I worked for Digital Equipment Corporation:
The currents along the Massachusetts coast were unusually warm during
the summer of 1981 and, at Duxbury Beach, we saw jellyfish for the first
time. They were found to be a harmless type, so the lifeguards scooped
them out of the water and piled them up on the beach.
Once we overcame our fear, we became curious. "Are they plant or
animal?" I mused. "They are a primitive form of animal life, with a very
simple nervous system," answered nine-year-old Matthew. After a moment
of contemplation, I added, "I do believe that the DECSYSTEM-20 is more
alive; it responds to more events in its environment!"
This was when my focus was on event-driven multi-tasking operating systems, of
which TOPS-20 for the DECSYSTEM-20 was one of the best designed, and most
interesting. I was already at that time interested in the nervous system, trying to
understand what impairments might cause autism.
Now my interest is in how peristalsis in the coelenterate gut is maintained, and how
through evolution, control of this function became transferred to the autonomic
system of vertebrate brains. Autonomic functions are under control of the brainstem
nuclei of high metabolic rate that are so vulnerable to sudden oxygen deprivation.
The evolution of hemoglobin function, releasing oxygen in exchange for carbon
dioxide, exquisitely protects these important control centers when oxygen is in short
supply (but not completely cut off).
Multicellular organisms were first dependent upon the gut, but then circulation with a
pumping mechanism for blood transporting hemoglobin, and gills or lungs
developed. The autonomic nervous system of vertebrates keeps the heart pumping
and the gills or lungs moving to obtain oxygen to be delivered by hemoglobin, and
maintains peristalsis of the GI system.
Autonomic functions appear to be impaired in people with mental illnesses, and
especially perhaps the GI system. Sleep apnea is another problem of great
concern. The evolution of nervous control of functions essential for life may be of
some interest in trying to understand the elaboration of higher cognitive functions.
The Boston Harbor jellyfish were described two years ago by the "Urban Pantheist" in
his blog at : http://urbpan.livejournal.com/data/rss?tag=jellies.
2 July 07 - Bilirubin & kernicterus, What breaches the blood-brain barrier?
Looking still for articles on kernicterus, I found the following by Harris et al. on
kernicterus in 85 premature infants with low levels of bilirubin. A scatter plot of the
levels is provided (p876) showing total bilirubin less than 30mg/10ml in all but three
cases, and "direct bilirubin did not exceed 1.6mg/100ml in any case." Use of
penicillin and gantrisin (known to be ototoxic) was associated with kernicterus.
HARRIS RC, LUCEY JF, MACLEAN JR. Kernicterus in premature infants
associated with low concentrations of bilirubin in the plasma. Pediatrics. 1958
Jun;21(6):875-84.
Abstract:
Concentrations of bilirubin in the plasma of 85 premature infants weighing
less than 2000 gm at birth were measured daily for the first 6 days of life.
These measurements are presented and discussed. Nine cases of
kernicterus which developed with relatively low concentrations of plasma
bilirubin are reported.
Laboratory studies are cited to support the hypothesis that the
development of kernicterus in these infants was enhanced by the use of the
antibacterial combination of penicillin and Gantrisin®.
Attention is called to the effect which antibacterial therapy may have upon
the concentration of bilirubin in the plasma of premature infants and to the
lower values for plasma bilirubin which occur in dying infants.
A 1998 commentary on a randomized controlled trial comparing penicillin/sulfioxazole
to oxytetracycline. "The trial is of major importance for at least three reasons. First, it
unmasked and put to an end the harm of an established but previously untested
practice. The trial exposed the hitherto unrecognized horror that the P/S regimen was
in fact causing kernicterus, and doing so at an alarming rate."
Sinclair JC PEDIATRICS Vol. 102 No. 1 Supplement July 1998, pp. 225-227
COMMENTARY: A Difference in Mortality Rate and Incidence of Kernicterus
Among Premature Infants Allotted to Two Prophylactic Antibacterial Regimens,
by William A. Silverman, et al, Pediatrics, 1956;18:614–624
Abstract of the original article:
Background. Low birth-weight (LBW) infants have a high incidence of
serious infections. These are difficult to diagnose early. Thus, prophylactic
treatment with antibiotics appears to be rational, but the best choice of
antibiotics is uncertain.
Objective. In newborn LBW infants, to compare the effects on death rate
and principal findings at necropsy of two prophylactic antibacterial
regimens, oxytetracycline (OT) versus penicillin/sulfisoxazole (P/S).
Methods. Consecutively admitted LBW infants (N = 193) were randomly
assigned, within three birth-weight strata, to receive either subcutaneous
0T or a combination of P/S. The primary outcomes were death before 120
hours, death before 28 days, and principal diagnoses at necropsy.
Results. Infants allocated to P/S had a large and statistically significant
increase in death rate, determined up to 120 hours (OT, 20.6%; P/S,
48.4%; absolute risk increase, 27.8%) and up to 28 days (0T, 27.8%; P/S,
63.2%; absolute risk increase, 35.3%). This increase in deaths was not
attributable to death from infection; the incidence of positive postmortem
blood culture results was lower in the P/S group, and there was no
significant difference between groups in the incidence of pneumonia or
other infections at necropsy. However, in the P/S group, there was a large,
unexpected, and statistically significant increase in the finding of
kernicterus at necropsy among necropsied deaths occurring up to 120
hours (0T, 6.3%; P/S 36.4%; absolute risk increase 30.1%) and up to 28
days (0T, 4.5%; P/S, 43.2%; absolute risk increase, 38.7%).
Conclusions. Infants who received P/S died at a significantly higher rate
and had a higher rate of kernicterus at necropsy than those who received
OT. The mechanism of the differences observed in rates of mortality and
death with kernicterus is unknown.
3 July 07 - Kernicterus, blood-brain barrier disruption, not bilirubin toxicity
Bilirubin appears normally not to be toxic to the brain. Bilirubin and many other
substances in the circulation may get into the brain and cause damage if the blood-
brain barrier is breached. Ranck and Windle (Experimental Neurology 1:130, 1959),
in their first report on the effects of experimental asphyxiation of newborn monkeys,
stated that the lesions found in the inferior colliculi and other subcortical sites were
similar to those affected in kernicterus, but without the yellow discoloration caused by
bilirubin. Asphyxia disrupts the blood-brain barrier, as do some antibiotics. Alcohol
in excess would appear to have the same effect, resulting in a very similar pattern of
brainstem injury.
Therefore, the concern over bilirubin levels in newborn infants may be misplaced. Of
much greater importance should be to avoid any lapse in respiration at birth
(therefore don't cut the umbilical cord until the infant is breathing), and antibiotics
should also be avoided. Prenatal exposure to alcohol and drugs is likewise very
dangerous.
Maisels MJ. What's in a name? Physiologic and pathologic jaundice: the conundrum
of defining normal bilirubin levels in the newborn. Pediatrics. 2006 Aug;118(2):805-7
"Because at some point during the first week after birth almost every
newborn has a total serum bilirubin (TSB) level that exceeds 1 mg/dL (17
micro-mol/L), the upper limit of normal for an adult, and about 2 of every 3
newborns are jaundiced to the clinician’s eye, this type of transient
bilirubinemia has been called 'physiologic jaundice.'” [p805]
"Term, healthy, North American, formula-fed infants have mean peak TSB
levels between 5 and 6 mg/dL (86 and 103 micro-mol/L)," [p806]
"Data from the Collaborative Perinatal Project, conducted from 1955 to
1961 (when 30% or fewer mothers breastfed their infants), indicated that
about 95% of infants had a TSB concentration that did not exceed 12.9
mg/dL (221 micro-mol/L), and this (95th percentile) became a commonly
accepted upper limit of physiologic jaundice." [p806]
"We should abandon the terms physiologic and pathologic jaundice and
substitute the term “newborn jaundice” or, better, 'neonatal bilirubinemia,'"
[p807]
Wennberg RP, Ahlfors CE, Bhutani VK, Johnson LH, Shapiro SM. Toward
understanding kernicterus: a challenge to improve the management of jaundiced
newborns. Pediatrics. 2006 Feb;117(2):474-85.
"In contrast to other reservoirs for bilirubin binding, the brain is unique by
having a BBB that slows the equilibrium between plasma and brain. If the
BBB is disrupted, bilirubin–albumin moves rapidly into the extracellular
space of brain (Levine et al. 1982), and at sufficiently high Bf (free bilirubin
concentration) bilirubin will produce immediate global neurotoxicity." [p476]
"Bilirubin can produce behavioral changes and alterations n the ABR
(brainstem auditory evoked response) at TSBs (total serum bilirubin
concentration) well below 20 mg/dL". [p477]
"Apnea is a common manifestation of toxicity in premature primates that are
infused with bilirubin and may precede changes in the ABR." [p477]
"In 1996, Starr et al described a syndrome of auditory neuropathy (or
auditory dyssynchrony) (AN/AD)63–65 characterized by an absent or
severely distorted ABR, normal otoacoustic emissions (ie, normal hair
cells), normal cochlear microphonic responses (auditory nerve), and
variable hearing impairment. The same constellation of findings had been
observed previously by Chisin et al66 in 1979 in children with hearing loss
caused by hyperbilirubinemia. In sparing the inner ear and acoustic nerve,
AN/AD is quite distinct from most causes of hearing loss.
Children with AN/AD have difficulty understanding speech in the absence of
significant hearing loss and may have delayed speech development,
behavioral problems, and learning disability. AN/AD may account for 11% of
children with permanent hearing deficits, with a reported prevalence of
5.3% to 14.8% in infants discharged from NICUs. Hyperbilirubinemia and
prematurity are significant risk factors for AN/AD, accounting for more than
half of the patients with the syndrome." [p477]
Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI. Auditory neuropathy.
Brain. 1996;119:741–753.
"A resurgence of kernicterus in the past decade107 has forced a
reevaluation of the 1994 practice parameters." [p482]
Oh W, Tyson JE, Fanaroff AA, Vohr BR, Perritt R, Stoll BJ, Ehrenkranz RA, Carlo WA,
Shankaran S, Poole K, Wright LL; National Institute of Child Health and Human
Development Neonatal Research Network. Association between peak serum bilirubin
and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics.
2003 Oct;112(4):773-9.
A current theory on the development of bilirubin encephalopathy is based
on the assumption that when the level of serum unconjugated bilirubin
exceeds the bilirubin binding capacity of albumin (BBCA), lipophilic
unconjugated unbound bilirubin readily crosses the blood-brain barrier,
resulting in neuronal injury. [pp773-774]
"During the past 2 decades, the survival rate of ELBW infants has improved
in part as a result of more common use of antenatal steroid and surfactant
therapy.21,22 Unfortunately, the incidence of neurodevelopmental
abnormalities among these survivors remains high." [pp777-778]
To add to the complexity of this issue is that bilirubin has recently been
shown to have some antioxidant effects, which may potentially be beneficial.
refs34–37 [p778]
Phototherapy has been associated with retinopathy of prematurity38 and
with patent ductus arteriosus.ref41 [p778]
Connolly AM, Volpe JJ. Clinical features of bilirubin encephalopathy. Clin Perinatol.
1990 Jun;17(2):371-9.
Clinical features of bilirubin encephalopathy vary depending on the age of
the infant and the degree of hyperbilirubinemia. In term infants with
hyperbilirubinemia, three distinct clinical phases are apparent in the first
weeks of life, and long-term consequences include extrapyramidal
disturbances (particularly athetosis), hearing loss, gaze abnormalities
(particularly limitation of upward gaze), and, in a minority, intellectual
deficits. In term infants with moderate hyperbilirubinemia, minor delay in
motor development during the first year has been demonstrated, but with
longer follow-up this delay is not apparent. Associated conditions such as
sepsis, anoxia, and acidosis may increase the likelihood of neurotoxicity of
bilirubin in these infants. The clinical consequences of moderate
hyperbilirubinemia in premature infants are unclear. No acute clinical
syndrome is recognizable during the first weeks. The results of follow-up
studies are variable. Hearing loss is the commonest consequence. Follow-
up through age 2 years in one large study suggests that static
encephalopathy may be a sequel. Longer follow-up is needed to
understand the clinical consequences of moderate hyperbilirubinemia in
this important group of infants.
Levine RL, Fredericks WR, Rapoport S. Entry of bilirubin into brain due to opening of
the blood-brain barrier. Pediatrics. 1982;69:255–259.
"The blood-brain barrier is a complex regulatory interface which strictly
controls passage of substances from cerebral vessels into the brain itself."
[p256]
"Experimentally, the barrier can be reversibly opened by several
techniques, including hypoxia! ischemia,ı#{176} hypertension,2’ and
hyperosmolality.22 We used osmotic opening in the studies reported here.
With this technique, hypertonic solutions reversibly open the blood-brain
barrier of one hemisphere." [p256]
"RESULTS: Yellow staining was prominent on the side of the brain infused
with arabinose to open the blood-brain barrier (Fig 1). The control side
showed little staining, and that seen was consistent with hemispheric
crossover of the arabinose, as noted previously. 22 Although somewhat
diffuse, the staining was not uniform, being consistent with regional
differences noted in human kernicterus." [p257]
"The kernicterogenic effect of sulfisoxazole is still most simply and elegantly
explained by the free biirubin mechanism discussed in the introduction.
Stifi, it remains possible that sulfaniamides act by opening the blood-brain
barrier.6’28" [p258]
"We consider it possible that blood-brain barrier damage leads to
kernicterus in the jaundiced neonate, especially in the asphyxiated or
otherwise ill baby." [p258]
"(Other toxic substances may also enter the brain, but they could go
unnoticed if they are colorless.)" [p258]
Breakdown of the barrier in the jaundiced newborn also permits mixing of
the cerebral and extracerebra! compartments. This would cause a
decrease in the serum bilirubin concentration, a phenomenon sometimes
noted to occur at the onset of kernicterus. pp[257-258]
Levine RL: Bilirubin: Worked out years ago? Pediatrics 64: 380, 1979
"The evidence is strong, but not conclusive, that bilirubin is the toxic
substance causing neural damage. However, it may be that bilirubin is only
a colorful marker of some other damaging event. For example, assume that
damage to the blood-brain barrier is the primary mechanism. Upon opening
of the barrier, bilirubin and many other compounds will gain access to areas
of the brain from which they are normally excluded." [p383]
5 July 07 - Kernicterus and drugs
Another paper on drugs and kernicterus:
Walker PC. Neonatal bilirubin toxicity. A review of kernicterus and the implications of
drug-induced bilirubin displacement. Clin Pharmacokinet. 1987 Jul;13(1):26-50.
Kernicterus, the primary manifestation of neonatal bilirubin toxicity, remains an
important complication of unconjugated hyperbilirubinaemia despite advances made
with phototherapy and exchange transfusions. It results from the penetration of
bilirubin into neuronal tissues of the CNS with subsequent damage to the
mitochondrion. A number of factors may modify or potentiate bilirubin toxicity,
including drugs administered to the infant. The importance of drug-bilirubin
interactions in the pathogenesis of kernicterus was first realised quite inadvertently in
the 1950s, and the potential risk for significant drug-bilirubin interactions has since
become an important consideration in neonatal drug therapy. All drugs intended for
use in newborn infants should be evaluated for their capacity to displace bilirubin. A
number of techniques have been developed which have facilitated investigation of
the mechanisms mediating the bilirubin-displacing effects of drugs and the
pharmacokinetics of drug-bilirubin interactions. Further, the clinical risk for inducing
kernicterus has been investigated for many of the drugs to which neonates may be
exposed by direct administration, transplacentally, or through breast milk. This review
summarises the available knowledge concerning the physicochemical properties and
toxicities of bilirubin, reviews the methodologies used in evaluating drug-bilirubin
interactions, and focuses on the mechanisms, pharmacokinetics and clinical
significance of the bilirubin displacing effects of antibiotics, anticonvulsants, diuretics,
and other important drug classes used in the treatment of neonates.
6-10 July 07 - Milieu research, privatization turmoil
Yesterday a huge group of new nurses and mental health workers were being given
the tour of Bridgewater State Hospital, and hopefully they will be able to start
working soon. The new contractor (MHM Correctional Services) had only one
month from when they were awarded the contract to when they took over on July 1.
I have been working many overtime hours since last Friday, between four units,
infirmary, intensive treatment unit, and admissions building units. Following patient
movements through these units has been most interesting, at the same time
pondering how many involuntary actions may be related to the behavioral problems
of so many of our patients -- tics, seizures (and possible seizure related motor
signs), Tourette-like outbursts, and Parkinson symptoms.
More later on some of these patients, some of whom appear to have good insight
into their developmental problems, and not afraid to make statements like, "I'm
certified MR," i.e retarded. Family visits and phone calls especially helpful for many
patients in the past few days.
11 July - Alex F. Robertson on errors in neonatology
In progress -- looking up citations in papers by Alex F. Robertson, on sulfisoxazole
(Gantrisan), the blood brain barrier and kernicterus, and other interesting
long-forgotten problems:
Robertson AF. Reflections on errors in neonatology: I. The "Hands-Off" years, 1920
to 1950. J Perinatol. 2003 Jan;23(1):48-55.
Robertson AF.Reflections on errors in neonatology: II. The "Heroic" years, 1950 to
1970. J Perinatol. 2003 Mar;23(2):154-61.
Robertson AF.Reflections on errors in neonatology III. The "experienced" years,
1970 to 2000. J Perinatol. 2003 Apr-May;23(3):240-9.
12 July 07 - People not laughing any more
Still tired from my last 16-hour shift, Tuesday, and hoping I won't end up in a
crash with a GOD (Guaranteed Overnight Delivery) truck on my way home at
midnight one of these times. I keep saying I'm ready for a swivel chair job in
an insurance company -- I do hope actuarial scientists are at work on how to
provide for the increased cases of autism in need of life-long assisted living,
and that they might demand more than the gene-gene interaction kinds of
research, funded by NIMH in academic institutions.
I signed up at our local Career Source job center yesterday, and went back
today for a seminar on Career Exploration. So many people out of work, or
working at minimum wage, and still trying to pay off college loans in their
forties and fifties.
One young woman at a computer terminal became upset that two of us were
chatting outside the seminar room, and distracting her efforts to use the Excel
tutorial. The center closed at 4:30, and as we left, this same very attractive
young women hissed at me, "I'm not laughing. If you think I'm laughing at you,
go sign up to see the psychologist in there. I have nothing to laugh about
any more." Wow, and I thought I've been dragging around sad all these
years over having sons with autism -- maybe she's dealing with that too. Too
many people are.