Die Struktur von Tadalafil erlaubt eine selektive Bindung an die Bindungsstelle der PDE5 und minimiert gleichzeitig die Interaktion mit PDE6, was visuelle Nebenwirkungen einschränkt. Seine Verteilung im Organismus erfolgt breit, wobei das Verteilungsvolumen etwa 63 Liter beträgt. Über 90 % des Wirkstoffs sind an Plasmaproteine gebunden. Die Wirkung bleibt unabhängig von der Nahrungsaufnahme konstant. Der Abbauweg über CYP3A4 kann durch Hemmer wie Ritonavir oder Ketoconazol verlangsamt werden, was die Plasmakonzentrationen deutlich erhöht. In diesem Kontext wird cialis 20mg preis häufig in Bezug auf pharmakokinetische Wechselwirkungen erwähnt.
Microsoft powerpoint - 2012 blackburn handout (part 2).pptx
Case: Early Preterm Infant (23 5/7 weeks)
• 560 gm male delivered via NSVD after 1 course
celestone. Apgars 2, 3, 6 and 7 at 1, 5, 10, 15 min
• Intubated in delivery room and placed on HFOV (very
• On DOL 129 was placed on room air.
Case: Early Preterm Infant (23 5/7 weeks)
• Retinopathy of prematurity: grade 3, left eye; grade
• Given a trial of food; developed rectal bleeding
abdominal distension , NEC (surgery with
• At DOL 4 he developed seizure activity (currently
• Neurulation/proscencephalic development (3-12 weeks)
• Organization (6 months to post birth)
• Myelinization (8 months to post birth)
• Neuronogenesis (2-4 months) fol owed by
– Development and closure of the neural tube
proliferation of glia and derivatives (5-8 months)
• Anencephaly, Spina bifida• Encephalocele
• Prosencephalic development (2-3 months)
• May be associated with alcohol, cocaine, radiation, maternal
– Early development of the brain and ventricular system
• Associated with growth disturbances • Associated with chromosome and neurocutaneous disorders
“Moving Cel s to Their Proper Location”
• CNS develops capacity to act as an integrated
whole and for different areas of the brain to talk
– Hypoplasia/agenesis of corpus cal osum
with each other and to other areas of the body
– Gyral anomalies – Radial glia act as guide-wires from germinal matrix to
• Enhanced by neurotransmitters, trophic factors,
• Initial migrating cel s travel to end of guide-wires
• Subplate neurons (maximal: 22-36 weeks)
(Medja et al in Sizun & Browne, 2005; Volpe, 2008)
• Making different types of glia such as
– Growing axons and dendrites to link nerve cel s
• Rapid proliferation from 24-32 weeks (peak 26 weeks)
– Developing synapses (points of communication)
• Found primarily in deep cortical layers and white matter
• Al ow brain to integrate and organize information
• Assist with axonal guidance, growth, brain structural
development, and functioning of blood-brain barrier
• Initial y overproduction • Later many eliminated based on early environment and
experiences and remaining stabilized and strengthened
• Premyelinization period (to ~32 weeks) = especial y
• Genetic control but influenced by environmental events
• Continue to develop throughout life (basis for learning and
– Microglia (brain macrophages-probably derived
• Removing excess elements (programmed cel
• Altered function, integration and learning
• Potential bases for organizational disorders
– Elimination of 15-50% of neurons (in various brain
– Abnormal chromosomes (Down, fragile X)– Perinatal insults (hypoxia, infections)
• Myelinization (prebirth to post birth)
• Myelin produced by glia and wraps around axon
– Delayed myelinization, white matter defects
• Neurosensory developmental processes and
• Hypothyroidism• Amino and organic acidopathies (example: PKU, MSUD)• Prematurity (white matter injury)
– Local control of brain blood flow modifying resistance to
compensate for changes in pressure, sustaining
• Fine balance between cerebral ischemia and potential
– Factors mediating AR present in fetal and neonatal
– Range of AR narrower, less able to limit CBF with
• Hypoxemia, hypercarbia, acidosis further alter AR
– CBF becomes pressure-passive (so rise in BP results in increase
• CBF close to level at which oxygen and nutrient delivery is
• Activities that lead to hypoxemia or increased BP
• Blood brain barrier: tight junctions between endothelial
cel s of brain capil aries and epithelial cel s in the choroid
• Protects developing brain but not ful y developed at
– Protective “barrier” to prevent proteins and other substances in
• May damage newborn brain where would not adult
• Free bilirubin enters brain and in presence of
– Maintains electrolyte homeostasis of brain
hypoxia damages basal ganglia (kernicterus)
– Detoxifying enzyme systems to metabolize lipid soluble
substances that would normal cross barrier
• Break down with injury or infection; temporarily
– Transport systems to move required water soluble substances
disrupted by sudden marked increases in BP or
• Neuropathology consists of multiple lesions
• Vulnerable to periventricular/intraventricular hemorrhage
related to CNS vulnerabilities including:
• Usual y preterm (<1500 grams, <34 weeks)• History of hypoxia, birth asphyxia, RDS
– Severe germinal matrix-intraventricular hemorrhage
• Altered venous return, increased venous pressure
– Timing: 90% occur within first 2 days; 10% later
• With periventricular hemorrhagic infarction
– Usual site: germinal matrix at head of caudate nucleus
– Periventricular leukomalacia (PVL) and accompanying
• Rupture into lateral ventricles then into 3rd and 4th• Blood col ects in subarachnoid space, basal cistern
neuronal/axonal abnormalities (“encephalopathy of
• Ventricular dilation may occur due to obstruction of CSF flow
• If severe, blood also in white matter due to associated hypoxic-
– Periventricular blood flow– Cerebral autoregulation
– Lack of vessel support– Fibrinolytic activity
Glial Cel s: Roles and Vulnerabilities in
Glial Cel s: Roles and Vulnerabilities in Preterm
Preterm Infants (Sizun & Browne, 2005; Volpe, 2008)
Infants (Sizun & Browne, 2005; Volpe, 2008)
– Rapid proliferation from 24-32 weeks (peak 26 weeks)
– Form found primarily in deep cortical layers and white
– Premyelinating period (to ~32 weeks) = especial y
– Assist with axonal guidance, growth, brain structural
development, and functioning of blood-brain barrier
– Can release transmitters (like glutamate) to send signals to
– Specific territory and may interact with several neurons and
– If activated with PVL, lead to cel ular injury initiated by
hundreds to thousands of synapses to integrate
ischemia and inflammation (mediated by ROS, cytokines,
Encephalopathy of Prematurity (Volpe, 2009)
• Primary destruction of brain tissue (PVL)
• Most common: white matter injury (PVL) accompanied
• Focal necrotic lesions deep in white matter with loss of al
• Termed: “Encephalopathy of Prematurity”
– Cystic form: lesions are several mm or more and evolve
– Noncystic form: lesions are microscopic and evolve to
• Leading cause of neurological disability in preterm
• Diffuse injury in central cerebral white matter with damage
to pre-OLs, astrogliosis, microglial infiltration
• Motor, cognitive, learning, behavioral sequelae
Factors Increasing Risk of WMI in Preterm
Infant (Back, 2006; Brussen & Harry, 2007; Khwaja & Volpe, 2008)
• Secondary developmental disturbances
(associated axonal/neuronal alterations in gray
• Interaction of 3 maturation-dependent factors
– Immature vascular supply to WM = reduced O2
– Cerebral WM (axons and subplate neurons)– Thalamus
– Impairments in cerebral autoregulation
– Vulnerabilities of premyelinating oligodendrocytes
to damage from free radicals, excess glutamate,
Potential Clinical Correlates of Cerebel ar
Abnormality in Premature Infants (Volpe, 2009)
• One of later brain structures to mature
• Acts as a node in distribution of neural networks with
– Spectrum from incoordination to overt ataxia (“mixed cerebral
interconnections with thalamus, parietal and prefontal
– Deficits in motor planning and execution
• Important in cognition; damage can alter language
development, behavioral function, cognitive function (Riva
– Involving visual-spatial abilities, verbal fluency, reading,
• Series of developmental events occur at end of
2nd/beginning of 3rd trimester that are essential for
• Involving regulation of shifts in attention Social/affective
the structural and functional integrity of the
• Mood abnormalities, autistic behavior
• Development of the neocortex (especial y 22 to
– Developing axons and dendrites to link nerve cel s
(neuron differentiation and arborization)
– Glia differentiation)– Developing synapses or points of communication
– Balancing excitatory and inhibitory synapses
– Removing excess elements and refining synapses
• Somatosensory (tactile and proprioceptive)
• Lack of competing stimuli during rapid
• Out-of sequence stimulation of one system
• Responsiveness to a stimulus does NOT imply it
was received, perceived, needed, or beneficial
• Shift from fluid and tissue conducted sound to air
– Fluid an bone conducted sound in utero
• Intrauterine sounds of low frequency and
– Low frequency (20-200 Hz) sounds predominate
– Attenuated by passing through tissues, fluid
• Differences between NICU and intrauterine
– Uterus relatively quite (recent studies)
– Frequencies paral el cochleal development
– Intrauterine sounds: Low frequency and intensity
– Extrauterine sounds: Across range with higher
• Shorter external canal increases resonance of
• Rapid maturation of cochlea and auditory nerve
• Rapid maturation of cochlea and auditory
• Initial auditory processing by 30 weeks
• Threshold 40 db, increased frequency range
• Increased speed of conduction to term
• Ossicles and electrophysiology complete by 36
• Hearing threshold 30 db, increasing range
• Altered ability of brain to interpret and integrate
• Increasing ability to localize and discriminate
– Interaction of hearing and language development
• Visual system primarily subcortical in newborn
– Gross structures in place by 23-24 weeks
• Gradual y becomes more integrated with increasing
– Extensive maturation and differentiation active until
• Neurosensory maturation influenced by visual
– Initial y endogenous (22-40 weeks) from retinal waves
– Later exogenous to refine eye structure, retinal to cortex
connections, maturation of primary visual cortex
Visual System Development In Preterm Infants
Visual System Development in Preterm Infants
at 24-28 Weeks (Adapted from Glass, 2005)
at 28-34 Weeks (Adapted from Glass, 2005)
• Lens: clearing, second layer complete, third forming
• Lens: cloudy, second of 4-layers forming
• Retina: rod complete except for fovea by 32 weeks,
• Retina: rod differentiation by 25 weeks; vascularization
• Visual cortex: rapid dendritic, synapse development
• Visual cortex: rapid dendritic growth
• Bright light causes sustained eyelid closure
• Eyelid tightening to bright light but quickly fatigues
• Abrupt reduction may cause eye opening
• VER to bright light but quickly fatigues
• Pupil ary response sluggish but more mature
• Spontaneous eye opening, brief fixation in low light
Visual System Development in Preterm Infants
• Pupils: complete pupil ary reflex by 36 weeks• Retina: cone numbers in fovea increase; Blood vessels
• Structural and growth alterations of the eye seen
• Visual cortex: morphological y similar to term• Increased alertness, less sustained than term
• ER resembles that of term infant with longer latency
• Spontaneous orientation toward soft light
• Beginning to track, show visual preferences• Less myopic
Comparison of Sensory Development to Sensory
Exposure in NICU (White-Traut et al., 1994)
• Alterations in vision function seen in preterm
Sensory Development NICU Sensory Exposure conception continuous moderate minimal
– Visual acuity, color vision, contrast sensitivity
VESTIBULAR VESTIBULAR
• Visual attention, pattern discrimination
OLFACTORY OLFACTORY
• Visual recognition memory, visual-motor
GUSTATORY GUSTATORY AUDITORY AUDITORY
• Biological y meaningful• Only if medical y stable, no recent care changes
• Introduce gradual y in order of development
http://www.marchofdimes.com/modpreemie/preemie.html
• Monitor responses, tolerance and modify• Support, not accelerate, normal maturational
• Ability to respond does not mean should stimulate• Model of optimal stimuli for early development
• Disorder that interrupts the normal vascularization
• Mainly a disease associated with prematurity,
• incidence and severity increase with decreasing
• Most cases of ROP resolve spontaneously, but
even with complete resolution, scarring of the retina
• Al infants with immature fundi or any stage of ROP
require close monitoring until the eyes have
matured or the ROP has completely resolved
• Retinal vascularization on internal retinal
surface begins at optic nerve at 16 weeks'
gestation and proceeds anteriorly; reaches
• 1984 and 1987 International Classification of ROP:
edge of the temporal retina at 40 weeks’
• Vascular endothelial growth factor (VEGF) is
a key factor in the progression of retinopathy
• Laser and cryotherapy destroy the majority of
the cel s that produce VEGF in the retina
Retinopathy of Prematurity Stages 1 and 2
Stage 4 - Partial retinal
• Stage 1 - demarcation line • Stage 2 – ridge of scar Stage 3 - Increased size Stage 5 - Complete retinal
Risk of Progression to Retinal Detachment
• Engorgement and tortuosity of blood vessels
• Growth and dilation of abnormal blood vessels
– Zone II, “plus disease” with stage 1, 2
on the surface of the iris, rigidity of the iris, and
– Stage 3 with 5 continuous clock hours or 8
• Can accompany any stage, but indicates
greater likelihood of progression to Stage 3 (or
• Infants with resolving (incompletely resolved) ROP need
careful fol ow-up because some revert to active disease.
• Sequelae depend on the extent of retinal scarring• Up to 80% of stage 3 ROP resolves spontaneously
without significant scarring; even in with ful y regressed
ROP, there may be subtle retinal changes resulting in
refractive errors, strabismus, or amblyopia
• Infant left with moderate scarring can experience retinal
tears, late retinal detachment, nystagmus, glaucoma,
cataracts, vitreous hemorrhage or membranes, and
severe scarring that can lead to blindness
• Frequency inversely proportional to GA and BW
• As high as 80% of infants <1000 g; 10-15% of
• DA connects main PA with aortic arch 5-10 mm
– High amounts of circulating prostaglandins,
• Medial tissue consists of dense layers of smooth
• PGE2 and PGI2 formed within wal of DA
• In fetus, 92-95% of VRV outflow shunted across
• Prostaglandin metabolized through lungs, so in utero
PDA to descending aorta (by passing pulmonary
levels are increased because of decreased pulmonary
• Removal of low-resistance placenta/lung inflation• Decreased PVR/increased SVR
• DA: thin wal ed, less likely to undergo ischemia-hypoxia–
stimulated remodeling unless BF completely ceases
• Less likely to constrict with birth due to the presence of
immature myosin isoforms, less responsiveness to oxygen
• Results in smooth muscle constriction of DA
inhibition, higher circulating PGE2 l(decreased clearance
• Functional closure in healthy term by 24-96 hours
by the immature lungs), increased sensitivity to the
• Anatomic closure by 2 to 3 months via ischemia-
• Thus agents such as indomethacin and ibuprofen, which
inhibit prostaglandin synthetase and thus prostaglandin
production, are effective in closing the ductus
• Hemodynamic shunting: degree determined by:
• Increased flow through the lungs with diastolic
– Pressure differences between aorta and PA
– Systemic and pulmonary resistances.
• Increased flow through the left atrium, LV, and
• Shunting left to right through ductus causing murmur and
• Left-to-right shunting to the pulmonary
• Reduced BF to gut, kidneys, spleen, skeletal muscle, skin
– Blood shunted from upper and lower aortic
• Activation of rennin-angiotensin aldosterone system
circulations with a large ductus and multiorgan
• Cardiac failure, shock, metabolic acidosis
• Most commonly acquired gastrointestinal
• Characterized by necrosis of the mucosal and
• Variable incidence; cases often cluster• 90-95% of cases are in preterm infants (<34 wks
• ~10% infants < 1500 grms (2 – 22%)• Most commonly involves the ileum and colon but
• Mildly il (temperature, apnea, lethargy)
• Prematurity (umbilical lines, low Apgar scores, PDA, )
• Mild GI signs (residuals, abdominal distention, heme positive
• Vasoconstrictive drugs (cocaine, indomethacin,
• Minimal x-ray findings (normal, dilation, ileus)
• More clinical findings (mild acidosis, mild thrombocytopenia)• More GI signs (absent bowel sounds, abdominal tenderness)
• More x-ray findings (pneumatosis, portal gas)
• Severe clinical il ness (hypotension)
• Congenital heart disease, arrhythmias
• Increased GI signs (marked abd distention, tenderness, signs
• Ominous x-ray findings (ascites, free air)
Major Factors Associated with Pathogenesis
– Decreased mesenteric BF with apnea, PDA, ECMO,
– Immature mucosa, with looser epithelial cel tight junctions
– Hypoxia-ischemia damages bowel mucosa
– ELBW infants have decreased number of bacterial species
– NEC occurs almost exclusively after enteral feedings
– Further decreased with antibiotic use
– Slow careful increases may decrease NEC incidence
– Decreased colonization with Bifidobacteria/Lactobacil us
– Incidence is lower in infants fed breast milk versus
– Breast milk increases the diversity of bacterial species
– Breast mils contains immunoprotective factors
– Levels increased in NEC, after formula feedings
• Seizures are a sign of neurologic dysfunction
and underlying disease process, not a disease
• Most frequent neonatal neurologic sign
– Usual y acute, disappear in few weeks– Recurrent/chronic = increase risk of sequelae
Difference in Seizure Activity in Neonates
– Alter Na+ and K+ across neuronal membrane
– Inability to propagate systemic general seizure
– Depolarization unbalanced by repolarization – Hypoxemia, ischemia, hypoglycemia
• Lack of arborization and synaptic connections
• Alteration in permeability of neuronal membrane
– Lack of arborization and synaptic connections (i.e.
“wiring” to recruit other neurons to fire in synchrony)
– Hypocalcemia, alkalosis, hyponatremia
• Excess excitatory vs inhibitory neurotransmitter
– Severe asphyxia, altered liver function
– Harder for neurons to fire rapidly and repetitively
Difference in Seizure Activity in Neonates
• More inhibitory synapses than excitatory
– Reduces chance that generalized seizure wil be
– Protective but countered by excesses glutamate and
• Seizures more likely to be generated in more
– In gyri and above corpus cal osum– Temporal lobe and limbic areas most mature
• Involved in sucking, drooling, chewing, oculomotor deviations
• Multifocal clonic (more term since are cortical)
– Rhythmic, jerky, clonic movement of 1 or more
• Bhutta, A.T. & Anand K.J.(2002). Vulnerability of the developing
brain: neuronal mechanisms, Clinics in Perinatology, 29, 357–372
• Blackburn S.T. (2012). Maternal, fetal and neonatal physiology: a
• Focal clonic (less common, mostly in term)
clinical perspective (4th Edition). St. Louis: Saunders.
• Blackburn, ST. (2009). Central nervous system vulnerabilities in
– Localized clonic jerking, usual y to 1 limb or face
preterm infants, part I. Journal of Perinatal & Neonatal Nursing,
– Associated with traumatic CNS injury, severe
• Blackburn, ST. (2009). Central nervous system vulnerabilities in
• Myoclonic (less common, rare in preterm)
preterm infants, part II. Journal of Perinatal & Neonatal Nursing, 23
– Single/multiple jerks with flexion of arms or legs
• Blackburn, S. T. & Ditzenberger, G. (2012, in press). Neurologic
system. In C. Kenner & J.W. Lott (Eds.), Comprehensive neonatal
– Seen with inborn errors, other metabolic problems
care: an interdisciplinary approach (5th Edition). NY: Springer.
• Deng W. (2010). Neurobiology of injury to the developing brain.
• Khwaja, O. & Volpe, J.J. (2008). Pathogenesis of white matter
injury of prematurity. Arch Dis Child Fetal Neonatal Ed, 93, 153-
• Glass, P. (2005). The vulnerable neonate and the neonatal
intensive care environment. In M.G. MacDonald, M.M.K. Seshia &
• Limperopoulos, C. (2010). Advanced neuroimaging techniques:
M.D. Mul ett, M.D. (Eds.). Avery’s Neonatology: pathophysiology
their role in development of future fetal and neonatal
and management of the newborn (6th ed.). Philadelphia: Lippincott,
neuroprotection. Semin Perinatol, 34, 93-101.
• Limperopoulos, C. (2010). Extreme prematurity, cerebel ar injury
• Gleason CA & Devaskar S. (2012). Avery's diseases of the
and autism. Semin Pediatr Neurol, 17, 25. newborn (9th ed.). Philadelphia: Saunders.
• Mercuri, E., Baranel o, G., et al. (2007). The development of vision,
• Graven, S.N. (2004). Early sensory visual development of the fetus
Early Human Development, 83, 795-800.
and newborn. Clinics in Perinatology, 31, 199-216.
• Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2011). The
• Greisen, G. (2009). To autoregulate or not to autoregulate-that is
developing human: Clinical y oriented embryology (9th edition.).
no longer the question. Semin Pediatr Neurol, 16, 207-215.
• Noori, S. (2010). Patent ductus arteriosus in the preterm infant: to
• Volpe, J.J. (2008). Neurology of the newborn (5th Edition).
treat or not tot treat? J Perinatol, 30 (Suppl), S31-S37.
• Philbin, M.K. (1996). Some implications of early auditory
• Volpe, J.J. (2009). The encephalopathy of prematurity-brain injury
development for the environment of hospitalized preterm infants.
and impaired brain development inextricably entwined. Semin
• Rennie, JM, & Boylan, GB. (2009). Seizure disorders of the
• Volpe, J.J. (2009). Cerebel um of the premature infant: rapidly
neonate. In M. I. Levene & F. A. Chervenak (Eds.), Fetal and
developing, vulnerable, clinical y important, J Child Neurol, 24,
neonatal neurology and neurosurgery (4th ed. Edinburgh:
• Volpe, J.J., et al. (2011). The developing oligodendrocyte: key
• Rivera JC, et al. (2011). Understanding retinopathy of prematurity
cel ular target in brain injury in the premature infant. Int J Dev
• Sizun, J. & Browne, J.V. (2006). Research on early developmental care in preterm neonates. John Libbey
Internet Journal of Medical Update 2010 January;5(1):35-41 Internet Journal of Medical Update Journal home page: http://www.akspublication.com/ijmu Review Article Proteomics: an evolving technology in Laboratory Medicine Dr. Javed Akhter*Ψ PhD, Dr. Waleed Al Tamimi* PhD, Dr. Abubaker El Fatih* FRCPath and Dr. D J Venter† MD *Department of Pathology and Laboratory Medic
Specifications Trimble SPS555H Heading Add-on Receiver Receiver Name SPS555H Heading Add-on receiver Configuration Option Vacuum Fluorescent display 16 characters by 2 rows. InvertableEscape and Enter keys for menu navigation4 arrow keys (up, down, left, right) for option scrolls and data entry24 cm × 12 cm × 5 cm (9.4 in x 4.7 in x 1.9 in) including connectors1.55 kg (3