Vitamin Information Center

Central Nervous System
The central nervous system (CNS) represents the largest part of the nervous system and consists of the brain and the spinal cord. The CNS and the ► peripheral nervous system (PNS) have a fundamental role in the control of behavior. The CNS acts as the main “processing center” for the entire nervous system and is responsible for the integration of all nervous activities.

After successful mouse models and studies that showed that Vitamin B3 can help reduce Alzheimer’s symptoms and lesions, Dr. Frank LaFerla, UC Irvine scientist and principal investigator of the experiment and Dr. Kim Green, lead author of the study and project scientist for the LaFerla lab, are now actively recruiting for patients to carry out a human clinical trial that is being funded by the Alzheimer’s Association.

The intention of these tests is to confirm that the vitamin’s effect in mice correlate with those who have Alzheimer’s disease (a neurodegenerative disease that contributes to memory loss).

Green points out that the lab selected Vitamin B3 due to its pharmacological properties to promote living longer successfully, rather than because it is a vitamin. Therefore, the lab uses vitamin B3 at far higher doses than required for its use as a vitamin.

LaFerla first noticed Vitamin B3’s effectiveness in treating Alzheimer’s disease while his lab collaborated with UCI doctors Leslie Thompson and Joan Steffan. They showed that the drug class was therapeutic in models of Huntington’s disease (a type of neurological disorder) and LaFerla thought it would be worth evaluating the vitamin in his mouse models of Alzheimer’s.

“The studies done in our mouse models suggest that the compound can help reduce some selective aspects of Alzheimer’s pathology and improve the cognitive phenotype,” LaFerla said.

Vitamin B3 aids in protecting the central nervous system. In their study of mouse models, the vitamin noticeably reduced tangles of a protein called Tau, while not affecting levels of protein beta amyloid (a waxy translucent substance consisting primarily of protein that is deposited in some animal organs and tissue under abnormal conditions). Both cause a clogging of brain cells which lead to Alzheimer’s lesions. LaFerla also noted that Vitamin B3 can also improve a normal person’s memory.

LaFerla pointed out that the main advantage of Vitamin B3 is that it is a “safe compound that is widely available.” Vitamin B3 is water-soluble, sold over-the-counter and is cheap. It currently helps people with diabetes complications and also those who have certain skin conditions since it contains anti-inflammatory properties. The compound can also be found in foods such as chicken, fish, peanuts, pork, salmon, sunflower seeds, tuna, turkey and veal.

The drawback of Vitamin B3 is that it can be poisonous in high doses, but has only been tested on mice and has not yet been tested extensively on humans.

Past research has indicated that Vitamin E, Vitamin C and Vitamin B12 can also reduce Alzheimer’s. However, LaFerla is not sure whether Vitamin B3 has an additive effect with the other drug compounds or if it will work with the other vitamins or substances that were researched previously.

Green notes that Professor Steve Schreiber of neurology is heading the human clinical trial at UCI. Patients enrolled have mild-moderate Alzheimer’s disease, and will be treated with high doses of Vitamin B3 for six months, while their cognitive abilities are being measured. They will receive 1500 mg twice daily. It is not recommended that anyone else take this high dose, as patients in the trial will be monitored for any adverse side effects.

“These studies have not yet been done, but it is my own personal belief that combination therapies will be the most effective way of treating Alzheimer’s disease in humans,” LaFerla said.

Presently, medical treatment of Alzheimer’s disease is limited and no known cure for Alzheimer’s disease exists.

Acute Life-Threatening Infections
MONIKA KORN
Klinik für Kinder und Jugendmedizin,
Friedrich Ebert Krankenhaus,
Neumünster, Germany
hkorn80663@aol.com
Synonyms
Highly dangerous infectious diseases; Infectious diseases
with a critical course
Definition
Acute life-threatening infectious diseases are characterized
by the fact that they can take a lethal course within
a few hours or a couple of days. The pathogens or their
toxins can cause a cardiocirculatory shock, a failure of
the functions of the central nervous system, respiratory
insufficiency or multiorganic failure.
Basic Characteristics
Reasons for Life-Threatening Courses of Infections
Whether an infectious disease takes a life-threatening
course or not, depends on various factors. The severity of an infection is determined by the virulence of
the pathogens and the organs or organic systems that
are involved; deadly courses have to be feared in cases
where impairment of vital functions or multiorganic
failure occur. The development of serious infections
is facilitated by a weakened immune status or underlying
(chronic) disease. Further important aspects are
the prophylactic and therapeutic possibilities. Avoidable
severe or even deadly courses can occur due to
a neglect of preventive measures, especially due to
missing active vaccinations ( immunization, active).
Other reasons for a treatable disease taking a lethal
course can be a lack of effective drugs (due to a shortage
of resources), or the late onset of therapy. The quick
introduction of treatment is highly significant in cases
of infections with toxin-building germs, like tetanus,
 anthrax infection and  gas gangrene. If there is no
therapy against a number of infecting organisms or their
toxins one has to be prepared for a lethal outcome.
 Hemorrhagic fevers belong to this category of infectious
disease.
Sepsis
A sepsis is an inflammatory reaction, which involves
the whole organism (SIRS=systemic inflammatory
response syndrome). Characteristic symptoms are bacteremia,
tachycardia, abnormal rapid breathing (tachypnea),
a changed body temperature (fever or hypothermia)
as well as changes in white blood cell count
(> 12/nl or < 4/nl). The various pathogens have typical
places of entrance, like wounds, the respiratory,
the urinary or the gastrointestinal tracts. From there
they reach the circulatory system and spread into other
organs. In 70–80% cases of sepsis, gram-negative
bacteria are responsible, and in 20–30% gram-positive.
Poisons (toxins), which are set free by the bacteria, play
an important role in the course of the sepsis. During
the destruction of gram-negative germs endotoxins are
released, and in the case of gram-positive pathogens
exotoxins are released. Staphylococci are responsible
for the  staphylococcal toxic-shock syndrome (TSS)
and streptococci for the  streptococcal toxic-shock
syndrome (STSS). In sepsis, substances, which mediate
inflammations (cytocines, interleukines), start a cascade
process that leads to a condition of life-threatening
shock. A complex impairment of immunological,
endocrinological, cardiovascular and metabolic functions results. Uncontrollable cardiocirculatory problems
(extreme decrease of blood pressure), serious
coagulation defects (consumption coagulopathy, disseminated
intravascular coagulation = DIC) and organic
failure of the lungs and kidneys are responsible
for the lethal course of septic shock. Besides
combined antibiotic treatment, surgical interventions
(drainage of abscesses, removal of necrotic material)
as well as intensive care measures (intravenous substitution
of volume deficits, cardiocirculatory therapy,
application of oxygen, mechanical ventilation) may
be required. A typical example of an infectious disease
leading to septic shock is meningococcal sepsis,
which is also known as Waterhouse-Friderichsen syndrome.
Encephalitis
Encephalitis is the inflammation of brain tissue. Most
frequently, the pathogens reach the brain via the blood
vessels (hematogenic); some germs can also get into
the central nervous by nerve tracts. Besides fever and
headache, impairment of central nervous functions,
cerebral seizures, neurological failure (pareses), impaired
consciousness or changes in behavior are all possible
symptoms of encephalitis. Therapy depends on the
pathogen responsible. Even if treatment is possible and
the course of the infection is not lethal, encephalitis is
always a serious condition. Neurological defects can
persist, which is not only a severe burden for the patient
and his relatives but also may lead to the need for costly
follow-up treatments. An extremely dreaded infection
is herpes-simplex encephalitis Without treatment,
it takes a lethal course in about 70% of cases. Prognosis
depends on the level of consciousness at the onset
of therapy. A lethality of 20–50% has to be assumed in
cases of Japan encephalitis. The prognosis is also bad
when encephalitis occurs as a complication of malaria
or  measles.
Meningitis
Meningitis is an inflammation of the membranes that
envelop the central nervous system. Diagnosis is confirmed
by an examination of cerebrospinal fluid. In general,
the micro-organisms come from the nose-throat
area and reach the meninges from the blood vessels. In
most cases, the course of a viral meningitis is not harmful.
Of the bacterial inflammations of the meninges 60–70% occur in childhood. In newborns, impaired breathing
is the most conspicuous symptom. In older babies,
fever, vomiting and agitation predominate. From the
age of one year, meningitis is characterized by fever,
headache, vomiting and nuchal rigidity (meningism);
cerebral seizures and an impairment of consciousness
can appear. Bacterial meningitis demands antibiotic
therapy; from the age of four weeks, ceftriaxone,
a 3rd generation cephalosporine, is the preferred
form of treatment. Even though a great number of
pathogens can cause meningitis, after the seven weeks
of age only three pathogens are of clinical relevance:
Neisseria meningitidis (meningococci), Streptococcus
pneumoniae (pneumococci) and Haemophilis influenzae
type B (Hib). Pneumococci are responsible for 6–
20% of meningitis deaths; meningococci or Hib cause
less than 5%. Possible long-term effects are impaired
hearing, impaired motor and neurophysiological development,
cerebral seizures and pareses.
Tetanus
Tetanus is caused by Clostridium tetani, a toxin- and
spore-building bacterium, which exists worldwide and
is found in the soil. Usually, infection is due to dirty
wounds. In newborn babies, the navel is the main route
of entry. Following an incubation period of 3 days to
3 weeks, in newborns after a short interval, tetanus
infection is primarily characterized by muscular spasms
and increased muscle tonus. The mouth cannot be
opened completely, and a characteristic facial expression
results, called “risus sardonicus”. The cardiac muscle
is damaged. Furthermore, hyperactivity of the sympathic
nervous system and impairment of carbohydrate
metabolismdevelop.After the onset of the disease, only
 symptomatic therapy can be carried out. To avoid
a further build up of toxins, excision of the wound
has to be performed. Death is primarily due to respiratory
insufficiency and cardiovascular complications.
Although 57 countries are known to have a high risk of
tetanus, 90% of all infections occur in only 27 of them.
The highest incidence of tetanus is found in the Middle
East (Iraq, Yemen), in Africa, South Asia (Afghanistan,
Bangladesh, India, Nepal, Pakistan), East Asia and in
the Pacific region (China, Indonesia, Cambodia). The
risk of a tetanus infection is extremely high if nonimmunized
women give birth to children under insufficient
hygienic circumstances (http://www.who.int/vaccines/en/neotetanus.shtml). Through wounds (for
example, when cutting through the umbilical cord) bacteria
can reach the blood circulation of mothers and
newborn babies. Every year about 250 000 newbornes
and 30 000 women die after birth due to a tetanus infection.
In newborn babies the infection takes a lethal
course in 70%. Thus it is responsible for 14% of deaths
in newborns. Prognosis, depends on the onset interval;
if this interval is less than 24 hours, lethality is 100%.
However, tetanus lethality is also high when the disease
occurs later in life. Depending on the incubation
period, it is 25–60%. The most important prophylactic
measure is active tetanus vaccination ( tetanus vaccination,
active). Under certain circumstances, a passive
tetanus vaccination ( tetanus vaccination, passive) or
a  simultaneous vaccination is indicated. To prevent
tetanus, it is necessary to carry out births under good
hygienic conditions.
Rabies
Rabies is a viral infection with a deadly course, which
is transmitted by the bite of an infected animal or by
contact with contagious spittle. Animals with suspected
rabies, show abnormal behavior: thus pets can be
aggressive, while wild animals appear tame and trusting.
The average incubation time of rabies is 3–8 weeks;
it is shorter in injuries near the head than in those distant
from the head. Initially, the virus affects muscle
cells and then later passes along the nerve tracts to
the brain. Finally, it gets into the salivary glands. In
humans the course of rabies shows three phases. At
the onset of the disease there are nonspecific symptoms
like fever and exhaustion, the area of the bite
is very sensitive to pain. During the following acute
neurological phase, fear and agitation appear as well
as changes in the frame of mind (aggressions, depressions).
As swallowing induces pharyngeal cramps, the
patients become afraid of drinking. To avoid swallowing,
they let the spittle flow out of their mouths. Even
the perception of water – visually or acoustically –
leads to agitation and cramps. This state, which is typical
of rabies, is called hydrophobia (or aquaphobia,
fear of water). During the final phase of the infection
the cramps decrease and progressive pareses inevitably
lead to death. As there is no chance of cure after the
onset of the disease, therapy should begin immediately
after the patient has been bitten by an animal suspected of having rabies. An active ( rabies vaccination,
active), and – if necessary – a passive rabies vaccination
( rabies vaccination, passive), is carried out.
Persons at risk, like veterinarians and hunters, should
receive an active rabies vaccination as a prophylactic
measure. It has to be recommended to be careful
with unknown and, particulary, free running animals
especially, if the animal cannot be caught for examination.
These precautionary measures should also be
taken seriously by travelers in regions with a high
incidence of rabies (http://www.cdc.gov/ncidod/dvrd/
rabies/).
Cross-References
 Anthrax Infection
 Gas Gangrene
 Immunization, Active
 Japan Encephalitis
 Malaria
 Measles
 Rabies Vaccination, Active
 Rabies Vaccination, Passive
 Simultaneous Vaccination
 Staphylococcal Toxic-Shock Syndrome (TSS)
 Streptococcal Toxic-Shock Syndrome (STSS)
 Symptomatic Therapy
 Tetanus Vaccination, Active
 Tetanus-Vaccination, Passive
 Tropical Diseases
 Tropical Diseases and Travel Medicine
Waterhouse–Friederichsen Syndrome
References
Behrman RE, Kliegman RM, Jenson HB (2003) Nelson Textbook
of Paediatrics, 17th edn. W.B. Saunders Company, Philadelphia
Gorbach SL, Bartlett JG, Blacklow NR (2004) Infectious diseases,
3rd edn. Lippincott Williams & Wilkins, Philadelphia
Hay WW, Myron Lewin MJ, Sondheimer JM, Deterding RR
(2005) Current pediatric diagnosis &treatment, 17th edn.Mc
Graw-Hill, New York
Kliegman RM, Greenbaum LA, Lye PS (2004) Practical strategies
in pediatric diagnosis and therapy, 2nd edn. Elsevier
Saunders, Philadelphia
Osborn LM, Thomas DeWitt TG, First LR, Zenel JA (2005) Pediatrics,
1st edn. Elsevier Mosby, Philadelphia
http://www.cdc.gov/ncidod/dvrd/rabies/
http://www.who.int/mediacentre/factsheets/fs114
http://www.who.int/vaccines/en/neotetanus.shtml
http://www.emedicinehealth.com/toxic_shock_syndrome/
article_em.htm

Researchers at Rutgers have unlocked some of the mysteries of how the developing embryo reacts to fluctuations in the amount of vitamin A present in the maternal blood stream. Their results are presented in the February 28 issue of the Journal of Biological Chemistry.

The researchers studied the role of LRAT, a protein that facilitates the formation of vitamin A stores in the body, during embryonic development. In particular, they showed how LRAT protects developing tissues from potentially toxic levels of vitamin A that have been ingested by the mother. Although this function of LRAT had previously been hypothesized in adults, this is the first time that its role has been demonstrated during embryonic development.

The developing mammalian embryo is entirely dependent on the maternal circulation for its supply of retinoids, the vitamin A metabolites produced in the body. These are essential nutrients and they control the formation of the embryo’s heart, central nervous system, eyes and other important organs and tissues. Malformations of the developing embryo can occur when too little, or too much, vitamin A is consumed by the mother.

“We were looking for the mechanisms that allow the fetus to maintain adequate amount of retinoids, whether the mother has over- or under-consumed vitamin A,” said Dr. Loredana Quadro, an assistant professor in the Department of Food Science and member of the Center for Lipid Research at the Rutgers School of Environmental and Biological Sciences. “We also looked at the effects of different levels of vitamin A being transferred from the mother to the fetus.”

When vitamin A is ingested, it is converted into retinyl ester (RE) in the intestine from where it is secreted in the bloodstream packaged with other dietary lipids into lipoprotein particles called chylomicrons. The majority of dietary RE reaches the liver, the main body storage site of vitamin A. Under insufficient dietary vitamin A intake, the liver transforms RE into retinol (ROH), which is then secreted into the bloodstream bound to retinol-binding protein (RBP), its sole specific serum carrier, to be delivered to the target tissues. Upon intake through a specific membrane receptor named Stra6, ROH is ultimately converted to retinoic acid (RA), which is the active form of vitamin A. If tissue RA is in excess, it is transformed into inactive forms, such as 4-hydroxy retinoic acid or 4-oxo retinoic acid (OXO-RA) by the action of a specific enzyme named Cyp26A1.

“When we think about vitamin A, we think about one compound,” said Quadro. “But in reality, the term vitamin A comprises a family of different compounds. Each one has a slightly different action, and plays a different role.”

The Rutgers researchers took a closer look at how ROH is metabolized into RE and RA to maintain an optimal balance of retinoids during the formation of the embryo. Mutant mice lacking both RBP and LRAT were generated to perform this study, so as to interfere with the two main pathways of maternal vitamin A delivery to the fetus (ROH-RBP from the liver stores and RE of dietary origin).

“We hypothesized that the lack of ROH-RBP and LRAT would make the embryo more vulnerable to changes in maternal dietary vitamin A intake,” said Quadro “and our data proved this to be correct. Indeed, a severe embryonic vitamin A deficiency is readily attainable when the mothers are deprived of dietary vitamin A during pregnancy. Therefore, this strain turned out to be a very good model to study how embryonic development is affected by fluctuations in the amount of retinoids present in the maternal diet and hence in the maternal circulation”.

The researchers identified LRAT, Cyp26A1 and Stra6 as the three key molecular players that act in coordination to protect the developing tissues from potentially detrimental levels of vitamin A ingested by the mother. “Understanding vitamin A metabolism in the developing fetus could have broad implications,” said Quadro. “Consumption of large doses of dietary supplements and vitamins, including vitamin A, has become a very common practice in recent years, generating the necessity to investigate the effects of high doses of vitamin A intake at different stages of the lifecycle, including pregnancy and development. These studies expand our knowledge of maternal-fetal nutrition and dietary contribution to embryonic development and may ultimately provide new insight into appropriate dietary practices during pregnancy.”

The paper was previously published on the Journal of Biological Chemistry’s web site on December 19, 2007.

Source: Rutgers University