X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.

The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.

The free radical flux theory of sleep.

A theory of sleep is proposed in which cerebral free radicals accumulate during wakefulness and are removed during sleep. Removal of excess free radicals during sleep is accomplished by decreased rate of formation of free radicals, and increased efficiency of endogenous antioxidant mechanisms. Thus, sleep functions essentially as an antioxidant for the brain.

Disseminated neonatal gastrointestinal mucormycosis: a case report and review of the literature.

Mucormycosis of the gastrointestinal tract is a rare and fatal infection of neonates and children. This report describes a case of disseminated mucormycosis originating in the gastrointestinal tract of a premature infant of 26 weeks gestational age. The antemortem impression was that of necrotizing enterocolitis, diagnosed at 15 days of age, followed by death at 22 days. However, autopsy revealed extensive colonization and invasion of the small intestine and colon by mucormycosis, with blood and peritoneal fluid cultures positive for Mucorales species but negative for bacteria. There was associated hematogenous and adjacent spread of organisms to other viscera.

Extramedullary hematopoiesis of the cranial dura and anhidrotic ectodermal dysplasia.

A 2-year-old amerasian male with anhidrotic ectodermal dysplasia (Christ-Siemens-Touraine Syndrome) was admitted for status epilepticus and Mycobacteria avium-intracellulare infection. A computed tomography scan of the head revealed a mass thought to be a subdural hematoma. The patient died following overwhelming Mycobacteria avium-intracellular and Pseudomonas aeruginosa sepsis. Autopsy revealed extensive extramedullary hematopoiesis of the dura forming a tumor-like thickening with focal subdural hemorrhage. To our knowledge, this is the first report of extramedullary hematopoiesis of the cranial dura associated with anhidrotic ectodermal dysplasia.

Bilateral renal parenchymal malacoplakia: a case report.

Histological examination of the radical nephrectomy and renal biopsy specimens in a 49-year-old woman revealed bilateral renal malacoplakia. The literature reports bilateral renal malacoplakia to be uniformly fatal. The preoperative diagnosis is based upon patient presentation and imaging studies. Insights into the bacterial etiology of this systemic disease are presented.

Sleep deprivation-induced dermatitis: further support of nicotinic acid depletion in sleep deprivation.

It is noted that some of the manifestations of prolonged sleep deprivation are similar to changes seen in pellagra. Dermatitis is one of the cardinal clinical manifestations of human pellagra. Prolonged sleep deprivation also typically induces a dermatitis in experimental animals. Both dermatidities are histopathologically similar. It is plausible that both may have a similar etiology, i.e. depletion of nicotonic acid and products derived from it.

Sleep deprivation-induced neuronal damage may be due to nicotinic acid depletion.

Prolonged sleep deprivation induces chromatolysis of central nervous system neurons. This unusual form of neuronal damage is curiously similar to the neuronal damage seen in pellagra. It is proposed that the neuronal damage of prolonged sleep deprivation is a consequence of nicotinic acid depletion.

Pigmented choroid plexus papilloma.

A pigmented choroid plexus papilloma was found in the left lateral ventricle of a 15-year-old white boy with a 10-year history of seizures. Grossly the lesion appeared finely lobular, orangish brown, rubbery, gritty, and friable. Microscopic examination revealed delicate papillary formations reminiscent of normal choroid plexus, with simple cuboidal to columnar epithelium overlying fibrovascular cores. Light- and electron-microscopic studies demonstrated that the neoplastic cell pigment consisted of both neuromelanin and lipofuscin. To our knowledge, this is the first reported case of neuromelanin pigmentation within a choroid plexus papilloma.

Inhibition of protein kinase C by defensins, antibiotic peptides from human neutrophils.

Defensins, human neutrophil peptide (HNP) antibiotics, potently inhibited phospholipid/Ca2+ protein kinase (protein kinase C, PKC) and phosphorylation of endogenous proteins from rat brains catalyzed by the enzyme. Of the three defensin peptides, HNP-2 appeared to be more potent than HNP-1 and HNP-3. Kinetic studies indicated that defensins inhibited PKC noncompetitively with respect to phosphatidylserine (a phospholipid cofactor), Ca2+ (an activator), ATP (a phosphoryl donor) and histone H1 (a substrate protein) with Ki values ranging from 1.2 to 1.7 microM. Defensins, unlike polymyxin B (another peptide inhibitor of PKC), did not inhibit the binding of [3H]phorbol 12,13-dibutyrate to PKC; however, defensins, like polymyxin B, inhibited the PKC activity stimulated by 12-O-tetradecanoylphorbol-13-acetate. Defensins had little or no effect on myosin light chain kinase (a calmodulin/Ca2+-dependent protein kinase) and the holoenzyme or catalytic subunit of cyclic AMP-dependent protein kinase, indicating a specificity of action of defensins. It is suggested that defensins, among the most potent peptide inhibitors of PKC so far identified, may have profound effects on functions of neutrophils and other mammalian cells, in addition to their well-recognized antimicrobial activities.

Butylated hydroxytoluene, lipid-enveloped viruses, and AIDS.

Butylated hydroxytoluene (BHT) is a potent inactivator of lipid-enveloped viruses. The viral envelope structure is physically disturbed by BHT, thereby interfering with viral adsorption to host cells. Since the virus responsible for AIDS (HTLV III) contains a lipid envelope, BHT warrants investigation as a potential antiviral agent against the AIDS virus.