Cholesterol 3-sulfate interferes with cornified envelope assembly by diverting transglutaminase 1 activity from the formation of cross-links and esters to the hydrolysis of glutamine.

The loss of transglutaminase 1 enzyme (TGase 1) activity causes lamellar ichthyosis. Recessive X-linked ichthyosis (XI) results from accumulation of excess cholesterol 3-sulfate (CSO(4)) in the epidermis but the pathomechanism how elevated epidermal CSO(4) causes ichthyosis is largely unknown. Here we provide evidence that XI is also a consequence of TGase 1 dysfunction. TGase 1 is a key component of barrier formation in keratinocytes: it participates in the cross-linking of cell envelope (CE) structural proteins, and also forms the lipid bound envelope by esterification of long chain omega-hydroxyceramides onto CE proteins. Using involucrin and an epidermal omega-hydroxyceramide analog as substrates, kinetic analyses revealed that at membrane concentrations above 4 mol %, CSO(4) caused a marked and dose-dependent inhibitory effect on isopeptide and ester bond formation. Sequencing of tryptic peptides from TGase 1-reacted involucrin showed a large increase in deamidation of substrate glutamines. We hypothesize that supraphysiological levels of CSO(4) in keratinocyte membranes distort the structure of TGase 1 and facilitate the access of water into its active site causing hydrolysis of substrate glutamine residues. Our findings provide further evidence for the pivotal role of the TGase 1 enzyme in CE formation.

Health peer outreach by high school students.

A health screening program was established in an inner-city New York public high school using the services of trained members of the student body as screeners. These students were trained to do a variety of health-related examinations and tests. Supervision and training were provided by a school health educator and members of a medical team from a nearby municipal hospital medical center. The primary goal was to reach, through peer involvement, those students who would be unlikely to interact with the routine health-care system. Of the 480 students receiving screening examinations, 291 were found to have abnormalities. In addition, a greater awareness of medical issues and available health-care facilities was seen among the student body. Through their training, the student screeners were exposed to various health-care fields, thus increasing their awareness of medical career potentials.

Alterations in norepinephrine, serotonin, c-AMP, and transsynaptic induction of tyrosine hydroxylase after spinal cord transection in the rat.

Tyrosine hydroxylase (TH) activity and the concentrations of norepinephrine (NE), serotonin (5-HT), and cyclic adenosine 3',5'-monophosphate (c-AMP) were measured in the heart, adrenals, and brain stem of paraplegic rats. Following spinal cord transection NE concentration in the heart dropped to 30% within 24 hours and that of 5-HT decreased to 60% of control. Tyrosine hydroxylase activity in the adrenals reached a peak at five days and was still twice that of sham-operated controls thirty days later. Five days following transection the TH activity and c-AMP levels in the brain stem were elevated while NE concentration remained low. At seven days, however, NE and 5-HT levels were higher than in controls while TH activity and c-AMP concentration dropped to control levels. The increase in TH activity in the brain stem may be due to curtailed end-product feedback inhibition and to reduced receptor activation. The sustained induction of the adrenal TH is probably a consequence of a continual stimulation of splanchnic nerves.

Head-up tilt effect on glomerular filtration rate, renal plasma flow, and mean arterial pressure in spinal man.

Changes in glomerular filtration rate (GRF), renal plasma flow (RPF), and mean arterial pressure (MAP) were measured in subjects tested in supine and head-up tilt positions with various levels of spinal cord lesion and thus with different degrees of supraspinal sympathetic vasomotor control. Responses of paraplegic subjects to head-up tilt were not significantly different from those of normal controls but GFR and RPF were significantly lower in quadriplegics in the supine position. With tilt, MAP and RPF decreased significantly, but the fall in GFR was not significant. In all 3 groups, the GFR during head-up tilt was similar, indicating that in spite of the great loss of supraspinal sympathetic control, quadriplegic subjects apparently equally-constrict their afferent and efferent renal arterioles during orthostatic stress and thus prevent excessive fall of GFR.

Hypertensive crises in quadriplegic patients. Changes in cardiac output, blood volume, serum dopamine-beta-hydroxylase activity, and arterial prostaglandin PGE2.

The syndrome of autonomic dysreflexia often occurs in quadriplegic subjects and is characterized by paroxysmal hypertension, headache, vasoconstriction below and flushing of the skin above the level of transection, and bradycardia. These attacks may cause hypertnesive encephalopathy, cerebral vascular accidents, and death. In five patients during crises, the mean arterial pressure changed from 95 to 154 mm Hg, heart rate 72 to 45 beats/min, cardiac output 4.76 to 4.70 L/min, and peripheral resistance 1650 to 2660 dynes.sec.cm-5. In eight subjects the control plasma, red cell, and total blood volumes were 19.1, 10.5, and 29.6 ml/cm body height, respectively, and when hypertensive, the plasma protein concentration increased by 9.9% and the hematocrit by 9.5%. Plasma volume was only reduced by an estimated 10-15%. At that time, arterial dopamine-beta-hydroxylase (DbetaH) activity increased 65% and prostaglandin E2 concentration by 68%. Thus, the augmented DbetaH activity presented primarily an elevated sympathetic tone and not hemoconcentration of that protein. The rise in prostaglandin may contribute to the severe headaches during hypertensive episodes.

Rates of tissue uptake of palmitic acid-1-14C complexed with albumin by two different procedures.

The effect was investigated of two different methods of preparing an albumin-palmitic acid complex on the tissue uptake of the palmitic acid, both in vivo and in vitro. Complex A was prepared by exposing monomolecular layers of palmitic acid-1-(14)C deposited on a solid surface to albumin dissolved in buffer. Complex B was prepared by the interaction of albumin with a micellar solution of palmitate-1-(14)C. The radioactivities and chemical compositions of the two complexes were almost identical. Rat epididymal fat pads took up, during a 1 hr incubation, about 2.5 times as much palmitic acid from complex A as from complex B; the extent of esterification of the incorporated label was equal for the two complexes. The fractional turnover rate of palmitic acid of complex A, administered intravenously to dogs, was about twice that of palmitic acid from complex B. The label of the two complexes recirculated in the esterified fatty acid fraction of plasma to an equal extent. It is proposed that differences in the orientation of the fatty acid molecules may affect their interaction with the binding sites of albumin and that the metabolic differences of the resulting complexes are related to differences in the ease of transfer of the fatty acid from the complex to receptor sites of tissues.