Lowell A. Goldsmith

What is the pathogenesis of acne

Abstract:  For a long time, the mantra of acne pathogenesis debates has been that acne vulgaris lesions develop when (supposedly largely androgen‐mediated) increased sebum production, ductal hypercornification, and propionibacteria come together with local inflammatory process in the unlucky affected individual. And yet, the exact sequence, precise interdependence, and choreography of pathogenic events in acne, especially the ‘match that lights the fire’ have remained surprisingly unclear, despite the venerable tradition of acne research over the past century.

Evidence that apoptosis and terminal differentiation of epidermal keratinocytes are distinct processes.

Abstract: Although there are clear parallels between apoptosis and epidermal terminal differentiation it is unclear whether terminal differentiation of keratinocytes is a form of apoptosis. We found that apoptosis was rare in adherent cultures of normal keratinocytes, even when growth factors were removed. When keratinocytes were placed in suspension for 24‐96 h the majority of cells were induced to undergo terminal differentiation, as assessed by involucrin expression and cornified envelope assembly, but few cells underwent apoptosis, as assessed by morphological examination, TUNEL labelling and by DNA laddering. Withdrawal of serum and growth factors stimulated apoptosis of suspended keratinocytes but led to some reduction in the number of cells that underwent terminal differentiation. At 96 h the majority of cells retained their nuclei in the presence or absence of serum and growth factors. In normal epidermis only occasional cells within the granular layer had apoptotic nuclei, determined by TUNEL labelling and light and electron microscopy. In affected epidermis of psoriasis, Dariers disease and pityriasis rubra pilaris, diseases characterized by perturbation of growth, differentiation or adhesion, light microscopy revealed no higher proportion of apoptotic nuclei than in normal epidermis. However, the majority of viable epidermal layers in diseased skin were positive by TUNEL labelling, suggesting that TUNEL is not always a specific marker of apoptosis in keratinocytes. We conclude that in vivo and in culture keratinocyte terminal differentiation and apoptosis are distinct cellular events, subject to different stimuli.

Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum

Abstract. We recently published the precise chromosomal localization on chromosome 16p13.1 of the genetic defect underlying pseudoxanthoma elasticum (PXE), an inherited disorder characterized by progressive calcification of elastic fibers in skin, eye, and the cardiovascular system. Here we report the identification of mutations in the gene encoding the transmembrane transporter protein, ABC-C6 (also known as MRP-6), one of the four genes located in the region of linkage, as cause of the disease. Sequence analysis in four independent consanguineous families from Switzerland, Mexico, and South Africa and in one non-consanguineous family from the United States demonstrated several different mis-sense mutations to cosegregate with the disease phenotype. These findings are consistent with the conclusion that PXE is a recessive disorder that displays allelic heterogeneity, which may explain the considerable phenotypic variance characteristic of the disorder.

A comparative study of the physicochemical properties of human keratinized tissues

Abstract Stratum corneum, hair and nail are all derived from ectodermal cells but show significant structural differences in their fully differentiated form. However, X-ray diffraction studies indicate that they all contain an α-fibrous protein with the same molecular dimensions. The greater tensile strength and stability to heating of hair and nail compared to stratum corneum can be explained by their higher content of half cystine. Studies of the isolated structural proteins indicate that the appendages contain a non-helical matrix component very rich in cystine while stratum corneum does not. Furthermore, stratum corneum has an α-fibrous protein with physicochemical properties quite different from those of hair and nail, which are very similar to one another. Despite different morphological characteristics, it appears that hair and nail have differentiated along very similar lines. However, subtle differences in the relative proportion and composition of the structural proteins can be detected. A distinguishing feature of stratum corneum is its large content of lipids which make it an effective barrier to the diffusion of water.

Tyrosinemia with plantar and palmar keratosis and keratitis

An 111/2-year-old boy, born of a consanguineous marriage, had mental retardation, painful plantar and palmar keratosis, and dendritic keratitis associated with tyrosinemia, p-hydroxyphenylpyruvicaciduria, p-hydroxylaceticaciduria, and p-hydroxyphenylaceticaciduria. Liver and renal functions were within normal ranges, and vitamin C loading did not correct the metabolic abnormalities. Maintenance on a low-tyrosine, low-phenylalanine diet was associated with resolution of the epithelial lesions and a decrease in the metabolic abnormalities. Four other patients with similar metabolic abnormalitiers may have had this clinical syndrome.

Percutaneous absorption of mercury vapor by man

Five volunteer male subjects who were 24 to 78 y of age exposed the skin of their forearm to mercury vapor (203Hg) at concentrations of 0.88-2.14 ng/cm3 for periods of 27-43 min. Approximately 216 to 844 ng was taken up by the skin at rates of 0.0101 to 0.0402 ng Hg per cm2 per min per ng Hg per cm3 air. About half of the mercury taken up was shed by desquamation of epidermal cells during several weeks. The remainder diffused into the general circulation and could be measured as systemic mercury. When the total skin area (of which the forearm skin was assumed to be representative) was compared to the lung as a route of entry for mercury vapor at the same concentration, the rate of uptake was estimated to be 2.2% of the rate of uptake by the lung. A model is proposed that describes the growth and loss of skin-derived systemic mercury.

HUMAN EPIDERMAL TRANSGLUTAMINASE

A monospecific antibody for human epidermal transglutaminase was prepared in rabbits. The antibody formed single immunoprecipitin lines with purified or crude human transglutaminases and quantitatively precipitated transglutaminase activity. There were no precipitin reactions between human factor XIII (zymogen or active enzyme) and antihuman epidermal transglutaminase or between human epidermal transglutaminase and antihuman factor XIII. Heating epidermal transglutaminase (56 degrees C, 15 min) in the presence of calcium increased the enzyme activity up to 10 times baseline levels. The heat-activated human epidermal transglutaminase was identical by immunodiffusion with the native enzyme, although slightly higher precipitation titers were detected following heating. There was no cross-reaction of antihuman epidermal transglutaminase with frog, rat, mouse, chicken, or human hair follicle transglutaminases.

Pityriasis rubra pilaris response to 13-cis-retinoic acid (isotretinoin)

Forty-five patients with pityriasis rubra pilaris were treated with oral 13-cis-retinoic acid (isotretinoin). There was marked improvement in the degree of erythema, in duration, and scaling noted within 4 weeks. Remission or maintained improvement persisted after stopping therapy in many of the patients. The drug is a significant addition to the therapeutic armamentarium in this difficult-to-treat disease.

The polypeptide composition of epidermal prekeratin.

An alpha-fibrous protein, prekeratin, has been isolated from cow snout epidermis with citrate buffer, pH 2.65. Using acrylamide electrophoresis with 0.1% sodium dodecyl sulfate, prekeratin can be shown to contain three polypeptide chains of different molecular weights. The two faster migrating components are very similar with a mol. wt of about 47,000 while the slower one has a mol. wt of about 58,000. Chromatography on a number of molecular sieve and exchange resins does not separate the components, but use of Sepharose 2B with 0.1 M Tris, pH 9.0, containing 10% propanol gives two peaks of protein. The first and major peak contains all three components while the second has only the two with the faster mobility. The two more rapidly migrating components and the slower one were isolated by acrylamide electrophoresis, and the latter has an amino acid composition more compatible with a non-helical protein. Enzymatic digestion with tosyl-L-phenylalanine chloromethylketone-treated (TPCK-)trypsin shows that the component of mol. wt 58,000 is more susceptible to hydrolysis than the other two. These data suggest that prekeratin is not homogenous in composition and consists of several interacting polypeptide chains. One of these components would appear to be non-helical in structure.

Acute and subchronic toxicity of sucralose.

The toxicity of sucralose has been evaluated in acute and subchronic toxicity studies. Acute oral toxicity studies in male and female mice and male rats documented no deaths or treatment-related signs at doses of 16g/kg for mice and 10g/kg for rats. Sucralose was administered to male and female rats for 4 and 8 weeks at dietary concentrations of 1.0, 2.5 or 5.0%. Achieved dose ranges (mg/kg/day) for the respective dietary levels were 737-1287, 1865-3218 and 2794-6406. There were no toxicologically significant effects observed at the 1.0% or 2.5% dietary levels. However, decreases in food consumption, body weight gain and selected organ weights and ratios as well as splenic and thymic histopathologic changes occurred in rats administered 5.0% for 4 or 8 weeks. A gavage study wherein doses of 0, 750, 1500 or 3000mg/kg/day were administered to male and female rats for 26 weeks investigated further the observations from the dietary study as well as general subchronic toxicity. The gavage study documented no sucralose-related toxicity. These results implicate the reduced palatability and digestibility of diets containing high concentrations of sucralose seen in the diet study as the cause for the decreased food consumption and other accompanying alterations. Dose selection for chronic toxicity studies in rats took into consideration the effect of high concentrations of sucralose on digestion and food consumption and the limitations that would be imposed on subsequent studies. In male and female dogs, no sucralose-related adverse effects were observed following the dietary administration of 0.3, 1.0 or 3.0% for 12 months achieving doses of approximately 90, 300 and 900mg/kg/day respectively. These studies establish that sucralose is non-toxic in rodents following acute oral administration. The rat no-observed-adverse-effect level ranged between 2.5 and 5.0% following subchronic dietary administration. A 3.0% dietary concentration equivalent to a dose of 900mg/kg/day produced no adverse effects in beagle dogs when fed for 12 months.