CDKN2A is not the principal target of deletions on the short arm of chromosome 9 in neuroendocrine (Merkel cell) carcinoma of the skin

The majority of small-cell lung cancers (SCLCs) express p16 but not pRb, Given our previous study showing loss of pRb in Merkel cell carcinoma (MCC)/neuroendocrine carcinoma of the skin and the clinicopathological similarities between SCLC acid MCC, we wished to determine if this was also the case in MCC, Twenty-nine MCC specimens from 23 patients were examined for deletions at 10 loci on 9p and I on 9p. No loss of heterozygosity (LO H) was peen in 9 patients including 2 for which tumour and cell line DNAs were examined. Four patients had LOH for all informative loci on 9p, Ten tumours showed more limited regions of loss on 9p, and from these 2 common regions of deletion were determined, Half of all informative cases had LOH at D95168, the most telomeric marker examined, and 3 specimens showed loss of only D9S168, A second region (InFNA-D9S126) showed L0H in 10(44%) cases, and case MCC26 showed LOH for only D9S126, implicating genes centromeric of the CDKN2A locus. No mutations in the coding regions of p16 were seen in 7 cell lines tested, and reactivity to anti-p16 antibody was seen in all Il tumour specimens examined and in 6 of 7 cell lines from 6 patients. Furthermore, all cell lines examined reacted with anti-p 14' antibody, These results suggest that neither transcript of the CDKN2A locus is the target of deletions on 9p in MCC and imply the existence of tumour-suppressor genes mapping both centromeric and telomeric of this locus. (C) 2001 Wiley-Liss, Inc.

G2 phase cell cycle arrest in human skin following UV irradiation

The contribution of the short wavelength ultraviolet (UV) component of sunlight to the aetiology of skin cancer has been widely acknowledged, although its direct contribution to tumour initiation or progression is still poorly understood. The loss of normal cell cycle controls, particularly checkpoint controls, are a common feature of cancer. UV radiation causes both GI and G2 phase checkpoint arrest in vitro cultured cells. In this study we have investigated the cell cycle responses to suberythemal doses of UV on skin. We have utilized short-term whole organ skin cultures, and multi parameter immunohistochemical and biochemical analysis to demonstrate that basal and suprabasal layer melanocytes and keratinocytes undergo a G2 phase cell cycle arrest for up to 48 h following irradiation. The arrest is associated with increased p16 expression but no apparent p53 involvement. This type of organ culture provides a very useful model system, combining the ease of in vitro manipulation with the ability to perform detailed molecular analysis in a normal tissue environment.

Cervical mobilisation: concurrent effects on pain, sympathetic nervous system activity and motor activity

Recent findings that spinal manual therapy (SMT) produces concurrent hypoalgesic and sympathoexcitatory effects have led to the proposal that SMT may exert its initial effects by activating descending inhibitory pathways from the dorsal periaqueductal gray area of the midbrain (dPAG). In addition to hypoalgesic and sympathoexcitatory effects, stimulation of the dPAG in animals has been shown to hal e a facilitatory effect on motor activity. This study sought to further investigate the proposal regarding SMT and the FAG by including a test of motor function in addition to the variables previously investigated, Using a condition randomised, placebo-controlled, double blind, repeated measures design, 30 subjects with mid to lon er cervical spine pain of insidious onset participated in the study. The results indicated that the cervical mobilisation technique produced a hypoalgesic effect as revealed by increased pressure pain thresholds on the side of treatment (P = 0.0001) and decreased resting visual analogue scale scores (P = 0.049). The treatment technique also produced a sympathoexcitatory effect with an increase in skin conductance (P < 0.002) and a decrease in skin temperature (P = < 0.02). There was a decrease in superficial neck flexor muscle activity (P < 0.0002) at the lower levels of a staged cranio-cervical flexion test. This could imply facilitation of the deep neck flexor muscles with a decreased need for co-activation of the superficial neck flexors, The combination of all findings,would support the proposal that SMT may, at least initially, exert part of its influence via activation of the PAG, (C) 2000 Harcourt Publishers Ltd.

Veterinary drug delivery: Potential for skin penetration enhancement

A range of topical products are used in veterinary medicine. The efficacy of many of these products has been enhanced by the addition of penetration enhancers. Evolution has led to not only a highly specialized skin in animals and humans, but also one whose anatomical structure and skin permeability differ between the various species. The skin provides an excellent barrier against the ingress of environmental contaminants, toxins, and microorganisms while performing a homeostatic role to permit terrestrial life. Over the past few years, major advances have been made in the field of transdermal drug delivery. An increasing number of drugs are being added to the list of therapeutic agents that can be delivered via the skin to the systemic circulation where clinically effective concentrations are reached. The therapeutic benefits of topically applied veterinary products is achieved in spite of the inherent protective functions of the stratum corneum (SQ, one of which is to exclude foreign substances from entering the body. Much of the recent success in this field is attributable to the rapidly expanding knowledge of the SC barrier structure and function. The bilayer domains of the intercellular lipid matrices within the SC form an excellent penetration barrier, which must be breached if poorly penetrating drugs are to be administered at an appropriate rate. One generalized approach to overcoming the barrier properties of the skin for drugs and biomolecules is the incorporation of suitable vehicles or other chemical compounds into a transdermal delivery system. Indeed, the incorporation of such compounds has become more prevalent and is a growing trend in transdermal drug delivery. Substances that help promote drug diffusion through the SC and epidermis are referred to as penetration enhancers, accelerants, adjuvants, or sorption promoters. It is interesting to note that many pour-on and spot-on formulations used in veterinary medicine contain inert ingredients (e.g., alcohols, amides, ethers, glycols, and hydrocarbon oils) that will act as penetration enhancers. These substances have the potential to reduce the capacity for drug binding and interact with some components of the skin, thereby improving drug transport. However, their inclusion in veterinary products with a high-absorbed dose may result in adverse dermatological reactions (e.g., toxicological irritations) and concerns about tissue residues. These a-re important considerations when formulating a veterinary transdermal product when such compounds ate added, either intentionally or otherwise, for their penetration enhancement ability. (C) 2001 Elsevier Science B.V. All rights reserved.

Can increasing the viscosity of formulations be used to reduce the human skin penetration of the sunscreen oxybenzone?

The effect of adding thickening agents on the penetration of a sunscreen benzophenone-3 through epidermal and a high-density polyethylene membrane was studied using both very thick (infinite dose) and thin tin use) applications. Contradictory results were obtained. Thickening agents retard skin penetration, in a manner consistent with a diffusional resistance in the formulation, when applied as an infinite dose. In contrast, when applied as in thin (in use) doses, thickening agents promote penetration, most likely through greater stratum corneum diffusivity arising from an enhanced hydration by the thicker formulations. The two key implications from this work are (i) a recognition of the danger in the potential extrapolation of infinite dosing to in use situations, and (ii) to recognize that thicker formulations may sometimes enhance the penetration of other topical agents when applied in use.

Skin-friction measurements in a supersonic combustor with crossflow fuel injection

Shock-tunnel experiments have been performed to measure the effect on skin-friction drag in a supersonic combustor of flow disturbances induced by hydrogen fuel injection transverse to the airstream. Constant-area, circular cross section combustors of lengths varying up to 0.52 m were employed. The experiments were done at a stagnation enthalpy of 7.2 MJ . kg(-1) and a Mach number of 4.3, with a boundary layer that was turbulent downstream of the 0.14-m station in the combustors. Combustor skin-friction drag was measured by a method based on the stress wave force balance, the method being validated by agreement between fuel-off skin-friction drag measurements and predictions using existing skin-friction theories. When fuel was injected, it was found that the drag remained at fuel-off values. Thus, the streamwise vortices and other flow disturbances induced by the fuel injection, mixing, and combustion, which are expected to be present in a scramjet combustor, did not influence the skin-friction drag of the combustors.

Dendromonocotyle colorni sp n. (Monogenea : Monocotylidae) from the skin of Himantura uarnak (Dasyatididae) from Israel and a new host record for D-octodiscus from the Bahamas

Dendromonocotyle colorni sp. n. (Monogenea: Monocotylidae) is described from the dorsal skin surface of two specimens of Himantura uarnak (Forsskal) kept at the Eilat Underwater Observatory in Israel. Dendromonocotyle colorni is distinguished from the other eight species in the genus by the morphology of the terminal papillar sclerite on the haptor, the distal portion of the male copulatory organ and the morphology of the vagina. The development of the male copulatory organ is detailed for D. colorni and the adaptations of species of Dendromonocotyle to life on the dorsal skin surface of rays are discussed. Dendromonocotyle octodiscus Hargis, 1955 was identified from the dorsal skin surface of the southern stingray Dasyatis americana Hildebrand et Schroeder off Bimini, Bahamas and represents a new host record.

Experimental susceptibility of some reef fish species to Benedenia lutjani (Monogenea : Capsalidae), a parasite of Lutjanus carponotatus (Pisces : Lutjanidae)

The susceptibility of species of lutjanid, lethrinid and serranid fish to infection by either larval or post-larval (juvenile and adult) specimens of the capsalid monogenean Benedenia lutjani Whittington and Kearn (1993) was examined experimentally. Four species of lutjanids became infected when exposed to larvae of B. lutjani, but three species of lethrinids and four species of serranids were not susceptible to larvae under the same conditions. Variability in the intensity of infection by larvae occurred within and between lutjanid species. Few post-larval specimens of B. lutjani transferred between individuals of the specific host Lutjanus carponotatus (Richardson 1842) in 60-l aquaria and none transferred between specimens of L. carponotatus in a 7,500-l concrete tank. These results indicate that transfer of post-larval B. lutjani between individuals of the specific host is unlikely to occur in the wild. Other lutjanid species did not become infected when exposed to specimens of L. carponotatus infected heavily by post-larval B. lutjani, but two lethrinid species were susceptible to infection under the same conditions. These data indicate that different factors may mediate host-specificity for larval and post-larval B. lutjani.

A new genus of viviparous gyrodactylid (Monogenea) from the Great Barrier Reef, Australia with descriptions of seven new species

Acanthoplacatus gen. nov., a new genus of viviparous gyrodactylid, is described from the rns and skin of siganid fishes from the Great Barrier Reef, Australia. The genus is characterized by a muscular, tube-like haptor with 16 marginal hooks on the posterior margin. The ventral lobe of the haptor is located anteriorly relative to the dorsal lobe and contains a pair of hamuli and a ventral bar with posteriorly-projecting ventral bar membrane. A dorsal bar is absent. Five pairs of posterior gland cells surround the posterior terminations of the gut. The male copulatory organ is a muscular, non-eversible bulb with several spines around the distal opening. Species of Acanthoplacatus have a bilateral excretory system consisting of six pairs of flame cells and a pair of excretory bladders. Seven new species are described: Acanthoplacatus adlardi sp. nov. and A. amplihamus sp. nov. from Siganus punctatus (Forster, 1801), A. brauni sp. nov. from S. corallinus (Valenciennes, 1835), A. parvihamus sp. nov. from S. vulpinus (Schlegel and Mueller, 1845), A. puelli sp. nov. from S. puellus Schlegel, 1852, A. shieldsi sp. nov. from S. lineatus (Valenciennes, 1835) and A. sigani sp. nov. from S. fuscescens (Houttuyn, 1782). Species can be discriminated by shape and size of the hamuli, marginal hooks and ventral bar and by male copulatory organ sclerite morphology. Three species (A. brauni sp. nov., A. shieldsi sp. nov. and A. sigani sp. nov.) were assessed for seasonal variation of sclerite size. Ten of thirteen morphological characters showed seasonal variation in size for at least one of the species. The characters were longer in winter except dorsal root tissue cap width. Only one character, marginal hook length, showed significant seasonal variation for all three species. Species of Acanthoplacatus were observed to attach using only the marginal hooks and the role of hamuli in attachment is unclear. The dorsal rn of the host is the preferred site for most species but the anal fin, caudal fin and body surfaces are preferred by some species. Prevalences for species range from 57 to 100%.

Modelling cement grinding circuits

Modelling and simulation studies were carried out at 26 cement clinker grinding circuits including tube mills, air separators and high pressure grinding rolls in 8 plants. The results reported earlier have shown that tube mills can be modelled as several mills in series, and the internal partition in tube mills can be modelled as a screen which must retain coarse particles in the first compartment but not impede the flow of drying air. In this work the modelling has been extended to show that the Tromp curve which describes separator (classifier) performance can be modelled in terms of d(50)(corr), by-pass, the fish hook, and the sharpness of the curve. Also the high pressure grinding rolls model developed at the Julius Kruttschnitt Mineral Research Centre gives satisfactory predictions using a breakage function derived from impact and compressed bed tests. Simulation studies of a full plant incorporating a tube mill, HPGR and separators showed that the models could successfully predict the performance of the another mill working under different conditions. The simulation capability can therefore be used for process optimization and design. (C) 2001 Elsevier Science Ltd. All rights reserved.

Skin flaps

Skin flaps are useful where a lesion cannot be removed by simple excision without excessive tension being placed on the wound or surrounding tissues may be distorted. The H-flap and the island advancement flap are described. (non-author abstract)

Abolition of (-)-CGP 12177-evoked cardiostimulation in double beta(1)/beta(2)-adrenoceptor knockout mice. Obligatory role of beta(1)-adrenoceptors for putative beta 4-adrenoceptor pharmacology

Some beta (1)- and beta (2)-adrenoceptor-blocking agents, such as (-)-CGP 12177, cause cardiostimulant effects at concentrations considerably higher than those that antagonise the effects of catecholamines. The cardiostimulant effects of these non-conventional partial agonists are relatively resistant to blockade by (-)-propranolol and have been proposed to be mediated through putative beta (4)-adrenoceptors or through atypical states of either beta (1)- or beta (2)-adrenoceptors. We investigated the effects of (-)-CGP 12177 on sinoatrial rate and left atrial contractile force as well as the ventricular binding of (-)-[H-3]CGP 12177 in tissues from wild-type, beta (2)-adrenoceptor knockout and beta (1)/beta (2)-adrenoceptor double knockout mice. The cardiostimulant effects of (-)-CGP 12177 were present in wildtype and beta (2)-adrenoceptor knockout mice but were absent in beta (1)/beta (2)-adrenoceptor double knockout mice. Thus, the presence of beta (1)-adrenoceptors is obligatory for the cardiostimulant effects of (-)-CGP 12177. It appears therefore that an atypical state of the beta (1)-adrenoceptor contributes to the mediation of the cardiostimulant effects induced by non-conventional partial agonists. Ventricular beta (1)- and beta (2)-adrenoceptors, labelled in wild-type with a K(D)similar to0.5 nmol/l (similar to 16 fmol/mg protein), were absent in beta (1)/beta (2)-adrenoceptor double knockout mice. However, a high density binding site (similar to 154-391 fmol/mg protein) that did not saturate completely (K(D)similar to 80-200 nM) was labelled by (-)-[H-3]CGP 12177 in the three groups of mice, being distinct from beta (1)- and beta (2)-adrenoceptors, as well as from the site mediating the agonist effects of(-)-CGP 12177.