Aplasia cutis congenita of the scalp: how much therapy is necessary in large defects?

AIM: To show that local antibiotic management and a regular inspection of aplasia cutis congenita of the skull can give an excellent result. METHOD: This case reports a girl born with aplasia cutis congenita of the skull presenting with a large aplasia of the epidermis, dermis, subcutaneous tissue and galea, including a bone defect without any additional risk factor, e.g. early eschar formation, cerebrospinal fluid leakage or uncommon dural blood vessels. RESULTS: A primarily conservative treatment with local wet and antibiotic dressings together with a systemic antibiotic treatment for the first 2 wk led to an excellent result and thus prevented untimely operative and peri-operative procedures. CONCLUSIONS: Here we have shown that conservative treatment might be an option, even if the wound diameter is greater than 1 cm(2), to prevent infants from any untimely operative procedure with an elevated operative risk if any additional risk factors are excluded.

Antibody directed against GD(2) produces mechanical allodynia, but not thermal hyperalgesia when administered systemically or intrathecally despite its dependence on capsaicin sensitive afferents.

Anti-GD(2) antibodies have been shown to be effective for immunotherapy of neuroblastoma and other GD(2) enriched malignancies. Infusion of anti-GD(2) antibodies frequently causes spontaneous pain and allodynia for the duration of the immunotherapy and occasionally longer lasting neuropathic pain. Bolus intravenous injection of anti-GD(2) in rats initiates mechanical allodynia as measured by withdrawal threshold of the hindpaws. In this study, thermal thresholds were measured prior to and for up to 6 h following systemic anti-GD(2) administration in adult rats. In addition, both thermal and mechanical thresholds were tested following intrathecal administration of anti-GD(2) and IgG(2a). Murine anti-GD(2) elicited mechanical allodynia when administered into either the vasculature or the intrathecal space. Effective systemic doses were 1--3 mg/kg as previously shown. Intrathecally, optimal doses ranged from 0.01 to 0.1 ng; a higher dose was ineffective. Thermal hyperalgesia was not observed via either route of administration. Intrathecal pretreatment 48--72 h prior to the experiment with capsaicin at doses sufficient to cause a 50% depletion of dorsal horn CGRP, caused a total blockade of the mechanical allodynia indicating an involvement of peptidergic fine afferent fibers. It is likely that the antibody reacts with an antigen on peripheral nerve and/or myelin to initiate its effect. The lack of observed thermal hyperalgesia is surprising especially in light of the capsaicin-associated blockade, however, it is consistent with several other immune system related models of pain.

Isoprostanes induce plasma extravasation in rat skin.

Isoprostane E2 (8-iso PGE) and isoprostane F2 alpha (8-iso PGF) contribute to numerous vascular, proinflammatory, and nociceptive functions. The underlying mechanisms for many of their actions are still under investigation. We examined the ability of isoprostanes to promote cutaneous inflammation using the Evan's blue dye method. Our data show that 4 micrograms subcutaneously (s.c.) injected 8-iso PGE or 8-iso PGF induced plasma extravasation in glabrous rat skin. Dye extravasation was also elicited in hairy skin after injections of 8-iso PGE, but not after 8-iso PGF. Isoprostane-evoked dye extravasation can be reduced by pretreatment with both the S+ and R- isomers of the cyclooxygenase (COX)-inhibitor ibuprofen (30 mg/kg intraperitoneally), indicating perhaps a nonspecific inhibition; pretreatment with ketorolac (1 and 10 mg/kg i.v.) was without effect. Unlike isoprostane-induced cutaneous nociceptor sensitization, which is blocked in a stereospecific and dose-dependent manner by COX-inhibitors, the effect of these drugs on isoprostane-induced cutaneous plasma extravasation is less consistent. We conclude that at least a large component of the isoprostane effect on cutaneous plasma extravasation is COX-independent.

C-nociceptor sensitization by isoprostanes is cyclooxygenase dependent.

Isoprostane E(2) (8-iso-PGE) and F(2alpha) (8-iso-PGF) sensitize nociceptors and capsaicin-sensitive DRG neurons. In this study we investigated the cyclooxygenase-dependence of isoprostane-induced C-nociceptor sensitization. Systemic pretreatment of rats with ketorolac (1 and 10 mg/kg) abolished 8-iso-PGF sensitization and reduced the effects of 8-iso-PGE. Ibuprofen (30 mg/kg) blocked all sensitizing effects. These data suggest that some algesic properties of isoprostanes are mediated via prostanoid synthesis.

Isoprostanes, novel eicosanoids that produce nociception and sensitize rat sensory neurons.

Isoprostanes are a novel class of eicosanoids primarily formed by peroxidation of arachidonic acid. Because of their potential as inflammatory and/or hyperalgesic agents whose formation is largely independent of cyclooxygenases, we examined whether 8-iso prostaglandin E(2) (8-iso PGE(2)) or 8-iso prostaglandin F(2alpha) (8-iso PGF(2alpha)) reduces mechanical and thermal withdrawal threshold in rats, and whether they sensitize rat sensory neurons. Injection of 1 microg of 8-iso PGE(2) (in 2.5 microl) into the hindpaw of rats significantly reduced mechanical and thermal withdrawal thresholds, whereas 1 microg of 8-iso PGF(2alpha) elicited a transient decrease in only the mechanical withdrawal threshold. Both isoprostanes enhanced the firing of C-nociceptors in a concentration-dependent manner when injected into peripheral receptive fields. Exposing sensory neurons grown in culture to 1 microM 8-iso PGE(2) or 8-iso PGF(2alpha) augmented the number of action potentials elicited by a ramp of depolarizing current. In contrast, 8-iso PGE(2) but not 8-iso PGF(2alpha) enhanced the release of substance P- and calcitonin gene-related peptide-like immunoreactivity from isolated sensory neurons. Ten micromolar 8-iso PGE(2) stimulated peptide release directly, whereas treatment with 1 microM 8-iso PGE(2) augmented the release evoked by either bradykinin or capsaicin. Pretreating neuronal cultures with the nonsteroidal anti-inflammatory drug ketorolac did not alter the sensitizing action of 8-iso PGE(2) on peptide release, suggesting that this action of the isoprostane was not secondary to the production of prostaglandins via the cyclooxygenase pathway. These data support the notion that isoprostanes are an important class of inflammatory mediators that augment nociception.

Nociceptive and inflammatory effects of subcutaneous TNFalpha.

Tumor necrosis factor alpha (TNF) is a potent pro-inflammatory cytokine that produces pain and hyperalgesia following injection. Its algesic effects are due to sensitizing actions on nociceptive primary afferents and to the upregulation of other pro-inflammatory and algesic proteins. In anesthetized rats, we investigated the effect of subcutaneously injected TNF on background activity and mechanical sensitivity of C nociceptors of the sural nerve, as well as its effects on cutaneous plasma extravasation. TNF sensitized C nociceptors dose-dependently; the optimal dose (5 ng) lowered threshold in 66.7% of the tested fibers. This sensitization occurred within 30 min and could last for 2 or more hours. Injected TNF had no effect on Abeta mechanoreceptive fibers. In addition, TNF evoked ongoing activity in 14% of C nociceptors and caused significant and dose-related increases in vascular permeability in glabrous skin. Our data suggest that TNF released during disease or after tissue injury participates in the generation of hyperalgesia and inflammation.

CNTF and GDNF, but not NT-4, support corticospinal motor neuron growth via direct mechanisms.

Axotomy and neurodegenerative diseases cause corticospinal motor neuron (CSMN) degeneration. We previously showed that CNTF, NT-4 and GDNF can support CSMN survival in enriched preparations. Here we developed a fluorescence-activated cell sorting method to highly purify CSMN (97+/-4.6%). We tested the neurotrophic activities of CNTF, NT-4 and GDNF on enriched and purified CSMN preparations. Similar to their effects on enriched CSMN preparations, CNTF and GDNF sustained the survival of purified CSMN for at least 5 days with ED50 values of 1.28+/-0.46 nM and 0.59+/-0.39 nM, respectively. In contrast, NT-4 supported survival of enriched but not of purified CSMN, indicating that CNTF and GDNF sustain motor neuron survival by direct action of CSMN, while NT-4 requires accessory cells present in enriched CSMN preparations.

[Experience in scaling up the film coating process for theophylline sustained-release pellets in mass production]. / Erfahrungen bei der Ubertragung des Filmcoating-Prozesses für Theophyllin-Retardpellets in den Produktionsmassstab.

The scale-up of the film coating process for the production of Bronchoretard pellets (theophylline, CAS 58-55-9) is an example for the successful setup of a modern production technology designed to meet the increasing GMP requirements while taking into consideration ecological and economical aspects. This technology provides a reduction in polymer losses on drying from approx. 20% to under 5% and a distinct improvement in the reproducibility of the in vitro dissolution profiles. Double batch sizes and higher spray rates allow for a substantially higher batch turnover. A production line installed exclusively for Bronchoretard pellets and specific process optimization measures resulted in considerably lower lag-times of the equipment.

Hypertonicity regulates the function of human neutrophils by modulating chemoattractant receptor signaling and activating mitogen-activated protein kinase p38.

Excessive neutrophil activation causes posttraumatic complications, which may be reduced with hypertonic saline (HS) resuscitation. We tested if this is because of modulated neutrophil function by HS. Clinically relevant hypertonicity (10-25 mM) suppressed degranulation and superoxide formation in response to fMLP and blocked the activation of the mitogen activated protein kinases (MAPK) ERK1/2 and p38, but did not affect Ca2+ mobilization. HS did not suppress oxidative burst in response to phorbol myristate acetate (PMA). This indicates that HS suppresses neutrophil function by intercepting signal pathways upstream of or apart from PKC. HS activated p38 by itself and enhanced degranulation in response to PKC activation. This enhancement was reduced by inhibition of p38 with SB203580, suggesting that p38 up-regulation participates in HS-induced enhancements of degranulation. HS had similar effects on the degranulation of cells that were previously stimulated with fMLP, but had no effect on its own, suggesting that HS enhancement of degranulation requires another signal. We conclude that depending on other stimuli, HS can suppress neutrophil activation by intercepting multiple receptor signals or augment degranulation by enhancing p38 signaling. In patients HS resuscitation may reduce posttraumatic complications by preventing neutrophil activation via chemotactic factors released during reperfusion.

Hypertonic saline resuscitation: a tool to modulate immune function in trauma patients?

Hypertonic saline (HS) resuscitation has recently gained attention from trauma physicians because it may benefit the immune system of trauma patients. We have found that HS augments in vitro and in vivo immune function of healthy T-cells. In addition, HS restored the function of suppressed T-cells in vitro and in vivo and reduced immunosuppression after hemorrhage, protecting mice from subsequent sepsis. These effects of HS are based on its direct influence on cellular signaling events through specific signaling pathway(s) that include protein tyrosine kinase and mitogen-activated protein kinase p38 activation. HS provides a costimulatory signal that enhances the proliferation of activated T-cells. HS may be able to substitute signals lost through blockage as a result of trauma induced suppressive factors, thereby restoring the function of suppressed T-cells. Although further work is needed to determine the optimal conditions and possible risks of HS resuscitation, the data presented in this short review of our recent work shed a favorable light on HS as a simple but effective tool to modulate cellular immune function after trauma.

Neurotrophin-4 (NT-4) and glial cell line-derived neurotrophic factor (GDNF) promote the survival of corticospinal motor neurons of neonatal rats in vitro.

We have used enriched dissociated, low density cultures of neonatal rat corticospinal motor neurons to evaluate the survival-promoting effect of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and glial cell line-derived neurotrophic factor (GDNF) and the ciliary neurotrophic factor (CNTF). Our current findings demonstrated that CNTF promoted the survival of corticospinal motor neurons, in the same fashion and at an equivalent potency, as was previously described using a different assay system. Among the other factors tested, we also found that NT-4 and GDNF increased the number of surviving neurons in a dose-dependent manner, whereas NGF, BDNF and NT-3 showed no survival promoting effect on corticospinal motor neurons.

Stability behaviour of molsidomine-containing pellet formulations.

Molsidomine in mixtures with different inactive ingredients has been subjected to a stability test. The fingerprint chromatogram obtained by HPLC with diode-array detection of mixtures of molsidomine with povidone 25 revealed decomposition products; the detection wavelength of 210 nm resulted in easy detection of the degradation products. Molsidomine-containing pellets were manufactured according to a compact procedure and by applying the active ingredient to placebo pellets. Compared with the nonpareil pellet formulations, compact pellets have a considerably higher water content and undergo decomposition of the active ingredient after storage for 50 months under different conditions. It is assumed that the decomposition of molsidomine is accelerated by the peroxide found in povidone.

Oral supplements in HIV-infected patients with chronic wasting. A prospective trial.

AIM: Supplementation with polymeric formula diet was evaluated as second step of a nutritional intervention program for malnourished, but otherwise clinically stable HIV-infected patients. PATIENTS AND METHODS: 34 patients with weight loss, without opportunistic infections, diarrhea or fever, not responding to nutritional counselling as first intervention, were included. They were given 1000 kcal per day as polymeric formula. If further weight loss occurred, dose was increased to 1500 kcal per day. Nutritional status was determined by body weight and bioelectrical impedance. RESULTS: After four weeks, 7/34 patients already stopped intake. Only 10/34 patients completed three months of treatment. The average intake during three months was 496 +/- 363 kcal/d. Reasons for drop-out were intervening clinical deterioration in eight, early improvement in six, but intolerance or loss to follow-up in ten patients. On average, body weight did not change. Intake of formula diet and weight changes were not correlated. CONCLUSION: Oral supplements are a feasible, cost-effective and safe treatment of malnutrition, but they are accepted only for short time and in limited amount. To estimate efficacy of this treatment, clinical reasons for malnutrition must be considered. More effective nutritional treatments are needed for chronically malnourished HIV infected patients.

[Sneddon syndrome with detection of anti-phospholipid antibodies]. / Sneddon-Syndrom bei Nachweis von Anti-Phospholipid-Antikörpern.

The association of livedo racemosa and neurological lesions is described as Sneddon's syndrome. A 48-year-old woman with Sneddon's syndrome accompanied by antiphospholipid antibodies is presented.

Retinal morphology of cyprinid fishes: a quantitative histological study of ontogenetic changes and interspecific variation.

Morphological patterns of the retina, cone size and density, rod density, rod-cone ratio, ganglion cell density, convergence of receptor cells, resolving power (RP) and regionalization were examined throughout life history in roach and in adults of asp, bream, common carp, roach and sabre carp. The retina of hatchlings is packed with small cones. During larval and juvenile growth the retina stretches, cones increase in diameter and rods are present in increasing numbers. Photopic and scotopic sensitivity as well as resolving power increase. Comparison of adults shows distinct interspecific differences in retinal parameters, which can be related to life style.

Elimination of pyridoxylated polyhemoglobin after partial exchange transfusion in chimpanzees.

Partial exchange transfusion with 8.5% pyridoxylated polyhemoglobin solution [PolyHb-PPa] was performed in five male chimpanzees weighing 22-30 kg. Serial blood and urine samples were obtained for 3 days. Percutaneous liver biopsies were performed on the 3rd to 4th, and the 9th to 11th days after PolyHb-PPa administration. Mean exchange volume was 42.5 +/- 10.7 ml/kg BW (26.8-54.6 ml/kg), mean Hb dose 3.7 +/- 0.9 g PolyHb-PPa/kg BW (2.4-4.8 g/kg), mean exchange rate 56.7 +/- 7.1% (48.2-67.4%). All animals survived long-term. Analysis of the plasma Hb concentration-time data showed a first order decline at a plasma level of 3.7 +/- 0.9 g PolyHb-PPa/kg BW. Mean intravascular half-life was 14.6 +/- 3.2 h. Total renal elimination of PolyHb-PPa was about 7%. PolyHb-PPa was absorbed and stored by Kupffer cells and transformed into hemosiderin. Siderosis of Kupffer cells and renal tubules had largely subsided 10 days after PolyHb-PPa indicating subsequent in vivo degradation and metabolization of the polymerized Hb fractions.

Hemodynamic effects after partial exchange transfusion with pyridoxylated polyhemoglobin in chimpanzees.

Partial exchange transfusion with 8.5% pyridoxylated polyhemoglobin solution [PolyHb-PPa] was performed in five anesthetized spontaneously-breathing male chimpanzees weighing 22-30 kg. Mean exchange volume was 42.5 +/- 10.7 ml/kg BW (26.8-54.6 ml/kg), mean exchange rate 56.7 +/- 7.1% (48.2-67.4%). All animals survived long-term. The chimpanzee's hemodynamics remained stable for the 5 h observation period. Right and left ventricular filling pressures remained constant, mean arterial pressure and mean pulmonary arterial pressure increased by up to 40% after the exchange. Cardiac output remained unaffected by the partial exchange and stroke volume did not change substantially although oxygen capacity and oxygen transport capacity decreased by about a third. The failure of cardiac output to rise after partial exchange transfusion with PolyHb-PPa contrasts with results after isovolemic hemodilution using non-oxygen-carrying blood substitutes and is not adequately explained by the oxygen capacity of 8.5% PolyHb-PPa (9.3 ml O2/dl).

Patterns of brain morphology in mid-European Cyprinidae (Pisces, Teleostei): a quantitative histological study.

The present study considers patterns of brain morphology in 14 common species of mid-European Cyprinidae. Sixteen areas per brain were measured on serial cryostat sections by computer-aided planimetry. The volumes of these areas were expressed as % of the total brain volume. These brain centres (ranked according to falling values of the coefficient of variation VR, of the interspecific mean) are: Lobus facialis, L. vagus, central acustic area, Crista cerebellaris, Bulbus olfactorius, Eminentia granularis, Stratum opticum (of the optic tectum), Torus longitudinalis, Nucleus habenularis, Valvula cerebelli, Corpus cerebelli, Telencephalon, Tectum opticum, Diencephalon, Torus semicircularis, mesencephalic tegmentum. Seven primary sensory areas are leading in VR; highest in interspecific variability were the two special viscerosensory brainstem lobes for external (L. facialis) and internal (L. vagus) taste. Low in interspecific variability were integration centres (see above). By plotting the relative volumina of those brain centres which represent three major sensory modalities: brain stem chemosense, acoustico-lateralis and sense of vision, species are separated into three groups: 1) Most species scatter along an axis from moderately (Aspius aspius, Rutilus rutilus, Leuciscus cephalus, Scardinius erythrophthalmus, Alburnus alburnus, Chondrostoma nasus) to highly developed chemo- and acustico-lateralis centres (Vimba vimba, Abramis brama, Abramis ballerus). Blicca bjoercna is situated in the middle of this axis. Within the latter group the optic centres are evenly well developed. 2) Carassius carassius, Gobio gobio and Tinca tinca are characterized by relatively small acoustico-lateralis and optic areas, but highly developed chemocentres. 3) Pelecus cultratus is monotypic among the species investigated by having large acoustico-lateralis and optic, but modestly developed chemocentres. The brain patterns relative to life style are discussed.

[Effect of hydroxyethyl starch, oxypolygelatin and human albumin on the phagocytic function of the reticuloendothelial system in healthy subjects]. / Auswirkungen von Hydroxyäthylstärke, Oxypolygelatine und Humanalbumin auf die Phagozytosefunktion des Retikuloendothelialen Systems (RES) gesunder Probanden.

RES phagocytic function was determined in healthy volunteers prior to and up to 5 h after application of 10 ml/kg body weight of 6% hydroxyethyl starch (450,000; 0.7), 5.5% oxypolygelatin (30,000), or 5.0% human albumin solution. Phagocytosis (phagocytic index K) was evaluated in vivo by intravascular lipid clearance (Lipofundin clearance test). Immediately after infusion, the phagocytic rate increased by 30% in the hydroxyethyl starch group (n = 10; p less than 0.05), 14% in the oxypolygelatin group (n = 10; ns), and 24% in the albumin group (n = 8; ns). 2 h after infusion phagocytosis was still increased by 35% in the hydroxyethyl starch group (n = 10; p less than 0.05), by 18% in the oxypolygelatin group (n = 10; ns), and 13% in the albumin group (n = 8; ns). 5 h after infusion, K values had returned to normal in the albumin group (n = 4), but were still increased by 40% in the hydroxyethyl starch group (n = 4; ns). No statistically significant differences could be established among the 3 groups. The increase in the phagocytic rate, particularly after application of hydroxyethyl starch, might be explained by a dilution effect.