Prospective multicentre cohort study on 9154 surgical procedures to assess the risk of postoperative bleeding - a DESSI study.

BACKGROUND: To date, there is still a debate how to deal with patients receiving antithrombotic agents prior to surgical procedures on the skin. OBJECTIVE: To prospectively assess complications after dermatosurgical interventions, especially bleeding, depending on anticoagulation therapy. METHODS: Patients underwent surgery consecutively as scheduled, without randomization, whether or not they were currently taking anticoagulants. Nine institutions of the DESSI (DErmatoSurgical Study Initiative) working group documented patient data prospectively on a standardized study sheet prior to and after 9154 dermatosurgical interventions. RESULTS: Bleeding complications were observed in 7.14% of cases (654/9154 surgeries). A severe bleed requiring intervention by a physician occurred in 83 surgeries (0.91%). In multivariate analysis, INR, length of the defect, perioperative antibiotic treatment, current treatment with anticoagulation therapy, age and surgery on hidradenitis suppurativa/acne inversa (HS/AI) were significant parameters independently influencing the risk of bleeding. Discontinuation of phenprocoumon therapy and subsequent switching to low molecular weight heparin was associated with the highest risk of bleeding (9.26%). CONCLUSION: Bleeding complications in skin surgery are generally rare. Even if slightly increased complication rates are found in patients taking anticoagulants during skin surgery, platelet inhibitors should not be stopped prior to surgery. If a surgical procedure in patients on a combination therapy of 2 or more antiplatelet cannot be postponed, it should be conducted with the patient remaining on combination therapy. Discontinuation of DOACs is recommended 24 h prior to surgery. Bridging of phenprocoumon should be terminated. In patients with a bleeding history, the INR value should be within the therapeutic range.

[Single center analysis of the dermatosurgical patient cohort of a tumor center in Germany]. / Betrachtung des dermatochirurgischen Patientenkollektivs an einem Hauttumorzentrum in Deutschland.

BACKGROUND: The incidence of skin cancer continues to increase. However, little is known about the dermatosurgical characteristics of the patients. PATIENTS AND METHODS: In this single center, retrospective study, dermatosurgical reports of all patients treated because of basal cell carcinomas (BCC), squamous cell carcinomas (SCC), and malignant melanoma (MM) between 2004 and 2013 were analyzed. RESULTS: During the observed period, the number of operated BCC rose by a factor of 1.86 and the number of MM by a factor of 2.3. In comparison to BCC/MM, there was a disproportionately high increase of SCC by a factor of 4.02. The average age was 71.5 ± 13.4 years (minimum: 14 years; maximum: 104 years), whereupon a significant increase of male age and a significant decrease of female age occurred. Almost 70% of all tumors were located in the head and neck area. The nose was most commonly treated. CONCLUSIONS: During the last 10 years, the cohort of dermatosurgical patients changed in the tumor center. This should be verified in multicenter studies.

A new subtype of pachydermodactyly: unilateral pachydermodactyly transgrediens.

Pachydermodactyly describes a rare condition of localized fibromatosis, usually symmetrically affecting the interphalangeal joints of both hands. We describe a case of a new subtype of pachydermodactyly in a 14-year-old boy, which we term 'unilateral pachydermodactyly transgrediens'. This atypical pattern is caused by specific localized mechanical manipulation of the hands. This condition contributes to the completely indolent spectrum of pachydermodactyly, and usually does not need therapy. Therefore it is essential not to misinterpret it as an inflammatory state such as juvenile idiopathic arthritis. The correct diagnosis of pachydermodactyly and its rare subtypes, as we describe in this case, often spares the affected patients unnecessary invasive diagnostic procedures and immunosuppressive therapy.

[Foam sclerotherapy. Uses and indications in dermatology and phlebology]. / Schaumsklerosierung. Anwendung und Indikation in der Dermatologie und Phlebologie.

Foam sclerotherapy is a minimally invasive, effective technique for the treatment of varicoses up though venous malformations. This efficient therapy can be easily integrated in daily clinical practice and shows only minor side effects. It provides an alternative to invasive therapies like vein stripping, endovenous laser therapy or endovenous radiofrequency ablation, but without the need for anesthesia. The treatment can be performed in an outpatient setting and the patient is able to return quickly to everyday life.

One-stage reconstruction of deep facial defects with a single layer dermal regeneration template.

BACKGROUND: The reconstruction of deep facial wounds in oncological surgery is challenging. Especially for elderly multimorbid patients, a rapid procedure with acceptable aesthetic and reliable functional outcome is required. Recently, a new single layer skin substitute was developed. Integra® dermal regeneration template single layer (IDRT-SL) allows one-stage surgery in combination with split thickness skin grafting. However, no study has yet analysed the efficiency of IDRT-SL treatment. OBJECTIVES: To evaluate applicability and efficiency of the IDRT-SL treatment in combination with split thickness skin grafting for a one-step closure of deep facial surgical wounds in elderly multimorbid patients. PATIENTS/METHODS: This prospective study analysed the functional and aesthetic outcome after reconstruction with an IDRT-SL template and an immediate split thickness skin graft in the face (80±3 years; >3 concomitant diseases). RESULTS: Nine tumours, four basal cell carcinoma, two lentigo maligna, one spinal cell carcinoma, one lentigo maligna melanoma and one Bowen carcinoma were resected. Five defects were located on the nose and four on the cheek. The mean defect size was 11±3 cm2. All but one graft were taken completely without any complication. One patient suffered from a partial graft loss (30%). All defects showed significant shrinkage of 61±4%. CONCLUSIONS: One-stage reconstruction with a combination of IDRT-SL and split thickness skin grafting is an elegant, easy and rapid method to treat deep skin defects. The take rates, functional and early cosmetic outcome are promising. This new method should be considered for selected cases of elderly multimorbid patients with deep facial wounds.

[Structures of lip reconstruction]. / Strukturierte Versorgung von Lippendefekten.

Although the incidence of tumors of the lips is low, they are the most common oral tumors and their therapy is often challenging for the surgeon. Depending on the extent of resected lip tissue, various surgical procedures are performed for reconstruction. They all follow the goal to combine complete tumor resection with maximal functional and aesthetic restoration. Surgical procedures are classified regarding the direction of tissue mobilization into one-, two- and three-dimensional techniques. Even though more than two hundred different techniques have been described, only a small number are used on a regular basis. To select the appropriate procedure for the individual patient the exact anatomic location and size of the defect have to be taken into consideration. Treatment algorithms may guide the surgeon to a suitable reconstructive procedure for each case. Complications may occur more often due to the size and the site of the procedure. Final functional and aesthetic results are usually satisfying.

[Asymptomatic nodule on an elderly lady's thumb tip]. / Asymptomatischer Nodus am Daumen einer älteren Frau.

A 71-year-old woman presented with an asymptomatic growing dermal tumor on her thumb. Clinical picture, ultrasound, laboratory investigations and histology were consistent with the diagnosis of gouty tophus. Pathogenesis, risk factors and therapy of tophaceous gout are discussed.

Expanding the horizons of histoplasmosis: disseminated histoplasmosis in a renal transplant patient after a trip to Bangladesh.

Histoplasmosis is recognized to occur in the Ohio and Mississippi River Valleys of the United States, but less widely appreciated is its worldwide distribution. We report a case of disseminated histoplasmosis with disease involving skin, lungs, and epiglottis in a renal transplant patient 6 months after a trip to Bangladesh, to highlight the potential risk of acquisition of this infection in the Indian subcontinent.

Long-term results after reconstruction of full thickness scalp defects with a dermal regeneration template.

OBJECTIVE: Large scalp defects in which the pericranium has to be resected can be reliably reconstructed using Integra. In the present study, we retrospectively analysed the long-term outcome of our patients. METHODS: Nineteen patients were included who had received Integra dermal regeneration template for treatment of full thickness scalp defects after resection of various malignant tumours. All patients were followed up with a mean follow-up time of 31 months (14-72). RESULTS: All transplants were on almost equal levels with the surrounding skin. Cosmetic results were acceptable and scars were stable. Nodal ultrasound status was negative in all patients. During the follow-up period of up to 72 months, no local recurrences were observed. One patient with a leiomyosarcoma received radiotherapy after transplantation. In the irradiated area, multiple small regular-shaped round ulcerations and later on partial necrosis of the transplant occurred when the patient developed renal failure 29 months after the initial operation. Five patients died of disease not related to the primary skin tumour. All other patients are alive and free of disease without any complications. CONCLUSION: After reconstruction of full thickness scalp defects with Integra, the cosmetic results are appealing and we observed no local recurrences during the follow-up period.

Influence of high dose tumescent local anaesthesia with prilocaine on systemic interleukin (IL)-6, IL-8 and tumour necrosis factor-α.

BACKGROUND AND OBJECTIVE: Tumescent local anaesthesia (TLA) with high prilocaine doses leads to formation of methemoglobin (MHb) which is known to be a potent activator of pro-inflammatory endothelial cell response in vitro. As TLA is widely used for large dermatological resections, the aim of this study was to investigate the effects of high prilocaine doses on the systemic inflammatory response in vivo and its clinical relevance. METHODS: This prospective study examines the influence of MHb on serum interleukin (IL)-6, IL-8 and tumour necrosis tumour necrosis (TNF)-α levels up to 72 h after application of TLA with prilocaine in doses higher than 600 mg. RESULTS: A total of 30 patients received prilocaine in a median dose of 1500 mg (range: 880-4160 mg) for large resections. Peak prilocaine serum concentration was reached 4 h (0.72 ± 0.07 µg/mL), the maximum concentration of MHb (7.43 ± 0.87%) and IL-6 (28.4 ± 4.1 U/L) 12 h after TLA application. TNF-α and IL-8 release were not found significantly increased. Three patients developed MHb concentrations >15%. CONCLUSIONS: This clinical study shows for the first time that a high prilocaine serum concentration leads in vivo to elevated systemic levels of IL-6 but not of IL-8 and TNF-α because of initial high MHb levels. Because of possible and unpredictable high MHb concentrations, TLA should only be performed with prilocaine in doses of 2.5 mg/kg. In general, new solutions of TLA are necessary to achieve adequate anaesthesia for large dermatological resections to decrease the risk of methemoglobinaemia.

Skin substitutes in dermatosurgery.

Skin substitutes are a growing market since technical advancements have allowed a substantial progress in treating extensive defects of the skin. A variety of skin substitutes with different properties and thus resulting different indications is offered on the market. Important benefits of skin substitutes are their ready availability in almost any quantity and the predictable product properties concerning implantation, incorporation, resorption and long-term outcome. Although, most skin substitutes still need skin grafts at a later date which is disadvantageous. Nevertheless dermal substitutes have reduced the need for thick skin grafts allowing the donor site and the patient to heal faster with fewer surgeries. The use of skin substitutes in dermatologic surgery is widespread and new fields of application are emerging. The variety of artificial skin has definitely changed the reconstructive ladder helping to cover larger defects with less time and effort which is an important issue especially in elderly and multimorbid patients. In the last years a growing number of studies in the literature report the use of artificial skin substitutes to secure a rapid reconstruction with reliable cosmetic and functional results after oncological resections. Furthermore, skin substitutes are used to cover chronic wounds like diabetic foot ulcers or venous leg ulcers to promote healing. Congenital diseases like giant hairy nevi, aplasia cutis congenital or epidermolysis bullosa are conditions in children where skin substitutes play a role. But even in tissue augmentation or in cosmetic surgery skin substitutes come into vogue. The latest advance are cultured autologous or allogenic substitutes some even in combination with alloplastic material. Besides of medical questions that arise from the use of these materials in reconstructive surgery legal and economic aspects have to be taken into account. This article is giving an overview over the most common skin substitutes and their use in dermatosurgery.

Effectiveness of highly active antiretroviral therapy using non-brand name drugs in Brazil.

In Brazil, HIV-infected individuals receive drugs (including non-brand name drugs which comprise locally produced generics and drugs that have not been tested in bioequivalence trials) free of charge from the government. The objective of the present study was to evaluate the effectiveness of highly active antiretroviral therapy (HAART) in Rio de Janeiro, Brazil, where non-brand drugs are widely used. For this purpose, we estimated the proportion of subjects with virologic failure (plasma HIV viral load greater than 400 copies/mL at 6 months after initiation of treatment). This was a retrospective cohort study of drug-naive HIV-infected subjects who initiated HAART. Subjects were included in the analysis if they were 18 years of age or older, were treatment naive, started HAART with a minimum of 3 drugs, and had available information on blood plasma HIV-1 viral load after 6 months on therapy. All subjects used antiretrovirals in dosing regimens recommended by the Brazilian National Advisory Committee for Antiretroviral Therapy. Chart reviews were conducted in three settings: at two public health outpatient units, at one clinical trial unit and at one private office. No comparisons of the effectiveness of non-brand name with the effectiveness of brand name drugs were made. We present results for 485 patients; of these, 354 (73%), 55 (11%), and 76 (16%) were seen at the public health outpatient units, private office, and clinical trial unit, respectively. Virologic failure was observed in 119 (25%) of the subjects. This study demonstrates the effectiveness of HAART in a setting where non-brand name drugs are widely used.

Mice with disrupted BK channel beta1 subunit gene feature abnormal Ca(2+) spark/STOC coupling and elevated blood pressure.

Large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) sense both changes in membrane potential and in intracellular Ca(2+) concentration. BK channels may serve as negative feedback regulators of vascular tone by linking membrane depolarization and local increases in intracellular Ca(2+) concentration (Ca(2+) sparks) to repolarizing spontaneous transient outward K(+) currents (STOCs). BK channels are composed of channel-forming BKalpha and auxiliary BKbeta1 subunits, which confer to BK channels an increased sensitivity for changes in membrane potential and Ca(2+). To assess the in vivo functions of this ss subunit, mice with a disrupted BKbeta1 gene were generated. Cerebral artery VSMCs from BKbeta1 -/- mice generated Ca(2+) sparks of normal amplitude and frequency, but STOC frequencies were largely reduced at physiological membrane potentials. Our results indicate that BKbeta1 -/- mice have an abnormal Ca(2+) spark/STOC coupling that is shifted to more depolarized potentials. Thoracic aortic rings from BKbeta1 -/- mice responded to agonist and elevated KCl with a increased contractility. BKbeta1 -/- mice had higher systemic blood pressure than BKbeta1 +/+ mice but responded normally to alpha(1)-adrenergic vasoconstriction and nitric oxide-mediated vasodilation. We propose that the elevated blood pressure in BKbeta1 -/- mice serves to normalize Ca(2+) spark/STOC coupling for regulating myogenic tone. The full text of this article is available at http://www.circresaha.org.

Lack of neurotrophin-4 causes selective structural and chemical deficits in sympathetic ganglia and their preganglionic innervation.

Neurotrophin-4 (NT-4) is perhaps the still most enigmatic member of the neurotrophin family. We show here that NT-4 is expressed in neurons of paravertebral and prevertebral sympathetic ganglia, i.e., the superior cervical (SCG), stellate (SG), and celiac (CG) ganglion. Mice deficient for NT-4 showed a significant reduction (20-30%) of preganglionic sympathetic neurons in the intermediolateral column (IML) of the thoracic spinal cord. In contrast, neuron numbers in the SCG, SG, and CG were unchanged. Numbers of axons in the thoracic sympathetic trunk (TST) connecting the SG with lower paravertebral ganglia were also reduced, whereas axon numbers in the cervical sympathetic trunk (CST) were unaltered. Axon losses in the TST were paralleled by losses of synaptic terminals on SG neurons visualized by electron microscopy. Furthermore, immunoreactivity for the synaptic vesicle antigen SV2 was clearly reduced in the SG and CG. Levels of catecholamines and tyrosine hydroxylase immunoreactivity were dramatically reduced in the SG and the CG but not in the SCG. Despite this severe phenotype in the sympathetic system, blood pressure levels were not reduced and displayed a pattern more typical of deficits in baroreceptor afferents. Numbers of IML neurons were unaltered at postnatal day 4, suggesting a postnatal requirement for their maintenance. In light of these and previous data, we hypothesize that NT-4 provided by postganglionic sympathetic neurons is required for establishing and/or maintaining synapses of IML neurons on postganglionic cells. Impairment of synaptic connectivity may consequently reduce impulse flow, causing a reduction in transmitter synthesis in postganglionic neurons.

Abnormal lysosomal sorting with an enhanced secretion of cathepsin D precursor molecules bearing monoester phosphate groups.

It has been reported that besides defects in the phosphorylation such as in the I-cell disease, a failure in the uncovering of mannose 6-phosphate residues may result in an increase of lysosomal enzyme activities in serum [Alexander et al., Hum. Genet. 73, 53-59 (1986)]. We examined fibroblasts that were derived from the original biopsy, observed an enhanced secretion of lysosomal enzymes including cathepsin D, but found that both the phosphorylation and uncovering of mannose 6-phosphate residues were normal. The enhanced secretion of cathepsin D was characterized by an increase in the secretion of phosphorylated molecules that were sensitive to a treatment with alkaline phosphatase. The enhanced secretion of the phosphatase-sensitive form of procathepsin D was further increased in the presence of antibodies directed to cation-independent mannose 6-phosphate receptors. In contrast, antibodies specific to cation-dependent mannose 6-phosphate receptors selectively inhibited the secretion of the phosphatase-sensitive procathepsin D molecules. A chromatographic analysis of oligosaccharides from the secreted procathepsin D confirmed that the cells secrete proenzyme molecules rich in oligosaccharides with two uncovered phosphate residues. It is suggested that the enhanced secretion of procathepsin D in the variant fibroblasts results from an abnormal sorting rather than processing of phosphorylated lysosomal enzymes.

Chronic ETA receptor blockade attenuates cardiac hypertrophy independently of blood pressure effects in renovascular hypertensive rats.

In isolated cardiac myocytes, the direct effects of angiotensin II on cellular growth and gene expression were shown to be mediated by endothelin via the endothelin subtype A (ETA) receptor. To determine whether this pathway is also involved in the cardiovascular adaptations to a chronic activation of the renin-angiotensin system in vivo, the effects of a selective ETA receptor antagonist (LU 127043) were investigated in adult rats with renal artery stenosis. Four groups of rats (n=107) were studied over a period of 10 days after surgery: (1) sham-operated animals with saline administration, (2) rats subjected to left renal artery clipping with saline administration, (3) sham-operated rats with LU 127043 administration, and (4) rats subjected to left renal artery clipping with LU 127043 administration. LU 127043 (50 mg/kg) or saline was given by gavage twice daily starting 1 day before the operation. In clipped rats with saline administration, plasma renin activity, the ratio of left ventricular weight to body weight, and mRNAs for beta-myosin heavy chain and atrial natriuretic peptide were significantly elevated as early as 2 days after surgery. Blood pressure started to rise on the third postoperative day and attained a steady state hypertensive level by day 6. Blockade of ETA receptors had no effects on plasma renin activity or the time course of hypertension in clipped animals but completely prevented left ventricular hypertrophy and the re-expression of the beta-myosin heavy chain and atrial natriuretic peptide genes on day 2. While the expressions of the beta-myosin heavy chain and atrial natriuretic peptide genes were not different from saline-treated, clipped animals after day 4, the development of left ventricular hypertrophy remained markedly blunted (-50%) during ETA receptor blockade until day 10. These results show that a continuous blockade of ETA receptors significantly attenuates the development of left ventricular hypertrophy and, more transiently, fetal gene expression in the early phase of renovascular hypertension. Since neither blood pressure nor the increase in plasma renin activity was significantly altered by ETA receptor blockade, the inhibitory influences of the ETA receptor antagonist on left ventricular hypertrophy and gene expression were mediated most likely through a direct blockade of myocardial ETA receptors.

Role of GABAA receptors in sleep regulation. Differential effects of muscimol and midazolam on sleep in rats.

To assess the influence of the gamma-aminobutyric acid (GABA)A receptor on sleep and sleep EEG, rats were injected intraperitoneally with vehicle, two doses of muscimol (0.2 and 0.4 mg/kg), a selective GABAA agonist, and midazolam (3 mg/kg), a benzodiazepine-GABAA agonist. EEG and EMG recordings were made for 6 or 8 hours. Muscimol dose-dependently increased the amount of nonrapid eye movement sleep (nonREMS) and REMS. The higher dose of muscimol enhanced EEG activity over almost the entire frequency range (0.5-25 Hz), including delta (0.5-4 Hz) and sigma (11-16 Hz) activity, within nonREMS and in the frequencies over 10 Hz within REMS. Midazolam also increased the amount of nonREMS. However, most of the other effects of midazolam contrasted the effects of muscimol: midazolam decreased REMS, reduced low frequency (< or = 11 Hz) EEG activity within nonREMS, and enhanced the activity in higher frequencies during both nonREMS and REMS. These data demonstrate the involvement of GABAA receptors in the regulation of sleep-wake behavior as well as in the generation of spindles and delta waves during nonREMS. The effects of these two GABAA agonists indicate that activation of different binding sites on the GABAA receptor complex differentially affect sleep states and sleep EEG.

Effect of the GABA uptake inhibitor tiagabine on sleep and EEG power spectra in the rat.

1. The sleep profiles induced by agonists and agonistic modulators of gamma-aminobutyric acidA (GABA[A]) receptors differ markedly. With regard to GABA(A) agonists, the effects may be due to the fact that these agents are poor substrates for uptake and are therefore likely to activate GABA(A) receptors tonically. To investigate this possibility, we assessed the sleep effects of two doses (2 and 10 mg kg[-1]) of the GABA re-uptake inhibitor tiagabine, administered intraperitoneally at light onset in 8 rats. Electroencephalogram (EEG) and electromyogram were recorded during the first 8 h after the injection. 2. Compared with vehicle, tiagabine had minimal effects on the temporal pattern of non-rapid eye movement sleep (non-REMS) and on the total time spent therein. However, tiagabine dose-dependently elevated EEG activity during non-REMs, most prominently in the lower frequencies (1-8 Hz) and least pronounced in the frequencies between 11 and 16 Hz. During the first 2 h after the injection, 10 mg kg(-1) tiagabine elicited repetitive episodes of hypersynchronous EEG waves during wakefulness and slightly suppressed REMS. Except for these effects, tiagabine hardly influenced the time spent in and EEG activity during wakefulness and REMS. 3. The effects of tiagabine on state-specific EEG activity were qualitatively very similar to those elicited by GABA(A) agonists. These findings support the hypothesis that the influence of GABA(A) agonists on EEG signals may be caused by tonic stimulation of GABA(A) receptors.

The GABAA agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans.

Recent studies in the rat demonstrated that systemic administration of muscimol and THIP, both selective GABAA receptor agonists, elevates slow wave activity in the EEG during non-rapid eye movement (NREM) sleep. In this placebo-controlled study, we assessed the influence of an oral dose of 20 mg THIP on nocturnal sleep in young healthy humans. Compared to placebo, THIP increased slow wave sleep by about 25 min. Spectral analysis of the EEG within NREM sleep revealed significant elevations in the lower frequencies (< 8 Hz) and reductions in the spindle frequency range (approximately 10-16 Hz). In accordance with previous findings in the rat, these data imply that GABAA agonists promote deep NREM sleep, without suppressing REM sleep. These effects are opposite to those induced by agonistic modulators of GABAA receptors such as benzodiazepines and are at variance with established mechanisms according to which GABAA agonists and modulatory agonists would have similar effects. The sleep response to GABAA agonists is highly similar to that evoked by sustained wakefulness, suggesting that GABAA receptors may be implicated in the homeostatic regulation of sleep.

The GABA(A) receptor antagonist picrotoxin attenuates most sleep changes induced by progesterone.

Progesterone has been shown to exert benzodiazepine-like effects on sleep, which suggests that they are mediated by an agonistic modulation of GABA(A) receptor functioning. To assess the involvement of GABA(A) receptors, we investigated the sleep responses to one dose of the GABA(A) antagonist picrotoxin (1.5 mg/kg) and progesterone (90 mg/kg), administered IP to eight rats alone and in combination, during the first 4 post-injection hours. Compared with vehicle, picrotoxin significantly delayed the latency to non-rapid eye movement sleep (non-REMS) and thereby decreased all sleep states, but barely affected the EEG activity within non-REMS. Progesterone significantly shortened non-REMS latency, increased pre-REMS, depressed low-frequency EEG activity (< or = 8 Hz) and augmented EEG activity in the higher frequencies within non-REMS. Except for the changes in high-frequency EEG activity, picrotoxin attenuated all effects of progesterone. These findings support the notion that GABA(A) receptors play an important role in the sleep effects of progesterone.