Electroacupuncture ameliorates abnormal defaecation and regulates corticotrophin-releasing factor in a rat model of stress.

OBJECTIVE: To examine the effect of electroacupuncture (EA) treatment on abnormal defaecation in a rat model of chronic heterotypic stress (CHS) and investigate the underlying mechanisms. METHODS: 20 male Sprague-Dawley rats were randomly divided into three groups: normal (n=6), CHS (n=7), and CHS+EA (n=7). Rats in the CHS group and CHS+EA groups received four different types of stressors for 7 days. For rats in the CHS+EA group, EA was applied at ST36 in the bilateral hind legs for 30 min before each stress-loading session. Rats in the normal group did not receive stressors or EA treatment. The faecal pellets of each rat were collected and weighed at a fixed time every day. Protein expression of corticotrophin-releasing factor (CRF) in the hypothalamus and colorectal tissues was measured by Western blotting at the end of the experiment on the 7th day. RESULTS: After 7 consecutive days of CHS, the number of faecal pellets, faecal wet weight, and faecal water content were significantly increased in the CHS group compared with the normal group (p=0.035, p=0.008 and p=0.008, respectively). All three parameters were significantly decreased in CHS+EA versus CHS groups (p=0.030, p=0.011 and p=0.006, respectively). Stress significantly increased CRF expression in both the hypothalamus and colorectal tissues. The excessive CRF responses seen following CHS were significantly suppressed by EA treatment. CONCLUSIONS: EA treatment can ameliorate stress loading induced abnormal defaecation in rats and decrease protein expression of CRF centrally (hypothalamus) and peripherally (colorectal tissues), suggesting a potentially therapeutic role for EA in stress-related responses.

Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience.

BACKGROUND: Symptoms of epidural compression (SEC) in children with neuroblastoma (particularly infants) may be misinterpreted, leading to delay in diagnosis. PATIENTS AND METHODS: Clinical, imaging and follow-up data of 34 infants with neuroblastoma and SEC diagnosed between 2000 and 2011 at Italian AIEOP centers were retrieved and reviewed. RESULTS: Median age at initial SEC was 104 days (IQR 47-234). Main symptoms included motor deficit (85.3%), pain (38.2%), bladder and bowel dysfunctions (20.6% each). In the symptom-diagnosis interval (S-DI) (median, 12 days; IQR 7-34), the frequency of grade 3 motor deficit increased from 11.8% to 44.1% and that of bladder dysfunction from 20.6% to 32.4%. S-DI was significantly longer (P = 0.011) for patients developing grade 3 motor deficit. First treatment of SEC was neurosurgery in 14 patients, and chemotherapy in 20. SEC regressed in 11 patients (32.3%), improved in 9 (26.5%), and remained stable in 14 (41.2%), without treatment-related differences. Median follow-up was 82 months. At last visit, 11 patients (32.3%) were sequelae-free while 23 (67.7%) had sequelae, including motor deficit (55.9%), bladder (50.0%) and bowel dysfunctions (28.4%), and spinal abnormalities (38.2%). Sequelae were rated severe in 50% of patients. Severe sequelae scores were more frequent in patients presenting with spinal canal invasion >66% (P = 0.039) and grade 3 motor deficit (P = 0.084). CONCLUSIONS: Both neurosurgery and chemotherapy provide unsatisfactory results once paraplegia has been established. Sequelae developed in the majority of study patients and were severe in a half of them. Greater awareness by parents and physicians regarding SEC is warranted.

c-Rel downregulation affects cell cycle progression of human keratinocytes.

The c-Rel protein, a member of the NF-κB transcription factor family, exerts unique and distinctive functions in various cell types. Although c-Rel is expressed in human epidermis, its functions in keratinocytes are poorly understood. Our small interfering RNA-based approach of c-Rel silencing in HaCaT keratinocytes induced altered cell morphology toward a spindle-shaped appearance. In addition, c-Rel downregulation resulted in increased apoptosis and significantly reduced proliferation towing to G2/M cell cycle delay, concomitant aberrant mitotic spindle formation, and induction of phospho-aurora A(Thr288). The relevance of c-Rel in epithelial carcinogenesis was further supported by detection of c-Rel expression in squamous cell carcinomas of the skin. Our studies indicate that c-Rel is a key regulator of cell fate decisions in keratinocytes such as cell growth and death and may have a role in epidermal carcinogenesis.

Involvement of mtDNA damage elicited by oxidative stress in the arsenical skin cancers.

Arsenic causes several human cancers. Arsenic-induced Bowen's disease (As-BD), the most common arsenical cancer, is characterized by increased proliferation, dysplasia, and individual cell apoptosis, all of which involve mitochondria. We reported that arsenic causes aberrant keratinocyte proliferation through mtTFA-mediated mitochondrial biogenesis in As-BD. Increasing mitochondrial biogenesis causes cells to undergo oxidative stress. However, how arsenic induces oxidative stress and causes mtDNA damage in arsenical cancers remains largely unknown. Using tissues from As-BD patients and arsenic-treated keratinocytes, we determined the oxidative stress, antioxidant enzymes, DNA-repair enzymes, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) level in mtDNA by immunofluorescence, real-time PCR, and western blot. The results showed that oxidative stress was enhanced in both As-BD and arsenic-treated keratinocytes. Antioxidant enzymes including manganese-superoxide anion and copper/zinc-superoxide anion and DNA-repair enzymes were upregulated concomitantly in tissues and cells. In arsenic-treated keratinocytes, increased mitochondrial oxidative stress and the 8-OHdG level in mtDNA were attenuated by pretreatment with ascorbic acid, a potent antioxidant. Further, we found several somatic mutations in the ND4, ND5, and ND6 genes of mtDNA in lesional but not in perilesional skin from As-BD patients. Taken together, the results suggest that oxidative damage and mutations to mtDNA might be involved in the arsenical skin cancers in the context of mitochondrial biogenesis.

Expression of cyclin D1 and cyclin E significantly associates with human papillomavirus subtypes in Bowenoid papulosis.

Human papillomavirus (HPV) incorporates high-risk HPV (hrHPV) and low-risk HPV (lrHPV) subtypes according to its contribution to oncogenesis. Different HPV subtypes could regulate the cell cycle of infected cells at different levels. To date, the expression of cyclin D1 and cyclin E in Bowenoid papulosis (BP) tissues and its association with HPV infection still remains elusive. In the present study, genotyping was performed to identify the HPV subtypes in 44 BP specimens. In addition, immunohistochemistry was performed to detect the expression of cell cycle related proteins cyclin D1 and cyclin E in BP tissues as well as normal tissues. We found that there were 20 patients with hrHPV subtypes, 6 patients with lrHPV subtypes, and 18 patients with combined high and low (hr/lr) HPV subtypes. Cyclin D1 expression in patients with hrHPV subtypes (P=0.0408), in patients with lrHPV subtypes (P=0.0002) and in patients with hr/lr HPV subtypes (P=0.0047) was significantly higher than that in normal controls, respectively. Cyclin D1 expression in patients with hr/lr HPV subtypes (P<0.0001) and in patients with lrHPV subtypes (P=0.0244) was significantly higher than that in patients with hrHPV subtypes, respectively. Cyclin E expression in patients with hrHPV subtypes (P<0.0001), in patients with lrHPV subtypes (P=0.0005), and in patients with hr/lr HPV subtypes (P<0.0001) was significantly higher than that in normal controls, respectively. Cyclin E expression in patients with hrHPV subtypes was significantly higher than that in patients with lrHPV subtypes (P=0.0032). Our data suggest that HPV infection is strongly associated with the pathogenesis of BP, and further support the notion that HPV may be involved in the regulation of the expression of cell cycle related proteins, cyclin D1 and cyclin E, in the pathogenesis of BP.

PpIX fluorescence combined with auto-fluorescence is more accurate than PpIX fluorescence alone in fluorescence detection of non-melanoma skin cancer: an intra-patient direct comparison study.

BACKGROUND: Previous research on fluorescence detection of non-melanoma had mixed results. An accurate non-invasive method for the detection of skin cancer is valuable to dermatologists because of the high incidence of skin cancer among the aging population. One notable difference between the methods of fluorescence detection previously studied was the use of the auto-fluorescence of the skin. Currently, there has not been a direct comparison between both methods of fluorescence detection. OBJECTIVE: To compare the accuracy of PpIX fluorescence and auto-fluorescence normalized PpIX fluorescence detection systems for the localization non-melanoma skin cancers (NMSC). METHODS: We conducted an observer blinded direct comparison of both methods. Thirty patients, 14 females and16 males, mean age 62 (SD = 9 years), skin type I to III and being suspected of having one or more NMSC, visited an independent treatment centre for dermatology. The patients were investigated using a fluorescence detection system capable of both normalized and non-normalized PpIX fluorescence measurements. Liposomal encapsulated 5-aminolevulinic acid was used as a photosensitizer. For each area being investigated, the associated normalized and non-normalized fluorescence measurements were directly compared. The results of the analysis were confirmed by clinical investigation using a dermatoscope. Both methods were evaluated based on the number of true and false positives and the number of true and false negatives. Specificity and sensitivity were calculated. Statistical significance of the findings was determined using Pearson's Chi-squared test. RESULTS: The non-normalized method was found to have a sensitivity of 27 % and a specificity of 39 % and the normalized method has a sensitivity of 97% and a specificity of 100%. This difference is statistically significant (p < 0.05). CONCLUSION: Using auto-fluorescence in PpIX fluorescence detection of NMSC is more accurate that PpIX fluorescence detection alone.

Photosensitizers and light sources for photodynamic therapy of the Bowen's disease.

Bowen's disease is a neoplastic skin disease, known as squamous cell carcinoma in situ. The treatment options for Bowen's disease are: cryotherapy, curettage, surgery, topical therapy and radiotherapy. In the past recent years, photodynamic therapy was used as a new treatment method. The purpose of this paper is to summarize the results of clinical and research studies with respect to the photodynamic therapy of Bowen's disease. A search of three databases was conducted using specific keywords and explicit inclusion and exclusion criteria for the study of photosensitizers, light sources and their efficacy in photodynamic therapy of Bowen's disease. Two photosensitizers have been used mainly for photodynamic therapy of Bowen's disease therapy: δ-aminolevulinic acid and methyl aminolevulinate. These photosensitizers have been activated with both coherent (lasers) and non-coherent (lamps and LEDs) light sources. Fluence has been set in a large domain (10-240 J/cm(2)) and irradiance was 0.23-100 mW/cm(2). All these light sources have the same efficacy. The high response rates were obtained using methyl aminolevulinate and light emitting diode as light source. These results have demonstrated that photodynamic therapy using methyl aminolevulinate as photosensitizer could be considered as one of the first therapeutic options for Bowen' disease.

Enfermedad de Bowen vulvar. Relación con el virus del papiloma humano / Bowen's disease of the vulva: association with human papillomavirus

La enfermedad de Bowen vulvar o neoplasia vulvar intraepitelial (VIN) es una lesión preinvasora en los genitales externos. La VIN de etiología viral está relacionada con la infección por virus del papiloma humano (VPH) (principalmente los serotipos 16 y 18), sobre todo a edades tempranas y en relación con cambios en la conducta sexual. Presentamos el caso clínico que corresponde a una paciente joven, portadora del VPH 16 y en control por neoplasia intraepitelial de cuello uterino tipo III (CIN III) tras una conización, que desarrolló una VIN extensa. Se realizó tratamiento quirúrgico (ninfectomía) sin recidiva a los 3 años y con buen resultado estético (AU)

Bowen’s disease of the vulva, also called vulvar intraepithelial neoplasia (VIN), is considered a premalignant lesion of the external genitalia. VIN of viral etiology is most often associated with human papillomavirus (HPV) subtypes 16 and 18 and typically occurs in younger premenopausal women. The main risk factor for HPV acquisition is sexual activity. We report the case of a young patient, a carrier of HPV subtype 16, with cervical intraepithelial neoplasia grade 3, who developed severe VIN. Wide local excision of the labia minora was performed. The cosmetic results were satisfactory and the patient has had no relapses after 3 years of follow-up (AU)

Enhanced gastrointestinal motility with orally active ghrelin receptor agonists.

The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders.

Long-term functional and quality of life outcomes of patients after repair of large perianal skin defects for Paget's and Bowen's disease.

INTRODUCTION: The assessment of long- term functional and quality of life outcomes of these patients following repair of large defects after surgical excision has not been reported. METHODS: Between 1992 and 2004, at two institutions, 18 patients underwent repair of a perianal defect for Paget's disease (n = 8) or Bowen's disease (n = 10) and were alive with intestinal continuity at last follow-up. Patients were mailed the fecal incontinence quality of life scale (FIQL) and the SF-36. RESULTS: Fourteen patients (78%) responded. Median follow-up for responders was 5 years. Mean age was 65 years with 12 females. Subcutaneous skin flaps (11) and split-thickness skin grafts (three) were used to repair the perianal defects, which were circumferential in 11 patients (79%). Nine patients reported incontinence and completed the FIQL. The FIQL scores of patients reporting incontinence were lower for lifestyle, coping/behavior, and embarrassment but not significantly different for depression compared to patients without incontinence. SF-36 scores of the patients were not significantly different from the normative population. CONCLUSION: Functional results after repair of large perianal defects are acceptable and overall quality of life (QOL) is similar to the normative population although a large proportion of patients have some form of incontinence that impacts certain aspects of their QOL.

Bladder and bowel dysfunction in Parkinson's disease.

Bladder dysfunction (urinary urgency/frequency) and bowel dysfunction (constipation) are common non-motor disorders in Parkinson's disease (PD). In contrast to motor disorder, the pelvic autonomic dysfunction is often non-responsive to levodopa treatment. Brain pathology mostly accounts for the bladder dysfunction (appearance of overactivity) via altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. In contrast, peripheral enteric pathology mostly accounts for the bowel dysfunction (slow transit and decreased phasic contraction) via altered dopamine-enteric nervous system circuit, which normally promotes the peristaltic reflex. In addition, weak strain and paradoxical anal contraction might be the results of brain pathology. Pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore it might aid the differential diagnosis. Drugs to treat bladder dysfunction in PD include anticholinergic agents. Drugs to treat bowel dysfunction in PD include dietary fibers, peripheral dopaminergic antagonists, and selective serotonergic agonists. These treatments might be beneficial not only in maximizing patients' quality of life, but also in promoting intestinal absorption of levodopa and avoiding gastrointestinal emergency.

Pathologic changes after photodynamic therapy for Basal cell carcinoma and Bowen disease: a histologic and immunohistochemical investigation.

OBJECTIVE: To investigate the in vivo reactions and the mechanisms of cell death after photodynamic therapy (PDT) for cutaneous carcinomas. Photodynamic therapy is a new treatment modality for nonmelanoma skin cancers. Its effects on target tissue have been well investigated in vitro, where apoptosis appears to be the main effector mechanism, but its effects remain undefined in vivo. DESIGN: Skin biopsy specimens were obtained sequentially after PDT for basal cell carcinoma and in situ squamous cell carcinoma (Bowen disease). Evidence from routine histologic evaluation was compared with a panel of apoptosis-related (TUNEL [terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick-end labeling], caspase-3, and Bcl-2) and inflammatory (CD4, CD8, CD20, CD68, and CD56) markers. We used electron microscopy to evaluate cell damage at the ultrastructural level. MAIN OUTCOME MEASURES: Evidence of the mechanisms of tumor cell damage after PDT, detection of histologic and/or immunohistochemical signs of apoptosis, and time course of the tumor destruction and inflammatory reaction. RESULTS: Early epidermal damage and an acute dermal inflammatory response were detected 15 minutes after PDT. In basal cell carcinoma, nodule damage progressed from scant apoptotic cells seen at the dermal-epithelial junction to massive destruction seen after 1 and 2 days. The periphery of the basaloid nodules consistently showed earlier and predominant damage, as demonstrated by the perfect coincidence of histologic and immunohistochemical evidence with apoptotic markers (TUNEL and caspase-3 staining). Fibrosis and lentigolike changes were seen in late biopsy specimens. CONCLUSIONS: This study defines the time course and characteristics of the skin tumor response to PDT. Taken together, our observations suggest that direct damage to cancer cells is the main effector mechanism leading to PDT response. The involvement of apoptosis is demonstrated by the simultaneous appearance of histologic, immunohistochemical, and ultrastructural markers that occur in the early phases of the cutaneous reaction to PDT. These observations could help to develop future refinements of the PDT technique.

A case of Bowen's disease showing a clinical tendency toward spontaneous regression.

We present a case of Bowen's disease showing a clinical tendency toward spontaneous regression. The patient, a healthy 86-year-old woman, complained that erythema had appeared on her left forearm two years earlier and had gradually enlarged. At the first examination, we observed a well-demarcated, 4 x 3 cm, erythematous plaque, partically covered with crusting and erosions near the wrist. Diagnosis of Bowen's disease was confirmed by a biopsy. Since the patient refused surgery and also discontinued hyperthermic treatment with disposable chemical pocket warmers after a brief trial, we decided to continue the observation of disease progression without any treatment. Two years after the initial visit, the lesion showed a clinical tendency toward spontaneous regression, with a fine erythematous plaque that showed the obscurely demarcated border of the lesion. After three years, although the patient exhibited a similar symptomatic improvement, a skin biopsy showed a few residual tumor cells. At the patient's request, we chose to observe the progress of the lesion. We review the literature of cases of Bowen's disease that have shown a similar tendency toward spontaneous regression, which have been rare.

Enfermedad de Bowen perianal / Perianal Bowen disease

Antecedentes: La Enfermedad de Bowen es un carcinoma intraepitelial, no queratinizado de células escamosas de la piel. La localización perineal es poco frecuente. Objetivos: Analizar su forma de presentación, el tratamiento implementado y los resultados obtenidos. Diseño: Trabajo retrospectivo. Población: Pacientes con Enfermedad de Bowen perianal asistidos en nuestro Hospital en los años 2000 y 2001. Método: En todos los casos el diagnóstico se realizó por biopsias de áreas condilomatosas; en 1 caso se realizó resección amplia de la lesión. Conclusiones: La escasa sintomatología de esta patología retrasan su diagnóstico. Ante su sospecha es fundamental el minucioso examen de toda la región anogenital y la biopsia de toda lesión sospechosa. En la actualidad el consenso general mantiene como tratamiento de elección a la resección ampliada. El curso clínico de la enfermedad de Bowen es relativamente benigno con un riesgo a desarrollar un carcinoma invasor que no supera el 2 al 6 por ciento. El seguimiento en el tiempo es imprescindible para prevenir recurrencias. (AU)

Arsenic-related Bowen's disease, palmar keratosis, and skin cancer.

Chronic arsenical intoxication can still be found in environmental and industrial settings. Symptoms of chronic arsenic intoxication include general pigmentation or focal "raindrop" pigmentation of the skin and the appearance of hyperkeratosis of the palms of the hands and soles of the feet. In addition to arsenic-related skin diseases including keratosis, Bowen's disease, basal-cell-carcinoma, and squamous-cell carcinoma, there is also an increased risk of some internal malignancies. Arsenic-related diseases are common in areas of the world where the drinking water has a high arsenic content. In this paper, we describe a 35-year-old male patient who had arsenic-related keratosis, squamous-cell carcinoma in the palmar area of his left hand, and Bowen's disease on his left thigh. The patient worked in a borax mine for 15 years, so he was exposed to arsenic in drinking water, airborne arsenic in his workplace, and had direct contact. The patient was treated for 11 months for arsenic-related keratosis until an axillary lymph node metastasis occurred; the lesion was excised and diagnosed to be malignant. Bowen's disease was detected when the patient was being treated for cancer. No other malignancy was found. The patient is still receiving regular follow-up care.

Bowen's disease and arsenism from tobacco smoke: an association?

Bowen's disease has long has been associated with arsenic ingestion. Due mostly to arsenic-containing insecticides, the arsenic content of American tobacco was quite high until the early 1960s. A chart review of sixteen patients seen with Bowen's disease in the past five years showed that eleven (including five women) had been smokers in the 1950s. While these data may be insignificant, this possible association deserves further analysis. Arsenism from tobacco might explain the discordant results of the studies on the carcinogenicity of psoralen/ultraviolet A.

Enfermedad de Bowen Perianal: Reporte de un caso / Perianal Bowen disease: report of a case

La enfermedad de Bowen es una neoplasia cutánea que puede localizarse en la región perianal y que en ocasiones coexiste en forma sincrónica o asincrónica con carcinomas en otros órganos. Se presenta el caso de un paciente del sexo masculino de 38 años de edad, con enfermedad de Bowen perianal y condiloma acuminado perianal asociado, nuevo años antes había sido tratado por seminoma. El diagnóstico de la enfermedad de sospechó clínicamente, pero se confirmó con el estudio histopatológico de la lesión. El tratamiento consistió en excisión local más electrofulguración del lecho, con buenos resultados después de 5 años de seguimiento. En casos avanzados debe recurrirse a cirugía amplia y radioterapia. Es obligado el seguimiento por tiempo prolongado en estos pacientes

Preservation of anal function after total excision of the anal mucosa for Bowen's disease.

Six women with Bowen's disease of the anogenital area were treated by total excision of the anal mucosa, perianal skin and, in some cases, partial vulvectomy. Two patients had foci of microinvasive squamous carcinoma. Adequate tumor margins were determined by frozen sections. The resulting mucosal and cutaneous defects were grafted with medium split-thickness skin grafts applied to the anal canal and sutured circumferentially to the rectal mucosa. Grafts were held in place by a finger cot inserted in the anal canal and stuffed with cotton balls. Patients were constipated five or six days with codeine. The skin grafts healed per primam. One additional patient was similarly treated for a chronic herpetic ulceration of the anus and healed. Contrary to dire predictions, all patients were able to distinguish between gaseous and solid rectal contents and sphincter function was preserved. In one patient, Bowen's disease has recurred in the grafted perianal skin.