Ovarian steroid regulation of the midbrain corticotropin releasing factor and urocortin systems in macaques.

A significant number of postmenopausal women report increased anxiety and vulnerability to stress, which has been linked to decreased secretion of ovarian steroids. Communication between the serotonin system and the corticotropin releasing factor (CRF) system determines stress sensitivity or resilience. This study examines the effects of the ovarian steroids, estradiol (E) and progesterone (P) on the CRF system components that impact serotonin neurons in the midbrain of nonhuman primates. Ovariectomized rhesus macaques were treated with placebo, E alone for 1 month, or E supplemented with P for the last 2 weeks. Quantitative (q)RT-PCR and immunocytochemistry were employed. E±P treatment decreased CRF-R1 and increased CRF-R2 gene expression in hemi-midbrain blocks and in laser captured serotonin neurons. Also in hemi-midbrains, E treatment increased urocortin 1 (UCN1) and CRFBP gene expression, but supplemental P treatment reversed these effects. E±P decreased CRF fiber density in the dorsal, interfascicular and median raphe nuclei and decreased CRF-R1 immunostaining in the dorsal raphe. E increased CRF-R2 immunostaining in the dorsal and median raphe. E±P increased UCN1 immunostaining in the cell bodies and increased UCN1 fiber density in the caudal linear nucleus. Estrogen receptor beta (ERß), but not ERα was detected in the nucleus of UCN1-positive neurons. While the mechanism of ovarian hormone regulation of the midbrain CRF system requires further investigation, these studies clearly demonstrate another pathway by which ovarian hormones may have positive effects on anxiety and mood regulation.

Hypothalamic gonadotrophin-releasing hormone expression in female monkeys with different sensitivity to stress.

Psychosocial stress, combined with mild dieting and moderate exercise, are observed in women seeking treatment for hypothalamic amenorrhea. Using female cynomolgus macaques, we previously reported that the same combination of mild stresses suppressed reproductive hormone secretion and menstrual cycles in some individuals (stress-sensitive, SS), but not in others (highly stress-resilient, HSR). Compared to HSR monkeys, SS monkeys exhibited lower oestradiol and progesterone levels at the midcycle peak and decreased gene expression in the central serotonergic system during nonstressed cycles. Because steroids and serotonin impinge upon the hypothalamic-pituitary-gonadal (HPG) axis, we hypothesised that the differences between SS and HSR monkeys in the sensitivity of the HPG axis to stress may ultimately manifest in differences in the gonadotrophin-releasing hormone (GnRH) system. GnRH in situ hybridisation and immunohistochemistry were performed with hypothalamic sections from SS and HSR animals, euthanised in the early follicular phase of a nonstressed menstrual cycle. Compared to HSR monkeys, SS monkeys exhibited a significantly higher number and density of GnRH cell bodies, as well as a higher number of soma with extremely robust expression of GnRH mRNA, but SS monkeys exhibited a lower density of immunostained GnRH fibres in the median eminence. We suggest that neuronal mechanisms involved in the control of GnRH synthesis, transport and release differ in SS compared to HSR animals.

Pancreatic panniculitis associated with allograft pancreatitis and rejection in a simultaneous pancreas-kidney transplant recipient.

Pancreatic panniculitis is an uncommon condition that can occur in association with pancreatic disease. We present a case of pancreatic panniculitis in a female pancreas-kidney transplant recipient 5 months post-transplant. The patient was on standard immunosuppressive medications and had acute rejection of her renal allograft. The diagnosis of allograft pancreatitis and rejection presenting with pancreatic panniculitis was supported clinically, histopathologically and by laboratory and imaging data. This is the fourth case of pancreatic panniculitis occurring in a transplant recipient and the first in a simultaneous pancreas-kidney transplant recipient. It is also the first case associated with allograft rejection. Clinicians should be aware that pancreatic panniculitis may be a manifestation of underlying allograft pancreatic disease.

Expression and sequence of canine SIRT2 and p53 genes in canine mammary tumour cells - effects on downstream targets Wip1 and p21/Cip1.

We have characterized gene dysfunction in a cellular model of spontaneous canine mammary cancer by investigating specific gene defects in SIRT2 and p53 genes for comparative studies among canine tumour-derived cell lines. These genes and their downstream targets are involved in regulating gene silencing, cell cycle progression and prevention of senescence and apoptosis. Canine SIR2 reverse transcriptase-polymerase chain reaction amplicons were most homologous to human SIRT2 and revealed detectable transcripts in all cell lines. Canine SIRT2 contained non-conserved amino acid substitutions, representing mutations or allelic differences and interspecies differences. Sequence differences between individuals in p53 and SIRT2 were found in two cell lines including a stop codon in p53 and substitutions of conserved cysteine residues in the Zn(2+)-binding motif in SIRT2. Mutations in SIRT2 were coincident with expression of the p53 modulator, Wip1; a failure to activate p21/Cip1 and extended G2/M phase. A third cell line appeared to function normally in these two pathways and likely possesses other defects in proliferation-control genes. This data identify potentially important defects in pathways regulated by p53 and SIRT2 that modulate cell proliferation and integrate development, apoptosis and proliferative lifespan. These genes offer promising therapeutic targets, contributing to the transformed/immortalized phenotype in spontaneous canine mammary cancer.

Serotonin-related gene expression in female monkeys with individual sensitivity to stress.

Female cynomolgus monkeys exhibit different degrees of reproductive dysfunction with moderate metabolic and psychosocial stress. In this study, the expression of four genes pivotal to serotonin neural function was assessed in monkeys previously categorized as highly stress resistant (n=3; normal menstrual cyclicity through two stress cycles), medium stress resistant (n=5; ovulatory in the first stress cycle but anovulatory in the second stress cycle), or low stress resistant (i.e. stress-sensitive; n=4; anovulatory as soon as stress is initiated). In situ hybridization and quantitative image analysis was used to measure mRNAs coding for SERT (serotonin transporter), 5HT1A autoreceptor, MAO-A and MAO-B (monoamine oxidases) at six levels of the dorsal raphe nucleus (DRN). Optical density (OD) and positive pixel area were measured with NIH Image software. In addition, serotonin neurons were immunostained and counted at three levels of the DRN. Finally, each animal was genotyped for the serotonin transporter long polymorphic region (5HTTLPR). Stress sensitive animals had lower expression of SERT mRNA in the caudal region of the DRN (P<0.04). SERT mRNA OD in the caudal DRN was positively correlated with serum progesterone during a pre-stress control cycle (P<0.0007). 5HT1A mRNA OD signal tended to decline in the stress-sensitive group, but statistical difference between averages was lacking in analysis of variance. However, 5HT1A mRNA signal was positively correlated with control cycle progesterone (P<0.009). There was significantly less MAO-A mRNA signal in the stress-sensitive group (P<0.007) and MAO-A OD was positively correlated with progesterone from a pre-stress control cycle (P<0.007). MAO-B mRNA exhibited a similar downward trend in the stress-sensitive group. MAO-B OD also correlated with control cycle progesterone (P<0.003). There were significantly fewer serotonin neurons in the stress-sensitive group. All animals contained only the long form of the 5HTTLPR. Thus, all serotonin-related mRNAs examined in the dorsal raphe to date were lower (SERT, MAO-A) or exhibited a lower trend (5HT1A, MAO-B) in the stress sensitive animals, which probably reflects the lower number of serotonin neurons present.

Expression of CD95 (Fas) in sun-exposed human skin and cutaneous carcinomas.

BACKGROUND: Carcinomas of the skin are by far the most common human malignancies. Continuous exposure to ultraviolet (UV) light facilitates the development of precancerous lesions (actinic keratosis [AK]) that may progress to invasive squamous carcinomas. Apoptosis, triggered by the activation of CD95 (Fas), is one of the most important defense mechanisms against UV light-induced carcinogenesis in experimental models, but the dynamics of CD95 expression in patients with sun-induced lesions are largely unknown. METHODS: The authors studied the expression of CD95 (Fas) in biopsy samples of normal skin (not exposed to sun) and compared it with chronically sun-exposed skin (as evidenced by solar elastosis), AK, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), and keratoacanthomas (KA). RESULTS: Normal skin keratinocytes expressed CD95 in cytoplasmic membranes and intercellular bridges in the basal layer. In chronically sun-exposed keratinocytes (solar elastosis, no evidence of dysplasia), CD95 expression was up-regulated and was observed throughout the entire thickness of the epidermis. However, in actinic keratosis there was a complete absence of Fas in approximately two-thirds of the cases (8 of 12). In invasive SCC, CD95 was expressed focally and weakly only at the sites of contact with stromal lymphocytes. Keratoacanthomas consistently expressed CD95 at the interface with the inflammatory cells. No staining was observed in BCC. CONCLUSIONS: CD95 (Fas) up-regulation in chronically sun-exposed keratinocytes indicates an important role in the control of sun-induced damage. Further sun exposure results, however, in significant down-regulation of this defense mechanism, proportional to the degree of dysplasia.

Dysplastic nevi of the scalp and forehead in children.

To determine if there is a significant difference in the relative frequency and degree of atypia of sporadic dysplastic nevi from the scalp, face, and neck area in children as compared with nevi from the rest of the body, we reviewed 99 consecutive biopsy specimens of melanocytic nevi from the scalp, face, and neck areas in children less than 18 years of age and compared them with 95 consecutive cases of nevi from other areas of the body in children of the same age. Large numbers of the nevi biopsied from the scalp (13 of 31; 41.93%) and forehead (2 of 10; 20%) were dysplastic. The number of dysplastic nevi from the neck (1 of 58; 1.72%) was not assessed as very different from the incidence found in other regions of the body, where 7 dysplastic nevi (7.36%) from a total of 95 nevi were found. Of the 13 dysplastic nevi from the scalp, 9 showed minimal atypia and 4 showed moderate atypia. No nevi with severe atypia were found. Many pigmented nevi from the scalp and forehead in children in this study were dysplastic. This finding points out the importance of examining the scalp of children for the presence of dysplastic nevi. The majority of nevi from the neck were common nevi.

Extramammary Paget disease is characterized by the consistent lack of estrogen and progesterone receptors but frequently expresses androgen receptor.

Extramammary Paget disease (EPD) is an uncommon cutaneous malignant neoplasm that arises in areas rich in apocrine glands (perineum, vulva, and axilla). Apocrine gland origin or apocrine differentiation of cells of EPD has been suggested. Estrongen, progesterone, and androgen hormone receptors have been reported to exhibit a characteristic pattern of expression in mammary apocrine type carcinomas; however, their expression in EPD has not been elucidated fully. By using immunohistochemical methods, we studied the expression of steroid receptors in EPD on formalin-fixed paraffin-embedded tissue samples from 28 patients with EPD without associated visceral malignant neoplasms or adnexal carcinoma. Androgen receptor (AR) was identified in 15 of 28 cases. The proportion of AR-positive cells varied from 1% to more than 75%; 8 cases expressed AR in more than 10% of cells. Strong AR expression also was seen in the invasive carcinoma arising from 1 case of EPD. All cases lacked immunohistochemically detectable estrogen and progesterone receptors. The immunophenotype characteristic of apocrine carcinomas (AR-positive, estrogen receptor-negative, progesterone receptor-negative) was seen in a substantial proportion of EPD cases. Results suggest that AR expression is a factor in pathogenesis of EPD. This may be important for the therapy of recurrent or invasive disease.

Atrophic and plaquelike dermatofibrosarcoma protuberans.

It is clinically important to realize that dermatofibrosarcoma protuberans (DFSP) often begins as a nonprotuberant plaque and occasionally persists as such. Cases of what has been called atrophic DFSP have recently been reported. None of these cases varied either histologically or prognostically from classical nodular DFSP, and all should be considered part of the clinical spectrum of DFSP. However, histologic variants of DFSP can portend a worse prognosis. The fibrosarcomatous variant, which is fascicular and does not immunostain with anti-CD34, is an example. Recently, another fascicular variant that does positively immunostain with anti-CD34 has been described as plaquelike DFSP. We described a case of a DFSP that had histologically banal, slender fascicles of anti-CD34 immunostaining spindle cells in a clinically nonprotuberant plaque despite subsequently developing a nodule with typical storiform histology. The importance of anti-CD34 immunoperoxidase staining in the diagnosis and prognosis of DFSP variants is emphasized.

Mucoepidermoid carcinoma with cutaneous presentation.

Mucoepidermoid carcinomas are malignant neoplasms that rarely involve the skin. Composed of both mucus-secreting cells and epidermoid-type cells in various proportions, mucoepidermoid carcinomas occur most commonly in salivary glands. In this case report, we describe a high-grade mucoepidermoid carcinoma with cutaneous involvement. Although this patient was referred for Mohs' micrographic surgery, further evaluation showed either direct or metastatic extension from the parotid gland to skin and distant metastases to the lung and bone. Despite extensive bone involvement, serum levels of ionized calcium, phosphorus, and lactate dehydrogenase remained normal. In view of the widespread metastases, the treatment plan was altered to radiotherapy and chemotherapy instead of surgery. Instructive lessons from this case include the recognition by dermatologists of this rare entity, the importance of a detailed history and complete evaluation of the patient before determining appropriate therapy, and the necessity of individualizing diagnostic tests to a particular patient.

Nonlipidized juvenile xanthogranuloma: a histologic and immunohistochemical study.

Among all patients with a pathologic diagnosis of juvenile xanthogranuloma (JXG) seen at our institution from 1983 to 1994, we identified five patients with an unusual histologic pattern that differed from the classic juvenile xanthogranuloma (CJXG) with foamy cells and Touton giant cells. Four of these five cases, which we termed nonlipidized juvenile xanthogranuloma (NJXG), were seen in infants. The histologic features include a monomorphic infiltrate with absent or few foam cells and Touton giant cells. There is little inflammation, and mitotic figures are easily found. Four cases exhibit a diffuse sheetlike pattern while one is trabecular. Immunoperoxidase staining was done. All lesions are consistently positive for factor XIIIa as opposed to only focally positive or negative in CJXG and negative in Langerhans cell histiocytosis (LCH). The S-100 was negative. NJXG represents an atypical histologic variant of JXG, which may suggest a malignant or aggressive tumor. The follow-up, however, indicates that these lesions behave in a fashion similar to those of CJXG. The differential diagnosis should be made with LCH, intradermal nevus, and reticulohistiocytosis. The immunoperoxidase findings help to differentiate NJXG from these entities.

Multiple angiolymphoid hyperplasia with eosinophilia of the hand: report of a case and review of the literature.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare angioproliferative disorder with a predilection for the head and neck region. ALHE is very rare in the extremities and even more rare in the hand, with only single cases reported in this location. We describe the occurrence of multiple lesions of ALHE on the right hand of a 26-year-old woman. We report this unusual occurrence and convey a clinical differential diagnosis with other benign and malignant conditions of the hand. All the lesions of the palm were excised out as a unit, the subungual lesion removed completely, and the involved segment of the right common digital artery excised. The tissues were processed for routine histologic examination as well as for histochemical and immunohistochemical tests. Electron microscopic study was also performed. Recurrent lesions on the same hand were also excised. Histologic examination of all the lesions revealed classic morphologic features of ALHE. The results of special studies confirmed the endothelial nature of the proliferating cells. ALHE can present as multiple lesions in the hand, and can arise in a subungual location. The possibility of larger arteries being involved should be considered. Recurrent lesions may appear months after the original presentation.

Congenital smooth muscle hamartoma presenting as a linear atrophic plaque: case report and review of the literature.

Congenital smooth muscle hamartoma usually manifests as a well-circumscribed, hyperpigmented plaque, frequently hypertrichotic, on the trunk or extremities. We report such a lesion in a 7-month-old girl that presented as a linear, mottled, purplish red plaque appearing in areas to be atrophic, involving her right buttock, posterior thigh and leg, and fifth toe. Although the clinical appearance suggested linear morphea, a biopsy specimen had numerous haphazardly oriented bundles of smooth muscle in the reticular dermis. Masson trichrome staining, smooth muscle specific actin, and electron microscopic studies confirmed the smooth muscle nature of the cells. A diagnosis of smooth muscle hamartoma was made. To our knowledge, this linear clinical presentation has not been described previously.

[Accumulated years of potential productive life lost due industrial accidents in Petróleos Mexicanos]. / Años acumulados de vida productiva potencial perdidos por accidentes de trabajo en Petróleos Mexicanos.

OBJECTIVE: There are different indicators to give priority to health problems within the area of occupational health; we propose the calculation of accumulated years of potential productive life lost (AYPPLL) to estimate the loss of material and human resources due to work accidents. MATERIAL AND METHODS: A total of 8 638 work accidents were analyzed using this method. Independent variables were: sex, age, place and type of accident, subject's income and work conditions. The dependent variable was permanent disability. RESULTS: Subjects who had some kind of permanent damage were 19.5%; the total number of AYPPLL was 5611, with an average of 3.2 YPPLL per accident. Variables associated with the highest AYPPLL were the sociodemographic variables, male sex, lowest income levels, temporary work contracts and injuries of the hand and wrist. CONCLUSIONS: The AYPPLL method was found to be a valuable indicator of the safety and hygiene of the worksite and a useful tool for planning and evaluating work accident programs.

Multiple cutaneous myxomas. Report of a case without other elements of Carney's complex.

An 11-year-old hispanic female was referred for evaluation of multiple asymptomatic papules which had slowly developed since age two. The patient had no significant medical history and no family members, including an older sibling, were similarly affected. Physical examination revealed multiple 2-6 mm flesh-colored to erythematous papules over the posterior scalp, trunk, and extremities, predominantly in a midline distribution. No lentigines, blue nevi, or evidence of endocrine ab-normalities were noted. Echocardiogram was normal with no evidence of myxoma. Six cutaneous biopsies showed myxomas, as evidenced by well-circumscribed dermal tumors composed of stellate, dendritic cells embedded in a mucinous stroma. Special stains and electron microscopy confirmed the H&E finding. Immunoperoxidase staining for Factor XIIIa was positive in the dendritic tumor cells, suggesting a relationship with dermal dendrocytes. This patient represents a case of multiple cutaneous myxomas without other components of Carney's complex of myxomas, spotty pigmentation, endocrine overactivity, and a variety of uncommon tumors. A long-term follow-up is indicated since some of the above cited elements of the syndrome could appear over time.