Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa.

BACKGROUND: The large unmet need of hidradenitis suppurativa/acne inversa (HS) therapy requires the elucidation of disease-driving mechanisms and tissue targeting. OBJECTIVE: Robust characterization of the underlying HS mechanisms and detection of the involved skin compartments. METHODS: Hidradenitis suppurativa/acne inversa molecular taxonomy and key signalling pathways were studied by whole transcriptome profiling. Dysregulated genes were detected by comparing lesional and non-lesional skin obtained from female HS patients and matched healthy controls using the Agilent array platform. The differential gene expression was confirmed by quantitative real-time PCR and targeted protein characterization via immunohistochemistry in another set of female patients. HS-involved skin compartments were also recognized by immunohistochemistry. RESULTS: Alterations to key regulatory pathways involving glucocorticoid receptor, atherosclerosis, HIF1α and IL17A signalling as well as inhibition of matrix metalloproteases were detected. From a functional standpoint, cellular assembly, maintenance and movement, haematological system development and function, immune cell trafficking and antimicrobial response were key processes probably being affected in HS. Sixteen genes were found to characterize HS from a molecular standpoint (DEFB4, MMP1, GJB2, PI3, KRT16, MMP9, SERPINB4, SERPINB3, SPRR3, S100A8, S100A9, S100A12, S100A7A (15), KRT6A, TCN1, TMPRSS11D). Among the proteins strongly expressed in HS, calgranulin-A, calgranulin-B and serpin-B4 were detected in the hair root sheath, koebnerisin and connexin-32 in stratum granulosum, transcobalamin-1 in stratum spinosum/hair root sheath, small prolin-rich protein-3 in apocrine sweat gland ducts/sebaceous glands-ducts and matrix metallopeptidase-9 in resident monocytes. CONCLUSION: Our findings highlight a panel of immune-related drivers in HS, which influence innate immunity and cell differentiation in follicular and epidermal keratinocytes as well as skin glands.

Diabetes mellitus and the skin.

Diabetes is a debilitating, life-threatening disease accounting in 2015 for the death of 5 million people worldwide. According to new estimations, 415 million adults currently suffer from the disease, and this number is expected to rise to 642 million by 2040. High glucose blood levels also affect the skin among systemic organs, and skin disorders can often predict the onset of this metabolic disorder. In this review, we address the pathomechanistic effects of diabetes on the skin and give an overview on the most common skin diseases associated with diabetes.

A novel Bcl-x splice product, Bcl-xAK, triggers apoptosis in human melanoma cells without BH3 domain.

Pro- and antiapoptotic proteins of the large Bcl-2 family are critical regulators of apoptosis via the mitochondrial pathway. Whereas antiapoptotic proteins of the family share all four Bcl-2 homology domains (BH1-BH4), proapoptotic members may lack some of these domains, but all so far described proapoptotic Bcl-2 proteins enclose BH3. The bcl-x gene gives rise to several alternative splice products resulting in proteins with distinct functions as the antiapoptotic Bcl-xL and proapoptotic Bcl-xS. Here, we describe a novel Bcl-x splice product of 138 amino acids termed Bcl-xAK (Atypical Killer), which encloses the Bcl-2 homology domains BH2 and BH4 as well as the transmembrane domain, but lacks BH1 and BH3. Weak endogenous expression of Bcl-xAK was seen in melanoma and other tumor cells. Interestingly, its overexpression by applying a tetracycline-inducible expression system resulted in significant induction of apoptosis in melanoma cells, which occurred in synergism with drug-induced apoptosis. After exogenous overexpression, Bcl-xAK was localized both in mitochondrial and in cytosolic cell fractions. By these findings, a completely new class of Bcl-2-related proteins is introduced, which promotes apoptosis independently from the BH3 domain and implies additional, new mechanisms for apoptosis regulation in melanoma cells.

[Abscess of the posterior cranial fossa. Report of 4 cases]. / Les abcès de la fosse cérébrale postérieure à propos de 4 cas.

The posterior cerebral fossa is an uncommon location for cerebral abscess. In most cases diagnosis is made at the encapsulation stage with the risk of life-threatening tonsillar herniation. The purpose of this retrospective study was to describe our experience in the management of four cases of abscess located in the posterior cerebral fossa between January 2000 and December 2004. All patients benefited from clinical examination and radiological study (CT-scan). Surgical treatment performed in all cases consisted of trepano-puncture of the abscess. The minimum duration of post-operative follow-up was 6 months. Mean patient age was 38.75 years. All patients presented infectious syndrome and intracranial hypertension. The male:female sex ratio was 3:1. A history of chronic middle ear otitis was noted in two patients. Diagnosis of abscess in the posterior cerebral fossa was confirmed by CT-scan in 2 cases. Cholesteatoma and triventricular hydrocephaly were noted in 2 cases. All patients benefited from trepano-puncture of the abscess. Bacteriologic study of pus was positive for Staphylococcus aureus in 1 case, and Providencia Sp associated with Bactéroïdes fragilis in another. Second-stage radical mastoidectomy was performed in 2 cases. One patient died. The outcome was favorable in 3 cases. Because of the small size of the posterior cerebral fossa, abscess in that location requires emergency treatment. Delay can be life-threatening due to the risk of obstructive hydrocephaly and tonsillar herniation.

[Posterior cranial fossa abscess secondary to cholesteatoma]. / Cholestéatome compliqué d'abcès de la fosse postérieure.

OBJECTIVE: The intra cranial complications of chronic ear disease continue to pose a challenge in Senegal, despite advances in anti microbial therapy. Posterior cranial fossa abscesses are rare and continue to be associated with significant morbidity and mortality rates. We describe the presentation and management of a large cerebellar abscess secondary to cholesteatoma. METHODS AND RESULTS: A 11-year-old female presented with an inflammed fluctuant swelling of the right temporal region with ipsilateral otorrhoea. Examination demonstrated an auto atticotomy, large marginal perforation of the tympanic membrane associated with polyp. A diagnosis of otomastoiditis secondary to cholesteatoma was made. The abscess of the right temporal region was incised and drained and the patient was commenced on broad spectrum antibiotics. However the patients clinical status did not improve and there was a deterioration in her neurological status. CT brain and temporal bones demonstrated a large abscess in the cerebellum. 30 CC of pus were drained through a posterior fossa burr hole by the neurosurgeons. A radical mastoidectomy for extensive cholesteatoma of the right ear was subsequently carried out when the patients condition improved. CONCLUSION: Cerebellar abscess is a life threathning condition. In the presence of complicated chronic ear disease, clinical suspicion must be high as early symptoms and signs may be misleading. A low threshold for the performance of brain imagining will aid early diagnosis and allow prompt definitive treatment.

The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis.

Defective cytochrome c release and the resulting loss of caspase-3 activation was recently shown to be essential for the susceptibility of human melanoma cells to CD95/Fas-induced apoptosis. Cytochrome c release from mitochondria is regulated by the relative amounts of apoptosis-promoting and apoptosis-inhibiting Bcl-2 proteins in the outer membrane of these organelles. The assignment of Bax/Bcl-2 ratios by quantitative Western blotting in 11 melanoma cell populations revealed a relation to the susceptibility to CD95-mediated apoptosis. We could show that a low Bax/Bcl-2 ratio was characteristic for resistant cells and a high Bax/Bcl-2 ratio was characteristic for sensitive cells. Low Bax expression was not a consequence of mutations in the p53 coding sequence. The Bax/Bcl-2 ratio was also in clear correlation with sensitivity to another cell death inducer, N-acetylsphingosine. Furthermore, Bcl-2 overexpression abolished apoptosis triggered by both apoptotic stimuli, confirming the critical role of the Bax/Bcl-2 ratio as a rheostat that determines the susceptibility to apoptosis in melanoma cells by regulating mitochondrial function. Interestingly, some chemotherapeutics lead to the activation of death pathways by CD95L upregulation, ceramide generation, direct activation of upstream caspases, or upregulation of proapoptotic genes. Taken together, these signals enter the apoptotic pathway upstream of mitochondria, resulting in activation of this central checkpoint. We therefore assumed that apoptosis deficiency of malignant melanoma can be circumvented by drugs directly influencing mitochondrial functions. For this purpose we used betulinic acid, a cytotoxic agent selective for melanoma, straightly perturbing mitochondrial functions. In fact, betulinic acid induced mitochondrial cytochrome c release and DNA fragmentation in both CD95-resistant and CD95-sensitive melanoma cell populations, independent of the Bax/Bcl-2 ratio.

Disruption of the VDAC2-Bak interaction by Bcl-x(S) mediates efficient induction of apoptosis in melanoma cells.

The proapoptotic B-cell lymphoma (Bcl)-2 protein Bcl-x(S) encloses the Bcl-2 homology (BH) domains BH3 and BH4 and triggers apoptosis via the multidomain protein Bak, however, the mechanism remained elusive. For investigating Bcl-x(S) efficacy and pathways, an adenoviral vector was constructed with its cDNA under tetracycline-off control. Bcl-x(S) overexpression resulted in efficient apoptosis induction and caspase activation in melanoma cells. Indicative of mitochondrial apoptosis pathways, Bcl-x(S) translocated to the mitochondria, disrupted the mitochondrial membrane potential and induced release of cytochrome c, apoptosis-inducing factor and second mitochondria-derived activator of caspases. In melanoma cells, Bcl-x(S) resulted in significant Bak activation, and Bak knockdown as well as Bcl-x(L) overexpression abrogated Bcl-x(S)-induced apoptosis, whereas Mcl-1 (myeloid cell leukemia-1) knockdown resulted in a sensitization. With regard to the particular role of voltage-dependent anion channel 2 (VDAC2) for inhibition of Bak, we identified here a notable interaction between Bcl-x(S) and VDAC2 in melanoma cells, which was proven in reciprocal coimmunoprecipitation analyses. On the other hand, Bcl-x(S) showed no direct interaction with Bak, and its binding to VDAC2 appeared as also independent of Bak expression. Suggesting a new proapoptotic mechanism, Bcl-x(S) overexpression resulted in disruption of the VDAC2-Bak interaction leading to release of Bak. Further supporting this pathway, overexpression of VDAC2 strongly decreased apoptosis by Bcl-x(S). New proapoptotic pathways are of principle interest for overcoming apoptosis deficiency of melanoma cells.

[Epidermoid cyst of the cisterna magna and the fourth ventricle: Report of four cases]. / Kystes épidermoïdes de la grande citerne et du quatrième ventricule : à propos de quatre cas.

INTRODUCTION: Epidermoid cyst is a congenital and benign tumor, developed from ectodermal inclusion. These cysts occur very rarely in the cisterna magna and the fourth ventricle. OBJECTIVE: To report four cases of epidermoid cyst of the cisterna magna and the fourth ventricle in the light of the data of literature. PATIENTS AND METHODS: We report a retrospective study of four cases of epidermoid cysts of the cisterna magna and the fourth ventricle. The data was collected from January 2000 to December 2006 from to series of 18 cases of epidermoid cysts of posterior cranial fossa (14 cases were localised at the cerebellopontine angle). All the patients had a physical examination and a complete neuroradiological imagery. The treatment was surgical. The follow-up was at least 9 months. RESULTS: There were two men and two women. The mean age was 47.75 years. All patients presented with cerebellar syndrome. Three patients had intracranial hypertension. Neuroradiological explorations showed a cystic lesion developed in the cisterna magna in two cases, in the fourth ventricle in one case and in the two locations in one case. Two patients had hydrocephalus. All patients had surgery with a posterior approach and one patient had first ventriculoperitoneal shunt. The diagnosis was confirmed by histological examination. Postoperatory outcome was favourable in all cases. One patient developed bilateral chronic subdural hematoma, which was surgically removed. A long time follow-up was good in all cases. CONCLUSION: Epidermoid cysts are characterized by a long evolution. The diagnosis is relatively characteristic in the imagery. The prognosis was favourable with a complete surgical resection.

[Intramedullary neuroglial cyst: a case report]. / Kyste neuroglial intramédullaire : à propos d'un cas.

BACKGROUND AND PURPOSE: Neuroglial cysts are uncommon congenital lesion with own wall, which can be confined into or outside the central nervous system. In the central nervous system the cyst is located commonly in the brain. Spinal intramedullary neuroglial cyst are exceptional. Our objective is to present a case of intramedullary neuroglial cyst, to discuss the differentiels diagnosis and to show difficulties of its medical taking care. CASE REPORT: A 60 year-old man, without past history, was admitted to the hospital with a compression of conus medullaris since one year. The clinical examination revealed paraparesis and genito-sphincterian disorders. MRI of the spine revealed intramedullary cyst at T12-L1 level. The patient underwent cystic evacuation, a large marsupialization of the cavity and a wall biopsy. Histopathological examination confirmed the diagnosis of neuroglial cyst. The postoperative outcome was favourable with a partial improvement of motor weakness. Postoperative MRI showed a persistent residual cavity. CONCLUSION: Neuroglial intramedullary cyst is uncommon. It is a benign lesion. Complete surgical resection is very difficult seen the absence of defined plan cleavage.

[The occipital encephaloceles: report of 16 cases]. / Leb cephaloceles occipitales: a propos de 16 cas.

The encephaloceles belong to dysraphic state abnormalities. Publications on this issue are rare and sparse in Africa. The aim of our study is to describe clinical patterns of occipital encephaloceles, and emphasize on surgery. We collect retrospectively a population of 16 patients. Cranial Ultrasound Echographia has been done for all of them. Only 3 patients got brain CT scan. Medium age was 2 months. The sex ratio was coted 1. The consanguinity was noted in 37% of the cases. The pedicular aspects were more frequent. With neuroimaging studies the diagnosis was reached everytime. It showed hydrocephalus on 3 patients. 15 patients have been operated. One dead before going to surgery. The outcome was good for 13 patients (81%). But 3 patients (18%) deaded, and among them, 2 deaded during post surgery period. A better clinical evaluation showed be done using MRI. The control of epidemiology of these conditions depend on the improvement of the quality of eating in particularly in women bearing child, and performing a genetic counseling.

Effect of 5alpha-dihydrotestosterone and testosterone on apoptosis in human dermal papilla cells.

Pathogenetic mechanisms in androgenetic alopecia are not yet fully understood; however, it is commonly accepted that androgens like testosterone (T) and 5alpha-dihydrotestosterone (5alpha-DHT) inhibit hair follicle activity with early induction of the catagen. Thus, we investigated the influence of T and 5alpha-DHT on proliferation, cell death and bcl-2/bax expression in cultured dermal papilla cells (DPC) from nonbalding scalp regions of healthy volunteers. T and 5alpha-DHT induced apoptosis in DPC in a dose-dependent and time-related manner; in addition a necrotic effect due to T at 10(-5) M was found. Interestingly, bcl-2 protein expression was decreased in T- and 5alpha-DHT-treated cells, leading to an increase in the bax/bcl-2 ratio. In addition, T and 5alpha-DHT induced proteolytic cleavage of caspase 8 and inhibited proliferation of DPC at 10(-5) M. High concentrations of T and 5alpha-DHT were needed to induce apoptotic effects in DPC. These data suggest that DPC from nonbalding scalp regions do have the capacity to undergo apoptosis, but need a high androgen stimulus. The present study provides an interesting new pathogenetic approach in androgenetic alopecia.