A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation.

STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied "dark" kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1.

Interlaboratory evaluation of genomic signatures for predicting carcinogenicity in the rat.

The Critical Path Institute recently established the Predictive Safety Testing Consortium, a collaboration between several companies and the U.S. Food and Drug Administration, aimed at evaluating and qualifying biomarkers for a variety of toxicological endpoints. The Carcinogenicity Working Group of the Predictive Safety Testing Consortium has concentrated on sharing data to test the predictivity of two published hepatic gene expression signatures, including the signature by Fielden et al. (2007, Toxicol. Sci. 99, 90-100) for predicting nongenotoxic hepatocarcinogens, and the signature by Nie et al. (2006, Mol. Carcinog. 45, 914-933) for predicting nongenotoxic carcinogens. Although not a rigorous prospective validation exercise, the consortium approach created an opportunity to perform a meta-analysis to evaluate microarray data from short-term rat studies on over 150 compounds. Despite significant differences in study designs and microarray platforms between laboratories, the signatures proved to be relatively robust and more accurate than expected by chance. The accuracy of the Fielden et al. signature was between 63 and 69%, whereas the accuracy of the Nie et al. signature was between 55 and 64%. As expected, the predictivity was reduced relative to internal validation estimates reported under identical test conditions. Although the signatures were not deemed suitable for use in regulatory decision making, they were deemed worthwhile in the early assessment of drugs to aid decision making in drug development. These results have prompted additional efforts to rederive and evaluate a QPCR-based signature using these samples. When combined with a standardized test procedure and prospective interlaboratory validation, the accuracy and potential utility in preclinical applications can be ascertained.

Clinicopathological and mycological spectrum of allergic fungal sinusitis in South India.

In the present study, we describe characteristic clinicopathological and radiological features as well as fungal culture results in a series of 24 patients with allergic fungal sinusitis (AFS). Nasal obstruction and discharge with nasal polyposis was the commonest (95.8%) clinical presentation. Allergic mucin was uniformly present in all patients. Aspergillus species were the commonest fungal isolates (95.8%). One case of mixed Aspergillus and Curvularia sinusitis as well as one case of Drechslera sinusitis were also identified. Typical computerized tomography scan features of hyperdense areas interspersed with soft tissue densities in the affected sinuses were seen in all patients. Application of appropriate diagnostic criteria is essential to establish the diagnosis of AFS and distinguish it from invasive fungal sinus infections.

Problems of classification of Henoch Schonlein purpura: an Indian perspective.

A 2-year prospective study was carried out in which 71 patients with primary cutaneous vasculitis were classified using the American College of Rheumatology (ACR) classification and the Chapel Hill Consensus Conference (CHCC) recommendations for Henoch Schonlein purpura (HSP). The sensitivity of the ACR criteria was 64.8% and that of the CHCC definition 31%. When the ACR criteria were combined with results of direct immunofluorescence (DIF) the sensitivity was 78.9%. The concordance between the two systems was low as only 12 patients fulfilled criteria for both classifications. Although the ACR criteria were found to be more useful in the classification of HSP our data suggest that they need to be modified to include adults with disease. The age at onset of disease was higher than that in the west. Seventy per cent of patients identified by either classification were > 20 years of age. The prevalence of gut involvement, microhaematuria and proteinuria was < 25% in both groups. The sensitivity of histopathology on the other hand was 80.4% and was not influenced by the duration of the lesion. The DIF test was a useful adjunct to histopathology if it was done within 48 h as the yield of a positive test was significantly higher in this group as compared to the patients who had the test done later.

Long-term outcome in patients with central neurocytoma following stereotactic biopsy and radiation therapy.

Total excision is usually the recommended treatment for central neurocytomas. The role of radiation therapy in their management is controversial, and is usually reserved for partially resected or recurrent tumours. Long-term outcome was studied in patients with central neurocytoma who were treated with radiation therapy. By retrospective chart review, eight patients with intraventricular tumours, who had undergone radiation therapy following stereotactic biopsy, were identified. The diagnosis of neurocytoma was confirmed based on positive immunostaining with synaptophysin. Clinical and radiological follow-up was obtained. Of eight patients, one died 5 years after treatment from shunt dysfunction and 1 had disseminated intracranial disease 15 months after treatment. Six patients were symptom-free at a mean follow-up period of 78 months and had good local control as demonstrated by CT. Since this tumour can be confused with an oligodendroglioma or an ependymoma on routine histopathology (as happened in seven of our cases); immunohistochemical studies with synaptophysin should be routinely performed for intraventricular glial tumours. Our study supports the beneficial effect of radiation therapy in the management of these tumours.

Pulmonary lipoblastoma: a case report.

We report a case of pulmonary lipoblastoma in a 2-year-old child. This pathology has not been previously reported in the English literature.

The calcified intracorporeal vacuole: an aid to the pathological diagnosis of solitary cerebral cysticercus granulomas.

Fifty four cases of single small (<20 mm) enhancing CT lesions (SSECTLs) of the brain that were excised between 1987 and 1995 were reviewed histologically. In 28 cases the entire cysticercus or its parts were found. In the remaining 26 cases, most had a histological picture suggestive of a parasitic granuloma. In six of these 26 cases, small ovoid masses corresponding in morphology to the intracorporeal vacuoles of a cysticercus were seen lying free in the cavitary space of the granuloma. This lends further strength to the contention that SSECTLs of the brain are caused by cysticercus, and that in the event of a surgical excision, absence of obvious parasitic parts should necessitate a closer search, as calcareous residues of the parasite might be the only evidence of the cysticercal aetiology in the granuloma.

Orbital apex leiomyoma with intracranial extension.

BACKGROUND: Leiomyoma is a rare, benign smooth muscle tumor of the orbit. It occasionally shows some histologic resemblance to other common tumors of the orbit like neurofibroma and schwannoma. Its location at the orbital apex is uncommon and only one case with intracranial extension has been reported so far. CASE DESCRIPTION: A nine-year-old boy presented to us with left orbital pain. Four years earlier he had undergone partial excision, elsewhere, of a tumor at the orbital apex, which was reported as a schwannoma. The computed tomography (CT) scan showed regrowth of the tumor with intracranial extension. The tumor was totally resected by an intracranial route. One year postoperatively there was no recurrence of the tumor. CONCLUSIONS: Leiomyoma of the orbit, though a benign tumor, does show regrowth after partial excision. Total excision, including any intracranial component, is advised. The cases reported so far are reviewed and the histopathology and possible etiopathogenesis of this tumor are discussed.

Quantitative analysis of CD1a (T6) positive Langerhans cells in human tonsil epithelium.

Fifty-one human palatine tonsils of both sexes and 4-54 years of age were studied for quantitative analysis of Langerhans cells in the epithelium using CD1a (T6), which is a specific immunological marker for Langerhans cells and indeterminate cells. Cryo-sections were stained using the avidin biotin peroxidase method. Using light microscopy, CD1a-positive dark brown cells with dendritic processes were identified as Langerhans cells, which were located in the epithelium, subepithelial tissue, follicles and interfollicular areas. The Langerhans cells were counted only in the tonsil epithelium per zone of 1.1 mm length of basement membrane. For each biopsy, 25 such zones were studied. The mean number (SEM) of Langerhans cells per zone of tonsil epithelium was found to be 37 (+/- 0.5). In the male, it was 36 (+/- 0.7) but in the female, it was 38 (+/- 0.2). In different age subgroups, the mean number (SEM) varied between 40 (+/- 1.7) and 14 (+/- 1.1). In the age subgroups of 11-15, 16-20, and 21-25 years, the mean number showed significant sex differences. Since the 11-15, 16-20, and 21-25 age subgroups in the female showed an increased number of Langerhans cells, it is concluded that the immunological role of the palatine tonsils is increased during puberty and adolescence. In the female, there was a negative correlation (r = -0.196, p < 0.01) between age subgroups and mean numbers, but in the male there was no correlation (r = 0.008). Overall, in all the 51 biopsies together, there was a negative correlation (r = -0.017, p < 0.01) and significant (p < 0.001) sex and age differences.

Role of S-100 staining in differentiating leprosy from other granulomatous diseases of the skin.

Since Mycobacterium leprae are rarely demonstrable in the tuberculoid spectrum of leprosy, a confirmatory diagnosis of leprosy can be made on the basis of finding active destruction of cutaneous nerves by granulomatous inflammation in a skin biopsy. Immunoperoxidase staining for S-100 protein, which is a marker for Schwann cells, was used to delineate nerves in lesional skin biopsies of 25 patients with tuberculoid and borderline tuberculoid leprosy as well as 15 controls with nonleprous granulomatous inflammation. Four different patterns of nerve damage were observed: infiltrated, fragmented, absent, and intact. All of the nonleprous granulomatous dermatoses showed only intact nerves, either inside or outside the granuloma, and so S-100 staining can be used to rule out leprosy.

Medullomyoblastoma: A case report.

Medullomyoblastoma is a rare tumour seen in childhood. We report a medullomyoblastoma occurring in the cerebellar vermis of a 4 year old boy. The light microscopic features, immunohistochemistry and histogenesis are described.

Subacute sclerosing panencephalitis : CT and MR imaging in a rapidly progressive case.

We report the findings on CT and MR imaging in a patient with rapidly progressive subacute sclerosing panencephalitis (SSPE), which correlated with the clinical progression of the disease. In view of the rapid neurological deterioration and CSF pleocytosis, a brain biopsy was done and this confirmed the diagnosis.

Effects of intranasal challenge with group A beta haemolytic streptococcus M type 49 in Swiss albino mice.

Mice are susceptible to natural infections with streptococci and therefore can serve as suitable animal models to study experimental streptococcal infections. In an earlier study, we had shown the development of pharyngeal colonization, antibody response and histopathological changes in the heart following intranasal (IN) challenge with a rheumatogenic serotype of group A beta haemolytic streptococcus, the M type 18. To determine if nonpharyngitis associated serotypes can also elicit similar responses, 30 Swiss albino mice were challenged intranasally with 2 x 10(7) colony forming units of a skin associated serotype of group A beta haemolytic streptococcus, the M type 49. Pharyngeal colonization varied from 64% (n = 30) in the first week to 69% (n = 16) during the fourth week after IN challenge. Eleven (36.7%) of the 30 animals studied showed antibody response to DNase B (ADNB) with peak titers varying from 150 to 1200 units. Wide variations were seen in ADNB titers in individual mice. Histopathological evidence for cardiac lesions were seen in three animals. The changes were mild and varied from mild to chronic endocardial inflammation to calcification. The study shows that Swiss albino mice are also susceptible to IN challenge with skin associated strains of GABHS and therefore can serve as useful models to study the effects of experimental infection with diverse serotypes of GABHS.

Krukenberg tumor of ovary with features of mucinous cystadenocarcinoma.

An unusual case of bilateral Krukenberg tumors having a predominant multicystic mucinous component which on gross and microscopic examination resembled a mucinous cystadenocarcinoma is presented. It is important to distinguish between these two tumors as Krukenberg tumours have a significantly worse prognosis.

Pharyngeal colonisation, ADNB response and development of cardiac lesions in mice following intranasal inoculation with group A beta haemolytic streptococcus M type 18.

Swiss albino mice from a randomly bred colony were inoculated intranasally with 1.6, 2 or 2.4 x 10(7) colony forming units of a mid-logarithmic phase culture of group A beta haemolytic streptococcus M type 18 for 3 days, 6 days or once a week respectively for three weeks. Pharyngeal colonisation could be observed in 67 (59.8%) of 112 mice on 4th day after inoculation and 14 (38%) of the 37 mice on 21st day. Out of 27 mice tested for determination of antibodies to deoxyribonuclease B at regular intervals for 98 days, 15 (55.5%) showed responses, with maximum titers varying from 50 units to 4800 units in individual mice. Histopathological evidence for cardiac lesions were seen in five (3.03%) of the 165 animals studied. These included one case of severe endocarditis, two cases of endocarditis with valvular lesions and one case with non-specific lymphocyte infiltration in the heart. One other animal showed subendocardial oval nodular aggregates. Although the cellular nature of these lesions were not determined, this study shows that Swiss albino mice can serve as suitable animal models to study experimental streptococcal infections. However these are preliminary observations and are to be confirmed and revalidated by further controlled experiments.

Histological studies in primary neuritic leprosy: changes in the apparently normal skin.

The visually normal skin of 196 patients diagnosed clinically to have primary neuritic leprosy was studied histologically to determine whether there were any specific changes due to the disease in this site. Histological changes due to leprosy were seen in 32.1% of the patients, and included, indeterminate leprosy in 19.4%, borderline tuberculoid leprosy in 6.6% and borderline lepromatous leprosy in 6.1%. The remaining biopsies showed mild non-specific dermal inflammation, mild nerve changes or no significant lesion. The nerve inflammation and/or granulomas were mostly in the deep dermal nerves or neurovascular complexes. This study shows that there is a cutaneous component to primary neuritic leprosy and the disease is not totally confined to nerves. The absence of visible hypopigmented patches in these patients is probably related to the deep location of the dermal inflammation.

Primary sphenoid and petrous apex esthesioneuroblastoma: case report.

A 62-year-old woman presented with raised intracranial pressure and features of a right cerebellopontine angle tumour with extension into the right middle cranial fossa. The patient died before a surgical excision could be performed. The autopsy revealed a primary esthesioneuroblastoma of the sphenoid sinus eroding the petrous bone and extending into the middle cranial fossa with metastatic tumour in the liver, and paratracheal and hilar lymph nodes. Although rare, esthesioneuroblastoma must be considered in the differential diagnosis of petrous-sphenoid lesions.

Cutis laxa.

Two sisters with inherited generalized cutis laxa and a young man with possible acquired cutis laxa are presented.