Keratin in human lung tumors. Patterns of localization of different-molecular-weight keratin proteins.

In this immunohistochemical study, antiserums to different molecular weight keratin proteins (45kd, 46kd, 55kd, and 63kd) were utilized to determine the profiles of keratin proteins present in a variety of pulmonary neoplasms. Different histologic types of lung carcinoma exhibited different patterns of keratin staining. Squamous cell carcinomas stained strongly for 45K, 46K, and 55K keratin, with staining for 63K restricted to areas or individual cells with cytoplasmic keratinization. Adenocarcinomas showed variable, generally weak staining for 45K, 46K, and 55K keratin and were uniformly negative for 63K keratin both in frozen and paraffin sections. Mesotheliomas and reactive mesothelial cells, by contrast, stained positively for 63K keratin in addition to keratins of lower molecular weights. Differences in staining for 63K keratin between mesothelioma and adenocarcinoma may have diagnostic application. Moreover, individual cytokeratins may serve as markers of tumor differentiation and provide information as to the origin of neoplastic cells.     

Degree of Immunity Induced by Killed Vaccines to Experimental Salmonellosis in Mice

Killed vaccines, deoxycholate-extracted or heated, were shown to induce an effective degree of immunity which protected against death (100%), prevented extensive multiplication, and left the mice with low residual salmonella populations in spleen and liver after intravenous (iv) or intraperitoneal (ip) challenge with virulent Salmonella typhimurium. Protection was most effective against the ip challenge route and less effective against the iv route. A study of the kinetics of the population of bacteria in the spleens and livers of immunized animals showed that after ip challenge there was an initial reduction of 99% at 6 hr after challenge, maintenance of levels of less than 10(3) bacteria per organ, and a final population of 10(2) to 10(3) per organ at 21 days. With iv challenge, after an initial reduction of 90% at 6 hr, growth ensued to levels above 10(6) bacteria per organ until 8 days, followed by a steady decline yielding residual populations of 10(3) to 10(4) in some cases. Organ hypertrophy correlated with bacterial population. Morbidity was prevented (as measured by gain in body weight) by immunization against ip challenge but not against iv challenge. Killed vaccines protected by their ability to induce an immune state which reduced the initial challenge population, prevented extensive multiplication, yet allowed "cellular immunity" to develop due to response to the living challenge infection itself. The consequence was a low-level carrier state similar to that induced by recovery from sublethal virulent infection.     

STXBP1: the second synaptic vesicle release gene involved in epilepsy

De novo mutations in the gene encoding STXBP1 (MUNC18‐1) cause early infantile epileptic encephalopathy
Saitsu et al. (2008)
Nature Genetics 40: 782–788     

Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases

Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerative diseases resulting from the inability to catabolize GM2 ganglioside by beta-hexosaminidase A (Hex A) due to mutations of the alpha subunit (Tay-Sachs disease) or beta subunit (Sandhoff disease) of Hex A. Hex B (beta beta homodimer) is also defective in Sandhoff disease. We previously developed mouse models of both diseases and showed that Hexa-/- (Tay-Sachs) mice remain asymptomatic to at least 1 year of age while Hexb-/- (Sandhoff) mice succumb to a profound neurodegenerative disease by 4-6 months of age. Here we find that neuron death in Hexb-/- mice is associated with apoptosis occurring throughout the CNS, while Hexa-/- mice were minimally involved at the same age. Studies of autopsy samples of brain and spinal cord from human Tay-Sachs and Sandhoff diseases revealed apoptosis in both instances, in keeping with the severe expression of both diseases. We suggest that neuron death is caused by unscheduled apoptosis, implicating accumulated GM2 ganglioside or a derivative in triggering of the apoptotic cascade.      

Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment

The antenatal variant of Bartter's syndrome is an autosomal recessive kidney disease characterized by polyhydramnios, premature delivery, hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous, having been linked recently to mutations in an ATP- sensitive, renal outer medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl co-transporter, NKCC2. We characterized four of the mutations reported in three heterozygous ROMK variants of antenatal Bartter's and found that each expressed a distinct phenotype in Sf9 cells. One mutation expressed normal function and appears to be an allelic polymorphism. The other three mutations produced channels with significantly reduced K+fluxes. However, the mechanisms in each case were different and reflected abnormalities in phosphorylation, proteolytic processing or protein trafficking. The different mechanisms may be important in the design of appropriate therapy for patients with this disease.