Faculty Bibliography

Hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D) is tightly linked to the Alzheimer amyloid precursor protein gene on chromosome 21, which codes for the amyloid beta-protein. A point mutation detected at position 1852 of the amyloid precursor protein gene in four HCHWA-D patients was hypothesized to be the basic defect. This study proves that 22 HCHWA-D patients from three pedigrees all carry this point mutation, whereas the mutation is absent in escapees from the HCHWA-D families as well as in randomly selected Dutch individuals. A mutation-specific oligonucleotide is now available for the confirmation of the HCHWA-D diagnosis. Therefore, presymptomatic testing and prenatal evaluation of individuals at risk in the HCHWA-D families is now feasible

Group A rotaviruses collected between 1985 and 1986 during comprehensive surveillance of treated diarrheal episodes occurring in a rural Bangladesh population were culture adapted and characterized by electropherotype, serotype, and subgroup. Of 454 episodes of rotavirus-associated diarrhea, rotaviruses were culture adapted from 381 (84%), and 335 contained 11 electrophoretically identical segments in unpassaged and cultured preparations. These 335 comprised 69 different electropherotypes with between 1 (32 isolates) and 79 representatives. The persistence of specific rotavirus strains within the study population, as defined by the detection of viruses with particular electropherotypes, was generally limited to a period of only a few months. All 335 isolates were serotyped by neutralization with hyperimmune antisera to prototype rotavirus strains representative of serotypes 1 to 4, i.e., Wa, DS-1, P, and ST-3. It was found that 80, 48, 119, and 88 isolates belonged to serotypes 1 to 4, respectively. The concentrations of hyperimmune antisera required to neutralize these isolates, however, were at least threefold greater than those needed to neutralize the homologous strains. Therefore, the isolates appeared to have altered neutralization epitopes from their prototype strains. Furthermore, the serotype 4 isolates were consistently shown to be much more closely related to the serotype 4B VA70 strain than the serotype 4A ST-3 strain. All but two isolates identified as serotypes 1, 3, or 4 had long electropherotypes and were subgroup II, and all but one serotype 2 isolate were subgroup I and had short electropherotypes. The three disparate strains appeared to be genetic reassortants. Evidence is presented that dual infections required for reassortant formation were not uncommon. Thus, formation of multiple reassortants may have been a cause for the observed rapid shift in viral strains within the study population.

Neurons in the dentate hilus or area CA3c of rat hippocampal slices were recorded intracellularly with electrodes containing the fluorescent dye Lucifer yellow. Stimulation of perforant path fibers in the molecular layer of the fascia dentata strongly excited most hilar neurons, with a much lower threshold for action potential generation than granule cells and area CA3c pyramidal cells that were recorded in the same area of the slice. Examination of dye-filled hilar neurons with a confocal microscope showed that hilar cells with a low threshold were morphologically heterogeneous: some were spiny 'mossy' cells, and others were aspiny interneurons. However, all hilar cells with low thresholds possessed dendrites that penetrated the granule cell layer and passed into the molecular layer, often reaching the outer molecular layer. The few hilar cells that had a threshold similar to, or greater than, granule cells did not possess visible dendrites in the molecular layer. The results suggest that the circuitry of the dentate region allows for (1) excitation of both granule cells and hilar cells by perforant path stimuli, and (2) strong excitation of most hilar cells when most granule cells are subthreshold for action potential generation. Given that hilar neurons project to many different sites in the ipsilateral and contralateral fascia dentata (Blackstad, 1956; Zimmer, 1971; Swanson et al., 1978; Laurberg and Sorensen, 1981), it is quite likely that hilar neurons are involved in the processing of information passing from entorhinal cortex to hippocampus

This is a study of factors associated with late recurrence (i.e. 10 or more years after definitive surgery) of cutaneous malignant melanoma (MM). Four factors were evaluated: Breslow thickness, site of the primary MM, age of the patient at initial treatment for MM, and gender. These factors were compared between two groups: (1) Stage I cases in the New York University Melanoma Cooperative Group (NYU-MCG) database that had 'early recurrence' (less than 10 years) of MM, and (2) cases in the literature with late recurrence of MM plus five new cases reported here. Compared to the group of patients with 'early recurrence' of MM, the group of patients who had late recurrence of MM were found more likely to have thinner primary melanomas (p less than 0.001), to be younger (p less than 0.001), to be female (p = 0.001), and, for females, to have the MM located on an extremity (p = 0.017). Because late recurrence does occur and because the risk of developing a new primary MM is increased in MM patients, any patient who has had a MM should be followed for life

Mouse NB2a/dl neuroblastoma cells elaborate axonal neurites in response to various chemical treatments including dibutyryl cyclic AMP and serum deprivation. Hirudin, a specific inhibitor of thrombin, initiated neurite outgrowth in NB2a/dl cells cultured in the presence of serum; however, these neurites typically retracted within 24 h. The cysteine protease inhibitors leupeptin and N-acetyl-leucyl-leucyl-norleucinal (CI; preferential inhibitor of micromolar calpain but also inhibits millimolar calpain) at 10(-6) M considerably enhanced neurite outgrowth induced by serum deprivation, but could not induce neuritogenesis in the presence of serum. A third cysteine protease inhibitor, N-acetyl-leucyl-leucyl-methional (CII; preferential inhibitor of millimolar calpain but also inhibits micromolar calpain), had no detectable effects by itself. Cells treated simultaneously with hirudin and either leupeptin, CI, or CII elaborated stable neurites in the presence of serum. Cell-free enzyme assays demonstrated that hirudin inhibited thrombin but not calpain, CI and CII inhibited calpain but not thrombin, and leupeptin inhibited both proteases. These results imply that distinct proteolytic events, possibly involving more than one protease, regulate the initiation and subsequent elongation and stabilization of axonal neurites. Since the addition of exogenous thrombin or calpain to serum-free medium did not modify neurite outgrowth, the proteolytic events affected by these inhibitors may be intracellular or involve proteases distinct from thrombin or calpain