John Call Dalton, Jr., MD: America's first neurophysiologist.

Before the discoveries of John Call Dalton, Jr., MD (1824-1889), innervation of laryngeal muscles, long-term effects of cerebellar lesions, and consequences of raised intracranial pressure were poorly understood. Dalton discovered that the posterior cricoarytenoid muscles adducted the vocal cords during inspiration. He confirmed Flourens' observations that acute ablation of the cerebellum of pigeons caused loss of coordination. Dalton observed that properly cared for pigeons gradually recovered "coordinating power." Dalton observed that prolonged raised intracranial pressure caused tachycardia and then fatal bradycardia in dogs. Before Dalton published his photographic atlas of the human brain, neuroanatomy atlases were sketched by Europeans and imported into the United States. Dalton's atlas of the human brain contained precise photographs of vertical and horizontal sections that equal modern works. Before Dalton introduced live demonstrations of animals, physiology was taught by recitation of texts only. Dalton was the first American-born professor to teach physiology employing demonstrations of live animals operated on under ether anesthesia. He wrote an essay advocating experimentation on animals as the proper method of acquiring knowledge of function and that humane animal experimentation would ultimately improve the health of man and animals. His eloquent advocacy for humane experimental physiology quelled attacks by contemporaneous antivivisectionists. Dalton was America's first experimental neurophysiologist.

The Process of Family Reconstruction after DNA Testing for Huntington Disease.

The needs of families to reconstruct their relationships in response to the DNA testing for Huntington disease of one or more of their asymptomatic members are presented. Data were collected from family interviews with 18 families, and from their responses on a post interview questionnaire. Findings are that families need to (a) address "unfinished business" associated with the decision for testing; (b) bring family members, peripheral in the decision for testing, into the loop; (c) reorganize patterns of communication and roles altered by the testing and heal ruptures in family membership; and (d) revise family stories about illness to provide a meaning for HD and explain the test results in a way that leaves them with a sense of mastery. Findings suggest that families should be more involved in the initial decision for testing of a member and that protocols should be established to provide help for their ongoing adjustment.

Impact of genetic testing for Huntington disease on the family system.

The psychological impact of DNA predictive testing on asymptomatic individuals at risk for Huntington disease (HD) has received considerable attention since the advent of the procedure in 1993. This study examined the impact of such testing on families from the families' perspective. Individuals asymptomatic at the time of testing, together with their families, were interviewed in their homes with a semi-structured interview. Eighteen families with a total of 55 individuals participated. Defining the family as the unit of analysis was consistent with Systems Theory that links interactions of individuals, families, and the social environment. Areas of affected family functioning noted by the respondents included: 1) family membership; 2) family patterns of communication; and 3) future care giving concerns as they influenced current relationships. Eighty-one percent of families experienced changes in family membership. Members in 50% of families experienced changes in patterns of communication, and 56% percent of persons reported changes in current relationships in response to test results and their implications for future caregiving. The data support the conclusion that genetic testing is a family, as opposed to an individual, matter and that family involvement in the decision making process should be strongly encouraged in order to help families adjust. The data imply that families will benefit in pre-test sessions from an examination of their patterns of dealing with illness issues, both past and present.

Two yeast La motif-containing proteins are RNA-binding proteins that associate with polyribosomes.

We have characterized two Saccharomyces cerevisiae proteins, Sro9p and Slf1p, which contain a highly conserved motif found in all known La proteins. Originally described as an autoantigen in patients with rheumatic disease, the La protein binds to newly synthesized RNA polymerase III transcripts. In yeast, the La protein homologue Lhp1p is required for the normal pathway of tRNA maturation and also stabilizes newly synthesized U6 RNA. We show that deletions in both SRO9 and SLF1 are not synthetically lethal with a deletion in LHP1, indicating that the three proteins do not function in a single essential process. Indirect immunofluorescence microscopy reveals that although Lhp1p is primarily localized to the nucleus, Sro9p is cytoplasmic. We demonstrate that Sro9p and Slf1p are RNA-binding proteins that associate preferentially with translating ribosomes. Consistent with a role in translation, strains lacking either Sro9p or Slf1p are less sensitive than wild-type strains to certain protein synthesis inhibitors. Thus, Sro9p and Slf1p define a new and possibly evolutionarily conserved class of La motif-containing proteins that may function in the cytoplasm to modulate mRNA translation.

Saccharomyces cerevisiae telomerase is an Sm small nuclear ribonucleoprotein particle.

Activation of the chromosome end-replicating enzyme telomerase can greatly extend the lifespan of normal human cells and is associated with most human cancers. In all eukaryotes examined, telomerase has an RNA subunit, a conserved reverse transcriptase subunit and additional proteins, but little is known about the assembly of these components. Here we show that the Saccharomyces cerevisiae telomerase RNA has a 5'-2,2,7-trimethylguanosine (TMG) cap and a binding site for the Sm proteins, both hallmarks of small nuclear ribonucleoprotein particles (snRNPs) that are involved in nuclear messenger RNA splicing. Immunoprecipitation of telomerase from yeast extracts shows that Sm proteins are assembled on the RNA and that most or all of the telomerase activity is associated with the Sm-containing complex. These data support a model in which telomerase RNA is transcribed by RNA polymerase II and 7-methylguanosine-capped, binds the seven Sm proteins, becomes TMG-capped and picks up the other protein subunits. We conclude that the functions of snRNPs assembled by this pathway are not restricted to RNA processing, but also include chromosome telomere replication.

Administrative update: utilization of services. III. Factors affecting emergency service utilization at a rural community mental health center.

Various factors may contribute to cyclical fluctuations in mental health emergency service utilization. Information regarding service utilization patterns would assist the planning and administration of such programs. Five years of data on emergency service contacts at a rural community mental health center were analyzed retrospectively in order to clarify which of an array of potential factors actually affect the utilization of emergency services. One way analyses of variance (ANOVA) or analogous nonparametric tests were performed. Furthermore analyses of significant group differences were performed by means of multiple comparison tests and confidence intervals. Significant associations with number of emergency contacts were found for season, day of week, holidays, school vacations and weather conditions. This study helps to elucidate those factors affecting psychiatric emergency service utilization at a rural community mental health center. Such factors may differ from those affecting other indicators of psychopathology.

Mini review: mitosis and the spindle pole body in Saccharomyces cerevisiae.

Cell duplication is characteristic of life. The coordination of cell growth with cell duplication and, specifically, the ordered steps necessary for this process are termed the cell cycle. Central to this process is the faithful replication and segregation of the chromosomes. The cycle consists of four phases: G1, where the decision to enter the cell cycle, which is known as Start, is made; S phase, during which the DNA is replicated; G2, during which controls assuring the completion of S phase operate; and M, or the mitotic phase, which is characterized by chromosome segregation, nuclear division, and cytokinesis. The budding yeast Saccharomyces cerevisiae has been developed into a model genetic system for the study of the cell division cycle (Hartwell et al. ["73] Genetics, 74:267-286). Here I review the basic processes by which chromosomes are segregated, with an emphasis on the physical structures fundamental to this process.

Incidence and correlates of tardive dyskinesia in first episode of schizophrenia.

BACKGROUND: There is controversy over whether tardive dyskinesia (TD) is solely a consequence of antipsychotic drug treatment or in part may reflect an intrinsic aspect of the disease process. Pathophysiologic factors could, independently or in concert with drug effects, lead to the development of dyskinetic signs. METHODS: We studied prospectively 118 patients in their first episode of psychosis who were treatment-naive or had less than 12 weeks of antipsychotic drug exposure at study entry. Patients received standardized antipsychotic drug treatment and were evaluated for up to 8 1/2 years with regular assessments of psychopathologic signs and symptoms and side effects. RESULTS: The cumulative incidence of presumptive TD was 6.3% after 1 year of follow-up, 11.5% after 2 years, 13.7% after 3 years, and 17.5% after 4 years. Persistent TD had a cumulative incidence of 4.8% after 1 year, 7.2% after 2 years, and 15.6% after 4 years. Taken individually, both antipsychotic drug dose, entered as a time-dependent covariate, and poor response to treatment of the first psychotic episode were significant predicters of time to TD. When antipsychotic drug dose and treatment response were examined together, treatment responders had significantly lower hazards for presumptive TD than nonresponders (hazard ratio, 0.29; 95% confidence interval, 0.09 to 0.97). Dose was a trend-level predicter, with each 100-mg chlorpromazine equivalent unit increase in dose associated with a 5% increase in the hazard of presumptive TD (hazard ratio, 1.05; 95% confidence interval, 0.99 to 1.11). CONCLUSION: Poor response to the treatment of a first episode of psychosis and, to a lesser extent, antipsychotic drug dose are important factors in the development of TD. This suggests that there may be a disease-related vulnerability to TD manifest with antipsychotic drug exposure. Potential pathophysiologic factors might include neurodevelopmentally induced structural neuropathologic characteristics, sensitization of nigrostriatal dopamine neurons, and the induction of glutamatergically mediated neurotoxic effects.

A highly divergent gamma-tubulin gene is essential for cell growth and proper microtubule organization in Saccharomyces cerevisiae.

A Saccharomyces cerevisiae gamma-tubulin-related gene, TUB4, has been characterized. The predicted amino acid sequence of the Tub4 protein (Tub4p) is 29-38% identical to members of the gamma-tubulin family. Indirect immunofluorescence experiments using a strain containing an epitope-tagged Tub4p indicate that Tub4p resides at the spindle pole body throughout the yeast cell cycle. Deletion of the TUB4 gene indicates that Tub4p is essential for yeast cell growth. Tub4p-depleted cells arrest during nuclear division; most arrested cells contain a large bud, replicated DNA, and a single nucleus. Immunofluorescence and nuclear staining experiments indicate that cells depleted of Tub4p contain defects in the organization of both cytoplasmic and nuclear microtubule arrays; such cells exhibit nuclear migration failure, defects in spindle formation, and/or aberrantly long cytoplasmic microtubule arrays. These data indicate that the S. cerevisiae gamma-tubulin protein is an important SPB component that organizes both cytoplasmic and nuclear microtubule arrays.

Toxic shock and Down syndromes in a dental patient: a case report and review of the literature.

A literature review of Toxic Shock Syndrome is presented, including epidemiology, etiology, signs, symptoms and management, and its relationship to infection susceptibility in the Down Syndrome patient. A case of a Down Syndrome patient with Toxic Shock Syndrome is described, and the role of odontogenic infection is discussed.

Drugs commonly used by the elderly: a review for dental practice.

Of all medications consumed in the U.S., the percentage used by the elderly is greater than can be justified by their numbers. Many medications have adverse effects. This paper reviews the 50 medications most used by the elderly and discusses adverse reactions which may present in the oral cavity or which have systemic effects with a potential impact on dental care. Composite tables summarizing the adverse reactions of interest to the dental practitioner are included for easy reference.

Combined Betaseron R (recombinant human interferon beta) and radiation for inoperable non-small cell lung cancer.

PURPOSE: Based on in vitro evidence of radiosensitization by Betaseron (beta-IFN), a Phase I/II study was undertaken to determine toxicity and response using combined radiation (RT) and B-IFN in patients with unresectable Stage III and nonsmall cell lung cancer. METHODS AND MATERIALS: Varying doses of beta-IFN(10 to 90 x 10(6) IU) were administered IV immediately preceding RT on the first three days of weeks 1, 3, and 5. The RT dose was 1.8 Gy/day, 5 days/week for a total of 54 or 59.4 Gy. RESULTS: Thirty-nine patients were entered, 32 of whom were evaluable. The median follow-up time at time of analysis was 60 months. Responses were based on CT scan. The response rate for the total group was 81% with 44% achieving complete response. Seventy-eight percent of patients with complete response survived a minimum of 21 months. Twenty-six patients had Stage III A/B disease with a median tumor size of 6.5 cm. and median survival was 19.7 months. The 5-year actuarial survival for this group was 31%, with a plateau persisting after 3 years. There were no treatment related deaths nor any event of life threatening toxicity. Of eight patients surviving 3-5 years, no long-term toxicity has been observed. Karnofsky indices were 90-100 and respiratory symptoms were minimal. CONCLUSION: beta-IFN is well-tolerated. Response and survival rates are sufficiently encouraging to warrant further investigation in a randomized trial which has been accepted as an RTOG study awaiting drug availability.

Cellular transcripts encoded at a locus which permits retrovirus expression in mouse embryonic cells.

Three independent recombinant retroviruses have been activated on insertion into the F2 locus of mouse F9 embryonal carcinoma cells. Each provirus has integrated downstream from the cellular F2 promoter, which is active in transient transfection assays using a chloramphenicol acetyltransferase reporter enzyme. The F2 promoter drives expression of a series of related transcripts in F9 and 3T3 cells, and a single 450-nt transcript in mouse tissues. F2 homologous sequences have been detected in the genomes of all mammalian species tested, and the 450-nucleotide (nt) F2 transcript is expressed in rat and human cells. Three pairs of differently sized F2 cDNA clones have been isolated and analyzed. The largest clones possess two 199-nt 98.5% identical repeats, one of which is present in the smaller clones, as well as the major 450-nt transcript. Activated proviral integration sites map to introns of the largest F2 cDNA clone. While none of the F2 cDNA contains a long open reading frame or homology to databank sequences, evidence suggests that the F2 locus encodes a constitutive function required at high levels, or represents an expressed but nonfunctional, single-copy element, conserved among mammals.

Retrovirus activation in embryonal carcinoma cells by cellular promoters.

Retrovirus expression in embryonal carcinoma (EC) cells is blocked at a postintegration stage of the viral life cycle, because of the inadequate function of the viral long terminal repeat (LTR) promoter in this cell type. However, rare sites in the EC cell genome permit provirus expression by undefined mechanisms. Our analysis of three expressed proviruses indicates that they have inserted into actively transcribed regions. Two of the three, examined in detail, integrated into the first introns of cellular transcription units in close proximity to active cellular promoters. One of these cellular genes is the probable murine homolog of the yeast ribosomal protein L3, responsible for trichodermin resistance. In all cases, virus activation appears to involve production of viral transcripts that are initiated in the 5'-flanking region, transcribed through the viral LTR, and subsequently spliced from a cellular donor to a viral acceptor. Our results suggest a general procedure for the isolation of active genes and promoters in different tissues.

Treatment of breast cancer with segmental mastectomy alone or segmental mastectomy plus radiation.

A retrospective review of the outcome of treatment for primary, Stage I and II breast cancer with segmental mastectomy (SGM) alone or segmental mastectomy plus postoperative irradiation (SGM + RT) at four Rochester, New York, city hospitals is reported. Between January 1971 and March 1984, 99 women were treated with SGM and 146 with SGM + RT. Groups were similar regarding significant clinical and histologic prognostic factors; they differed, however, in that the SGM group was considerably older (means = 72) than the SGM + RT group (means = 56). Among SGM patients, local and total locoregional failure was 26.44 and 35.2%, respectively. Local and total locoregional failure (7.6 and 12.4%, respectively) was significantly reduced among patients treated with SGM + RT (p less than 0.0001). Among SGM patients, there was scant advantage in enlarging the extent of resection from local excision (29.5% local failure) to wide local excision (27.3%) to quadrantectomy (22.2%). Among women receiving SGM + RT, similar rates of local failure occurred among patients receiving local excision (15.5%) and wide local excision (12.5%). By contrast, only 2.8% of those receiving quadrantectomy failed. Results are viewed as supportive of findings of NSABP-B06. Findings suggest that SGM constitutes inadequate treatment of Stage I and II breast cancer. Locoregional failure rates of 30-40% may be reduced to around 10% with postoperative irradiation.

Treatment of breast cancer among elderly women with segmental mastectomy or segmental mastectomy plus postoperative radiotherapy.

Elderly women with cancer are often treated non-aggressively. Between January 1972 and March 1984, 128 women greater than 60 years were treated for Stage I or II breast cancer with segmental mastectomy (SGM) plus/minus postoperative radiation at one of our four area hospitals. Whereas 82% of similar patients less than 60 years were referred for postop radiation, only 39.8% of patients greater than 60 were so referred. Referral rates progressively diminished with increasing patient age above 60. Thus, we reviewed the outcome of 77 elderly women treated with SGM and 51 treated with SGM+RT. Treatment groups were similar with regard to prognostic clinical and histologic parameters. Mean follow-up is 51.4 months. Among SGM patients, 45.5% of patients between 60-70 years, 37.9% of those greater than 70, and 20% of those greater than 80 years experienced loco/regional failure prior to death. Conversely, only two local failures occurred among all elderly women treated with SGM+RT. Distant failure was approximately 11% and was unaffected by treatment. Complications of SGM+RT were modest. These data suggest that SGM+RT can be safely and effectively applied to the elderly. Moreover, the data suggests that postop radiation may be more beneficial when extended to elderly patients post segmental mastectomy than among younger women. Referring surgeons should focus upon their patients' physiologic and not chronologic age as a basis for treatment allocation decisions.

Psychiatric consultations in two Israeli general hospitals.

Data were gathered on 479 inpatients of two Israeli general hospitals for whom psychiatric consultations were requested over a 1-year period. The data presented here include age and sex of referred patients, source of referral, reason for referral, psychiatric and physical diagnoses, and consultant's recommendation. Emergency ward consultations are included. Additional data were collected on patients transferred to psychiatric wards. Our findings are similar in general to those reported from other countries, although such comparisons are limited by the lack of uniformity in the classifications used by the various workers.