Biomedical subjects
Publications and source records attributed to M McGuire.
The diagnosis and treatment of the "gummy smile" (altered passive eruption, excessive gingival display) help the periodontist to provide the most beautiful smiles possible for patients. This article describes diagnosis, surgical planning, and case reports that show the benefits of treatment of this common clinical problem for the patient and restorative dentist who can now provide ideal cosmetic results for their patients.
Clostridium symbiosum pyruvate phosphate dikinase (PPDK) catalyzes the interconversion of adenosine 5'-triphosphate (ATP), orthophosphate (P(i)), and pyruvate with adenosine 5'-monophosphate (AMP), pyrophosphate (PP(i)), and phosphoenolpyruvate (PEP). The nucleotide binding site of this enzyme was labeled using the photoaffinity reagent [32P]-8-azidoadenosine 5'-triphosphate ([32P]-8-azidoATP). Subtilisin cleavage of the [alpha-32P]-8-azidoATP-photolabeled PPDK into domain-sized fragments, prior to SDS-PAGE analysis, allowed us to identify two sites of modification: one between residues 1 and 226 and the other between residues 227 and 334. Saturation of the ATP binding site with adenylyl imidodiphosphate afforded protection against photolabeling. Next, small peptide fragments of [gamma-32P]- 8-azidoATP-photolabeled PPDK were generated by treating the denatured protein with trypsin or alpha-chymotrypsin. A pair of overlapping radiolabeled peptide fragments were separated from the two digests, DMQDMEFTIEEGK (positions 318-330 in trypsin-treated PPDK) and RDMQDMEFTIEEGKL (positions 317-331 in alpha-chymotrypsin-treated PPDK), thus locating one of the positions of covalent modification. Next, catalysis by site-directed mutants generated by amino acid replacement of invariant residues of the PPDK N-terminal domain was tested. K163L, D168A, D170A, D175A, K177L, and G248I PPDK mutants retained substantial catalytic activity while G254I, R337L, and E323L PPDK mutants were inhibited. Comparison of the steady-state kinetic constants measured (at pH 6.8, 25 degrees C) for wild-type PPDK (kcat = 36 s-1, AMPK(m) = 7 microM, PP(i)K(m) = 70 microM, PEPK(m) = 27 microM) to those of R337L PPDK (kcat = 2 s-1, AMPK(m) = 85 microM, PP(i)K(m) = 3700 microM, PEPK(m) = 6 microM) and G254I PPDK (kcat = 0.1 s-1, AMPK(m) = 1300 microM, PP(i)K(m) = 1200 microM, PEPK(m) = 12 microM) indicated impaired catalysis of the nucleotide partial reaction (E.ATP.P(i) --> E-PP.AMP.P(i) --> E-P.AMP.PP(i) in these mutants. The single turnover reactions of [32P]PEP to [32P]E-P.pyruvate catalyzed by the PPDK mutants were shown to be comparable to those of wild-type PPDK. In contrast, the formation of [32P]E-PP/[32P]E-P in single turnover reactions of [beta-32P]ATP/P(i) was significantly inhibited. Finally, the location of the adenosine 5'-diphosphate binding site within the nucleotide binding domain of D-alanine-D-alanine ligase, a structural homologue of the PPDK N-terminal domain [Herzberg, O. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 2652-2657] indicates, by analogy, the location of the nucleotide binding site in PPDK. Residues G254, R337, and E323 as well as the site of photoaffinity labeling are located within this region.
The crystal structure of pyruvate phosphate dikinase, a histidyl multiphosphotransfer enzyme that synthesizes adenosine triphosphate, reveals a three-domain molecule in which the phosphohistidine domain is flanked by the nucleotide and the phosphoenolpyruvate/pyruvate domains, with the two substrate binding sites approximately 45 angstroms apart. The modes of substrate binding have been deduced by analogy to D-Ala-D-Ala ligase and to pyruvate kinase. Coupling between the two remote active sites is facilitated by two conformational states of the phosphohistidine domain. While the crystal structure represents the state of interaction with the nucleotide, the second state is achieved by swiveling around two flexible peptide linkers. This dramatic conformational transition brings the phosphocarrier residue in close proximity to phosphoenolpyruvate/pyruvate. The swiveling-domain paradigm provides an effective mechanism for communication in complex multidomain/multiactive site proteins.
BACKGROUND: This study estimates lifetime and one-month prevalence of psychiatric disorders among elderly public housing residents. METHOD: Nine hundred forty-five residents of six public housing developments for the elderly were administered the General Health Questionnaire (GHQ), the Mini-Mental State Examination (MMSE), and the CAGE by lay interviewers. Residents screening positive and a 10% random sample of screen negatives were administered the Structured Clinical Interview for DSM-III-R (SCID) and a DSM-III-R derived algorithm for dementia and delirium. Prevalence rates were estimated based on weighted data from 298 subjects. RESULTS: Thirty-six percent of participants screened positive on at least one instrument. Based on the case identification interview, estimated lifetime prevalence of psychiatric disorders was 57.6%, and one-month prevalence was 27.9%. Cognitive disorder (10.5%), mood disorder (8.0%), psychotic disorder (4.6%), and substance abuse/dependence (4.4%) were the most common current disorders. Mood disorders (26.6%) and substance abuse/dependence (23.0%) were the most prevalent lifetime disorders. Compared to data from the Epidemiologic Catchment Area, public housing residents have higher current rates of mood disorder, schizophrenia, and substance use disorder. CONCLUSIONS: Elderly residents of public housing suffer higher rates of psychiatric morbidity than older people living independently in the community. The high prevalence of psychiatric disorders in this growing population of low-income elderly presents a challenge to the delivery of mental health service.
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Previous studies had indicated that pyruvate phosphate dikinase (PPDK), an enzyme which catalyzes the interconversion of adenosine 5'-triphosphate (ATP), orthophosphate (P(i)), and pyruvate with adenosine 5'-monophosphate (AMP), pyrophosphate (PP(i)), and phosphoenolpyruvate (PEP), is made up of 25, 13, 18, and 35 kDa domains [Carroll, L. J., Xu, Y., Thrall, S. H., Martin, B. M. & Dunaway-Mariano, D. (1994) Biochemistry 33, 1134]. The catalytic histidine (which mediates the phosphoryl group transfers from ATP to P(i) and pyruvate) is located on the 18 kDa domain while the 25 and 13 kDa domains appear to contain the ATP binding site and the 35 kDa domain appears to contain the pyruvate binding site, respectively. The goal of this investigation was to examine functional interdependency of the putative ATP and pyruvate binding domains. Two truncated forms of PPDK were created by using recombinant DNA techniques. The 35 kDa (C-terminal) deletion mutant was found to catalyze the E+ATP+P(i)<-->E-P+AMP+PP(i) partial reaction but not the E-P+pyruvate<-->E+PEP partial reaction. The 25 kDa (N-terminal) deletion mutant was found to catalyze the E-P+pyruvate<-->E+PEP partial reaction but not the E+ATP+P(i)<-->E-P+AMP+PP(i) partial reaction. Neither mutant catalyzes the full ATP+P(i)+pyruvate<-->AMP+PP(i)+PEP reaction. These results are interpreted to mean that the ATP and pyruvate binding domains in PPDK are functionally independent, thus providing evidence for separate active sites for catalysis of the two partial reactions.
BACKGROUND: Although schizotypal personality disorder aggregates in relatives of schizophrenic probands, the criteria for this disorder may not be optimal either in describing the dimensions of schizotypal phenomena or in identifying those with a high familial liability to schizophrenia. METHODS: In the Roscommon Family Study, an epidemiologically based family study of major psychiatric disorders conducted in the west of Ireland, we examined 25 individual schizotypal symptoms and signs, assessed by structured personal interview, in 1544 first-degree relatives (without chronic psychosis or mental retardation) of five proband groups: schizophrenia; other nonaffective psychoses; psychotic affective illness; nonpsychotic affective illness; and matched, unscreened controls. RESULTS: We obtained seven meaningful schizotypal factors: negative schizotypy, positive schizotypy, borderline symptoms, social dysfunction, avoidant symptoms, odd speech, and suspicious behavior. Taken individually, all of these factors, except borderline symptoms, significantly discriminated relatives of schizophrenic probands from relatives of controls; in descending order of the odds ratios, they were odd speech, social dysfunction, suspicious behavior, negative schizotypy, avoidant symptoms, and positive schizotypy. In a multivariate analysis, four of these factors remained significant: odd speech, negative symptoms, social dysfunction, and avoidant symptoms. These schizotypal factors differed in their specificity. Three of the four most predictive schizotypal factors also significantly discriminated relatives of probands with other nonaffective psychoses from relatives of controls. CONCLUSION: "Schizotypy" is a complex, multidimensional clinical construct, whose various dimensions differ widely both in the degree and specificity with which they reflect the familial liability to schizophrenia. Subpsychotic thought disorder; negative schizotypal signs, such as poor rapport and odd behavior; deficient occupational functioning; and social isolation/avoidance best characterized relatives of schizophrenic probands compared with relatives of matched controls.
Exercise in chronic airflow limitation (CAL) is often limited by symptoms before the physiologic boundaries of maximal ventilatory or cardiovascular capacities are attained. Symptom amelioration should translate directly into improved exercise performance. We studied the impact of a 6-wk supervised multimodality endurance exercise program (EXT) on perceived breathlessness (B) and leg effort (LE) and sought a physiologic rationale for symptom improvement. Thirty patients with CAL (FEV1/FVC = 42 +/- 2%, mean +/- SEM) were tested before and after EXT. Their responses were compared with those of a matched control group (n = 30; FEV1/FVC = 44 +/- 2%) after a nonintervention period. Testing included pulmonary function tests, chronic dyspnea evaluation (Baseline/Transition Dyspnea Index [BDI/TDI]), and graded cycle exercise with cardioventilatory monitoring and Borg scaling of B and LE. Spirometry did not change (delta) post-EXT. EXT significantly (p < 0.001) reduced chronic breathlessness (TDI = +2.8 +/- 0.3) compared with control (TDI = 0.0 +/- 0.3). Exertional symptoms of B and LE also fell (p < 0.01) after EXT (slopes of B and LE relative to VO2 fell by 14 and 23%, respectively; delta B/VO2 was associated with delta LE/VO2, r = 0.52, p < 0.01). Post-EXT slopes of B over ventilation (VE) also decreased by 10% (p < 0.025). Total cycle work increased 142 +/- 70% (p < 0.001) post-EXT and correlated primarily with delta B/VO2 (r = -0.64, p < 0.001). The best correlate of delta B/VO2 was delta VE/VO2 (r = 0.47, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVE: The authors sought to assess whether the DSM-III-R category of schizoaffective disorder differs meaningfully from schizophrenia and affective illness in clinical features, outcome, and familial psychopathology. In addition, the authors evaluated the validity of two proposed subtyping systems for schizoaffective disorder: 1) bipolar versus depressive (based on presence or absence of a full manic syndrome in the past) and 2) good versus poor interepisode recovery. METHOD: In the epidemiologically based Roscommon Family Study, index probands with diagnoses of schizophrenia or affective illness were selected from a case registry. Personal interviews were conducted with 88% of traceable, living probands and 86% of traceable, living first-degree relatives. RESULTS: Probands with schizoaffective disorder differed significantly from both those with schizophrenia and those with affective illness on lifetime psychotic symptoms as well as on outcome and negative symptoms assessed as follow-up. Relatives of probands with schizoaffective disorder had significantly higher rates of affective illness than relatives of schizophrenic probands and significantly higher rates of schizophrenia than relatives of probands with affective illness. Probands with bipolar and depressive schizoaffective disorder did not differ substantially with respect to psychotic symptoms, negative symptoms, outcome, or family history. Schizoaffective disorder probands with good interepisode recovery had fewer negative symptoms and a better outcome than those with poor recovery, but there were no significant differences in family history. Both the epidemiologic and family data are consistent with the hypothesis that schizoaffective disorder results from the co-occurrence of a high liability to both schizophrenia and affective illness. CONCLUSIONS: On the basis of the validators examined, DSM-III-R criteria for schizoaffective disorder define a syndrome that differs meaningfully from both schizophrenia and affective illness. The division of schizoaffective disorder into bipolar and depressive subtypes was, however, not validated. The separation of schizoaffective disorder into subtypes based on level of interepisode recovery defined subtypes that differed clinically but not with respect to familial psychopathology.
The purpose of this study was to evaluate the results of a single injection of corticosteroids in patients with painful heel syndrome. Twenty-seven heels in 24 patients were injected with a combination of 1 ml of lidocaine and 1 ml of betamethasone (6 mg). These patients had never previously received an injection to their heels and had continued symptoms of pain after a trial of other nonoperative treatment modalities. After the injection, patients were seen and surveyed periodically for a period of 5 months to 8 months. The amount of pain relief that they obtained, the length of time this lasted, and the amount of heel pain present at the final follow-up were recorded. Based on the results of our study, we believe that a steroid injection is a reasonable adjunct in the treatment of painful heel syndrome, but that it is unlikely to provide permanent pain relief.
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Ten halogenated monoterpenes (2-6 and 8-12) related to the novel antitumor compound halomon (1) or to the carbocyclic analog 7 have been isolated from different geographic collections of the red alga, Portieria hornemannii. Structures were assigned to the basis of spectral analyses (primarily NMR and MS). The absolute configuration of isohalomon (2) was further established by X-ray crystallography. The compounds were comparatively evaluated alongside 1 and 7 in the U.S. National Cancer Institute's in vitro human tumor cell line screening panel. The results provide some interesting initial insights into the structure/activity relationships in this series.
Individuals with schizophrenia vary widely in their symptoms, course of illness and outcome. Family background is the strongest known risk factor for schizophrenia. We know little of the relationship between clinical variability in this disorder and the level of familial vulnerability to schizophrenia and other major mental disorders. Therefore, in schizophrenic probands meeting DSM-III-R criteria (n = 126) from the epidemiologically based Roscommon Family Study, we systematically assessed 9 major symptoms, course, global outcome, Schedule for Negative Symptoms and the Levels of Functioning Scale. These clinical characteristics were related t the risk of mental disorders in first-degree relatives assessed by personal interview or hospital records (n = 354) utilizing both the "familial/sporadic" and the Cox proportional hazard models. Using either statistical method, no consistent and significant relationship was found between any of our measures of symptoms, course or outcome and the risk for schizophrenia or schizophrenia spectrum disorders in relatives. Similarly, no relationship was found between these clinical measures and the risk for affective illness, alcoholism or anxiety disorders. Our results are not consistent with previously articulated hypotheses that negative symptoms or poor outcome in schizophrenia reflect a high familial liability to illness. While familial factors contribute substantially to an individual's vulnerability to schizophrenia, our results suggest that once an individual is affected, these same factors do not strongly influence either the kinds of symptoms displayed or the course and outcome of the illness.
OBJECTIVE: The authors sought to estimate the prevalence of simple schizophrenia, compare the clinical presentations and courses of simple and "typical" schizophrenia, and examine psychopathology in first-degree relatives of probands with simple schizophrenia, probands with typical schizophrenia, and community comparison subjects. METHOD: The authors followed up all individuals with a recorded diagnosis of schizophrenia (N = 285) and 75% of those with a diagnosis of severe affective illness (N = 99) from the Roscommon County Case Register, which includes all individuals seeking psychiatric care in a rural county in western Ireland. The authors interviewed all available first-degree relatives of these groups and of matched unscreened community comparison subjects. RESULTS: Eleven cases of simple schizophrenia were diagnosed in the probands, for an estimated population prevalence and morbid risk in County Roscommon of 5.3 (SE = 1.6) and 6.2 (SE = 1.9) per 10,000, respectively. Individuals with typical schizophrenia (N = 126) had more marked delusions, hallucinations, and positive thought disorder; individuals with simple schizophrenia had more pronounced negative thought disorder and a more chronic course. Neither social/occupational functioning nor negative symptoms differed between the two groups. The risks for schizophrenia and all nonaffective psychoses were greater in the relatives of the probands with simple schizophrenia than in the relatives of the community comparison subjects. CONCLUSIONS: In this sample, simple schizophrenia was relatively rare, was rather debilitating, and resembled typical schizophrenia in presentation and course except for the absence of positive psychotic symptoms. From a familial perspective, simple schizophrenia appears to be related to typical schizophrenia.
OBJECTIVE: The authors sought to clarify differences in outcome and familial psychopathology among the classical subtypes of schizophrenia. METHOD: In the epidemiologically based Roscommon Family Study, personal interviews were conducted with 88% of traceable living probands (N = 415) an average of 16 years after illness onset and with 86% of traceable living first-degree relatives (N = 1,753). Probands meeting the DSM-III-R criteria for schizophrenia were subtyped by DSM-III-R and ICD-9. RESULTS: By both diagnostic systems, age at onset differed significantly across subtypes, being earliest in the subjects with the hebephrenic and catatonic subtypes and latest in the paranoid subjects. The probands with the paranoid subtype had substantially better outcome, especially in occupational functioning and capacity for self-care. The DSM-III-R criteria for paranoid schizophrenia were considerably more successful than the ICD-9 criteria in selecting good-outcome cases. Neither the risk for schizophrenia nor the risk for schizophrenia spectrum disorders significantly differed in relatives as a function of the proband subtype. The subtypes of schizophrenia did not "breed true" within families. CONCLUSIONS: Paranoid schizophrenia, especially when narrowly defined, as in DSM-III-R, has a substantially better outcome than other subtypes. From a familial perspective, 1) paranoid schizophrenia is not a milder form of schizophrenia and 2) catatonic schizophrenia is probably closely related to typical schizophrenia. The subtypes of schizophrenia are not, from a familial perspective, etiologically distinct syndromes.
OBJECTIVES: We sought to examine, in a rural county in the West of Ireland, the degree of familial relationship between schizophrenia and other nonaffective psychoses and affective illness (AI). DESIGN: A case-controlled epidemiologic family study using DSM-III-R criteria. PARTICIPANTS: This study included three proband groups: (1) all cases with a clinical diagnosis of schizophrenia from the Roscommon County Case Register born from 1930 onward (n = 285); (2) a random sample of cases from the register with a clinical diagnosis of severe AI (n = 99); and (3) a matched, random sample of Roscommon residents ascertained from the electoral register (n = 150). Face-to-face structured interviews were conducted with 86% of traceable, living relatives (n = 1, 753) and 88% of traceable, living probands (n = 415). RESULTS: In interviewed relatives, the lifetime risks (+/- SE) for schizophrenia, as a function of the "blind" proband diagnosis, were as follows: schizophrenia, 6.5% +/- 1.6%; schizoaffective disorder, 6.8% +/- 2.5%; schizotypal personality disorder, 6.9% +/- 3.9%; other nonaffective psychoses, 5.1% +/- 2.4%; psychotic AI, 2.8% +/- 1.2%; nonpsychotic AI, 0.6% +/- 0.6%; and control, 0.5% +/- 0.3%. Individuals with schizophrenia reproduced at a rate about one quarter that of controls and the risk for schizophrenia in parents of probands was much less than that found in siblings. CONCLUSIONS: These results support the following hypotheses: (1) in the West of Ireland, as in other populations, schizophrenia is a strongly familial disorder; (2) schizophrenia shares a familial predisposition with a spectrum of clinical syndromes that includes schizoaffective disorder, other nonaffective psychoses, schizotypal personality disorder, and probably psychotic AI, but not nonpsychotic AI; and (3) the diminished reproductive rates associated with schizophrenia have a large impact on the pattern of risk of illness in relatives.
OBJECTIVE: We sought to clarify the familial relationship between the nonschizophrenic, nonaffective psychoses (schizoaffective disorder [SAD], schizophreniform disorder, delusional disorder, and atypical psychosis) and schizophrenia and affective illness (AI). DESIGN: A case-controlled epidemiologic family study using DSM-III-R criteria. RESULTS: Compared with relatives of unscreened controls, the risk of nonschizophrenic, nonaffective psychoses was significantly elevated in relatives of probands with schizophrenia, SAD, schizotypal personality disorder, and psychotic AI. No significant elevation in risk to these disorders was seen in relatives of probands with nonpsychotic AI. The risk for SAD alone was significantly increased in relatives of probands with psychotic or bipolar AI. CONCLUSIONS: The nonschizophrenic, nonaffective psychoses have a significant familial relationship with both schizophrenia and schizotypical personality disorder. Schizoaffective disorder, as defined by DSM-III-R, shares familial etiologic factors with at least some forms of AI.