Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease.

BACKGROUND: Mortality and morbidity related to AIDS have decreased among HIV-infected patients taking highly active anti-retroviral therapy (HAART), but previous studies may have been confounded by other changes in treatment. OBJECTIVE: To assess the benefit of HAART in patients with advanced AIDS and anemia. DESIGN: Prospective, multicenter cohort study. SETTING: The Viral Activation Transfusion Study (VATS), with enrollment from August 1995 through July 1998 and follow-up through June 1999. PATIENTS: 528 HIV-infected patients with cytomegalovirus (CMV) seropositivity or disease who were receiving a first red blood cell transfusion for anemia. MEASUREMENTS: In a person-year analysis of follow-up before and after initiation of HAART, Poisson regression was used to calculate crude rate ratios and rate ratios adjusted for CD4 count, HIV RNA level, calendar period, time on study, sex, ethnicity, and injection drug use. RESULTS: At baseline, patients had a median CD4(+) lymphocyte count of 0.015 x 10(9) cell/L, median plasma HIV RNA level of 4.8 log(10) copies/mL, and median hemoglobin concentration of 73 g/L. Use of HAART increased from 1% of active patients in January 1996 to 79% of active patients in January 1999. The crude death rate was 0.24 event/person-year among patients taking HAART and 0.88 event/person-year among those not taking HAART (rate ratio, 0.26; adjusted rate ratio, 0.38; P < 0.001 for both comparisons). Rates of non-CMV disease were 0.15 event/ person-year after HAART and 0.45 event/person-year before HAART (crude rate ratio, 0.34 [ P < 0.001]; adjusted rate ratio, 0.66 [ P < 0.05]). Rates of CMV disease were 0.10 event/person-year after HAART and 0.25 before HAART (crude rate ratio, 0.42 [ P < 0.01]; adjusted rate ratio, 1.01 [ P > 0.2]). Results were similar in patients with baseline CD4(+) lymphocyte counts less than 0.010 x 10(9) cells/L. CONCLUSIONS: The data support an independent reduction in mortality and opportunistic events attributable to HAART, even in patients with very advanced HIV disease. However, patients with CMV infection or disease may not have a reduction in new CMV events due to HAART.

Third place--Resident Research Competition, AAO-2000. Antisense cyclin D1 inhibits growth of head and neck cancer xenografts in nude mice.

PROBLEM: Cyclin D1 is a regulatory factor essential in the progression of the cell cycle from G1 through S phase. Amplification and overexpression of cyclin D1 have been observed in many human cancers including head and neck squamous cell carcinoma (HNSCC). We have previously transfected a HNSCC control cell line (CCL23) with an antisense cyclin D1 plasmid and demonstrated inhibition of cell proliferation in vitro. In this study, we examine whether antisense cyclin D1 could inhibit tumor growth in vivo. Methods/measures: The CCL23 and its antisense cyclin D1 transfected clone (CCL23 AS) were injected into the flanks of nude mice. Tumor growth was monitored weekly. After 5 weeks, tumors were removed and studied for tumor size, cyclin D1 expression, cyclin D1-dependent kinase activity, and retinoblastoma (Rb) phosphorylation. RESULTS: Compared with the control tumors, 11 of 19 antisense tumors were smaller, 7 tumors were of equal size, and 1 tumor was larger. Immunohistochemical analysis with an anti-cyclin D1 antibody demonstrated decreased cyclin D1 expression in CCL23 AS and the smaller antisense tumors. Cyclin D1-dependent kinase activity was reduced in CCL23 AS and the smaller antisense tumors, and this was accompanied by a relative decrease in phosphorylated Rb in these samples. CONCLUSION: Antisense cyclin D1 inhibits growth of HNSCC tumors. Cyclin D1 expression, cyclin D1-dependent kinase activity, and Rb phosphorylation are decreased in these tumors. CLINICAL SIGNIFICANCE: These findings lend support for the potential use of antisense cyclin D1 as gene therapy for HNSCC.

Qualitative and quantitative PCR measures of cytomegalovirus in patients with advanced HIV infection who require transfusions.

The Viral Activation Transfusion Study (VATS) was a randomized trial that compared leukocyte-reduced transfusions with unfiltered red blood cell transfusions in HIV and cytomegalovirus (CMV) antibody-positive patients with anemia who were undergoing their first blood transfusion. The relations of the baseline qualitative and quantitative polymerase chain reaction (PCR) measures of plasma CMV viremia, HIV RNA, CD4(+) cell counts, and quality of life in these study subjects were examined. The 511 study subjects had a median CD4(+) cell count equal to 15 cells/mm3, and 110 (21.5%) had CMV viremia by qualitative assay. In multivariate models, frequency of positive qualitative CMV increased with decreasing CD4(+) cell counts (p =.04 trend), higher HIV RNA (p <.001), and a history of CMV disease (p <.001). Quantitative CMV PCR were performed on the 110 qualitative assay-positive study subjects. Median CMV viral load was 1780 copies/ml. In multivariate regression models, lower CD4(+) cell count (p =.03), and a history of CMV disease (p <.001) correlated with the level of CMV load. HIV RNA load and CMV load were not correlated. A lower Karnofsky score was associated with both the presence and quantity of CMV DNA.

The Eating Attitudes Test: validation with DSM-IV eating disorder criteria.

The Eating Attitudes Test (EAT; Garner & Garfinkel, 1979) is one of the most widely used self-report eating disorder instruments. Originally developed to diagnose anorexia nervosa, it is often used in nonclinical samples where it has a high false-positive rate, which is likely due to changes in diagnostic criteria. Because the EAT has not been validated with Diagnostic and Statistical Manual of Mental Disorders (4th ed. [DSM-IV]; American Psychiatric Association, 1994) criteria, we examined its criterion validity for discriminating between nonclinical women with and without an undifferentiated DSM-IV eating disorder diagnosis. We also examined differences in mean EAT scores among eating-disordered, symptomatic, and asymptomatic participants. Results show that the EAT has an accuracy rate of at least 90% when used to differentially diagnose those with and without eating disorders and that mean EAT scores differed among eating-disordered, symptomatic, and asymptomatic participants.

Evaluation and molecular characterization of EHD1, a candidate gene for Bardet-Biedl syndrome 1 (BBS1).

Bardet-Biedl Syndrome (BBS) is an autosomal recessive disorder characterized by developmental abnormalities including mental retardation, obesity, retinitis pigmentosa, polydactyly, short stature, and hypogenitalism. To date, five BBS loci have been identified. BBS1, located on 11q13, is reported to be the most prevalent form of BBS in the Caucasian population. A positional cloning approach is being used to identify the gene responsible for BBS1. EHD1, a new member of the EH-domain containing proteins, was identified in this study as lying within the BBS1 disease interval. RNA analysis of many tissues revealed that expression of EHD1 is ubiquitous, with elevated levels in the testis. The genomic structure of EHD1 was elucidated by direct BAC sequencing. Following identification of the intron/exon boundaries, mutational analysis was performed by single strand conformation polymorphism and direct sequencing of affected individuals from several large kindreds linked to the BBS1 locus, as well as a cohort of unrelated probands. No disease-causing mutations were identified in this analysis, but several polymorphisms were found.

EHD1--an EH-domain-containing protein with a specific expression pattern.

A cDNA that is a member of the eps15 homology (EH)-domain-containing family and is expressed differentially in testis was isolated from mouse and human. The corresponding genes map to the centromeric region of mouse chromosome 19 and to the region of conserved synteny on human chromosome 11q13. Northern analysis revealed two RNA species in mouse. In addition to the high levels in testis, expression was noted in kidney, heart, intestine, and brain. In human, three RNA species were evident. The smaller one was predominant in testis, while the largest species was evident in other tissues as well. The predicted protein sequence has an EH domain at its C-terminus, including an EF, a Ca2+ binding motif, and a central coiled-coil structure, as well as a nucleotide binding consensus site at its N-terminus. As such, it is a member of the EH-domain-containing protein family and was designated EHD1 (EH domain-containing 1). In cells in tissue culture, we localized EHD1 as a green fluorescent protein fusion protein, in transferrin-containing, endocytic vesicles. Immunostaining of different adult mouse organs revealed major expression of EHD1 in germ cells in meiosis, in the testes, in adipocytes, and in specific retinal layers. Results of in situ hybridization to whole embryos and immunohistochemical analyses indicated that EHD1 expression was already noted at day 9.5 in the limb buds and pharyngeal arches and at day 10.5 in sclerotomes, at various elements of the branchial apparatus (mandible and hyoid), and in the occipital region. At day 15.5 EHD1 expression peaked in cartilage, preceding hypertrophy and ossification, and at day 17.5 there was no expression in the bones. The EHD1 gene is highly conserved between nematode, Drosophila, mouse, and human. Its predicted protein structure and cellular localization point to the possibility that EHD1 participates in ligand-induced endocytosis.

Schizophrenic patients' perceptions of their relatives' attitudes.

Although the attitudes of family members as revealed by measures of expressed emotion (EE) have been shown to be associated with the course of schizophrenic illness, little is known about how the patients perceive these attitudes. A detailed interview was used to assess patients' perceptions of their family members' behaviors toward them. Family member's EE was assessed with the Five-Minute Speech Sample (FMSS). Overall, patients' perceptions of criticism were congruent with a component of the FMSS-EE that measures criticism. Results indicated that when family members had high EE/critical scores, patients perceived them as displaying more instances of critical behavior. All cases in which patients' perceptions of criticism were incongruent with measures of FMSS-EE occurred among ethnic minority group members. Although the FMSS-EE did not predict outcome in this study, patients who perceived their relatives as higher in criticism had more negative outcomes at 1 year. These findings suggest that when family environments are examined in patients from ethnic minority groups, the patients' perspective may be a more potent predictor of outcome than traditional measures of EE.

Tumor necrosis factor-alpha plays a central role in interleukin-2-induced pulmonary vascular leak and lymphocyte accumulation.

Administration of interleukin-2 (IL-2) leads to pulmonary vascular leak. This form of pulmonary edema has previously been postulated to be due to the in vivo induction of tumor necrosis factor-alpha (TNF-alpha). To determine whether TNF-alpha plays a role in IL-2-induced pulmonary vascular leak, we performed in situ hybridization of lung sections and reverse transcriptase-polymerase chain reaction of bronchoalveolar lavage macrophages from IL-2-challenged mice. The results confirm an in situ upregulation of TNF-alpha mRNA expression in the lungs associated with vascular leak. In addition, a significant increase in TNF-alpha protein production was found in the lung following IL-2 administration, as measured by TNF-alpha-specific ELISA of lung supernatants (P = 0.028). Intravenous administration of a soluble TNF receptor significantly diminished IL-2-induced pulmonary vascular leak (P = 0.006). These findings confirm a central role for TNF-alpha in mediating the pulmonary vascular leak associated with IL-2 toxicity.

Construction of a yeast artificial chromosome contig spanning the pseudoautosomal region and isolation of 25 new sequence-tagged sites.

Thirty-one yeast artificial chromosomes (YACs) from the human pseudoautosomal region were identified by a combination of sequence-tagged site (STS) screenings and colony hybridizations, using a subtelomeric interspersed repetitive element mapping predominantly to the pseudoautosomal region. Twenty-five new pseudoautosomal STSs were generated, of which 4 detected restriction fragment length polymorphisms. A total of 33 STSs were used to assemble the 31 YACs into a single contiguous set of overlapping DNA fragments spanning at least 2.3 megabases of the pseudoautosomal region. In addition, four pseudoautosomal genes including hydroxyindole O-methyltransferase have been positioned on this set of fragments.

Patients' perceptions of family emotional climate and outcome in schizophrenia.

Thirty-nine chronic schizophrenic male out-patients and their relatives were interviewed separately to assess their perceptions of their current relationships. Two simple 5-point rating scales predicted the risk of psychotic exacerbation during a one-year follow-up: patients' perceptions of the relatives' attitudes towards them, and patients' own attitudes towards the relatives. Survival analysis of data in a 2 x 2 factorial--combining degree of contact with the key relatives and the patients' perceptions of their relatives--found that patients in frequent contact with a positively perceived relative had significantly better survival rates without psychotic exacerbation. Patients' perceptions of their relatives may help identify patients at risk of exacerbation of their illness.

Failure of the porous-coated anatomic prosthesis in total knee arthroplasty due to severe polyethylene wear.

Four hundred and eighty-seven total knee arthroplasties were performed by a single surgeon with use of a porous-coated anatomic prosthesis between 1982 and 1989. There were thirty-two clinical failures (7 per cent) due to severe wear of the surfaces of the tibial and patellar polyethylene components. Thirty patients had a revision. The average time to failure of the implant was four and one-half years. The initial clinical symptoms of failure by wear consisted of a painless effusion with a decreased range of motion. Subsequent pain was considered as the criterion for failure necessitating operative intervention. Increased weight and decreased age of the patient and a thinner tibial component were significant predictors of an increased risk of failure (p < 0.01). Examination of retrieved tibial components revealed extensive delamination caused by fracture of the polyethylene at a depth of about one millimeter below the surface. Cracks that had propagated in from the medial and lateral peripheries of the tibial component toward the center of the condyles were also a common finding. It appears that the design of the implant as well as clinical factors (the age and weight of the patient) contributed to the mechanical failure of the polyethylene of these implants.

Treatments of depression and the functional capacity to work.

This study evaluated the effects of antidepressants and psychotherapy on work impairment in depressed patients. Original databases from 10 published treatment studies were compiled and analyzed (N = 827). Functional work impairment was common at baseline, manifested by unemployment (11%) or on-the-job performance problems (absenteeism, decreased productivity, interpersonal problems, 44%). Generally, work outcomes were good when treatment was symptomatically effective, but the trajectories of work restoration and symptom remission were different, with work recovery appearing to take considerably longer. Relapse was an important determinant of long-term occupational outcome, particularly for seriously ill patients for whom relapse meant rehospitalization or other profound social disruption. Affective impairment was distinguished from functional impairment, with the former characterizing milder depression and the latter characterizing moderate to severe depression. Some methodological recommendations are discussed.

Wear of polyethylene in total joint replacements. Observations from retrieved PCA knee implants.

Observations of wear damage were performed on 12 retrieved porous coated anatomic (PCA) tibial components, all of which were removed because of excessive polyethylene wear. Density measurements of the remaining polyethylene were obtained as a function of depth from the surface of the components. Comparison to previous results from similar studies of total condylar type knee components and total hip acetabular components revealed distinct differences between the types and severity of damage, emphasizing the influence of design factors on the corresponding wear damage. These results confirm previous conclusions that nonconforming articulating surfaces on thin polyethylene components will be at higher risk of damage than more conforming surfaces on thicker components. It also appears that the high cyclic loads to which polyethylene implants are subjected in vivo are most responsible for the degradation in properties of the material near the articulating surface, although the heat pressing of the articulating surface of the PCA components may contribute to the problem.

The arthroscopic evaluation and characteristics of severe polyethylene wear in total knee arthroplasty.

Four hundred eighty-seven porous-coated anatomic (PCA) total arthroplasties were performed by the same surgeon between January 1982 and December 1989. Forty-three patients developed an effusion, pain, or decreased range of motion after a period of pain-free function. Average time to onset of symptoms was 4.5 years. Joint fluid aspirations were sterile and revealed the presence of high-density polyethylene crystals, best seen under a polarizing microscope. Thirty-three of these patients were arthroscopically evaluated. Extensive polyethylene wear and delamination were identified. Wear was most extensive on the medial tibial plateau. Patellar polyethylene wear was also identified. Substantial femoral component abrasions were present in areas where exposure of the tibial and patellar base plates had occurred. Diffuse granulomatous synovial tissue revealed an extensive foreign-body giant-cell reaction to polyethylene particles. In all patients, temporary symptomatic relief was obtained after arthroscopy. Thirty-two patients have, subsequently, had revision surgery. Intraoperative findings and biopsies at the time of revision confirmed the arthroscopic observations. Arthroscopy allowed the accurate diagnosis of polyethylene wear, provided temporary symptomatic relief, and facilitated preoperative revision planning. Polyethylene wear in PCA total knee replacements was related to patient characteristics (larger, younger, more active patients), nonconforming femotibial articular surfaces, thin polyethylene, heat-pressed polyethylene, and nonrigid mechanical attachment of polyethylene to metal base plate. Younger, more active, larger patients with total knee arthroplasties should be observed closely for evidence of polyethylene wear.

The natural history of congenital kyphosis in myelomeningocele. A review of 51 children.

The progression of congenital lumbar kyphosis in myelomeningocele is a well-known problem, but rates of progression are not well documented in the literature. Fifty-one children with congenital kyphosis and myelomeningocele were followed for an average of 4.8 years. Minimum follow-up was 1 year. Group I (35 patients) had initial radiographs at 1 year of age or less. Group II (16 patients) had radiographs taken after the age of 1 year. Curves less than or equal to 90 degrees in Group I progressed 7.7 degrees/yr; those greater than 90 degrees progressed 12.1 degrees/yr. Curves less than or equal to 90 degrees and greater than 90 degrees progressed at similar rates, regardless of initial curve magnitude: 6.4 degrees/yr and 6.7 degrees/yr, respectively. No correlation existed among the rate of curve progression, the frequency of shunt revisions, or the presence of vertebral anomalies, aside from the dysraphism.

The initial onset of schizophrenia and family expressed emotion. Some methodological considerations.

The relationships between duration of schizophrenic illness before first hospital admission, expressed emotion in key relatives, and illness course have yielded conflicting reports. This study examined the issue from a methodological perspective in a sample of first-episode schizophrenic patients. A 'best estimate' of illness onset, based on a compilation of all sources, was compared with an estimate based on parental report. Parental estimates suggested that the children of high-EE parents had been ill for significantly longer, but this difference was not confirmed by the best estimate. In most cases, the ill children of high-EE parents were living at home before hospital admission and their parents' estimates of duration were quite accurate. In the few cases in which the child was living away from home, high-EE parents strikingly overestimated duration. Children of low-EE families were more likely to be living away from home, but this factor did not explain the consistent underestimates of duration made by their parents. Although duration of illness did not relate to EE, successful engagement in out-patient before in-patient treatment was more common among children from low-EE families.

Expressed emotion and relapse in first episodes of schizophrenia. A rejoinder to Macmillan et al (1986).

Re-analyses of data presented by Macmillan et al (1986b) challenge their conclusions that high expressed emotion is not prognostically significant for the course of schizophrenia or unrelated to the level of behavioural disturbance prior to admission. Several equally plausible models of causal relationships between EE and duration of untreated illness are presented. We conclude that our re-analyses of the Macmillan data do not warrant premature closure regarding the significance of the EE variable.