The causal relationships between neurocognition, social cognition and functional outcome over time in schizophrenia: a latent difference score approach.

BACKGROUND: Social cognition has been identified as a significant construct for schizophrenia research with relevance to diagnosis, assessment, treatment and functional outcome. However, social cognition has not been clearly understood in terms of its relationships with neurocognition and functional outcomes. The present study sought to examine the empirical independence of social cognition and neurocognition; to investigate the possible causal structure among social cognition, neurocognition and psychosocial functioning. METHOD: The sample consists of 130 individuals diagnosed with schizophrenia. All participants were recruited as they were admitted to four community-based psychosocial rehabilitation programs. Social cognition, neurocognition and psychosocial functioning were measured at baseline and 12 months. The empirical independence of social cognition and neurocognition was tested using confirmatory factor analysis (CFA) and the possible causal structure among social cognition, neurocognition and psychosocial functioning was investigated using latent difference score (LDS) analysis. RESULTS: A two-factor model of social cognition and neurocognition fit the data very well, indicating the empirical independence of social cognition, whereas the longitudinal CFA results show that the empirical independence of neurocognition and social cognition is maintained over time. The results of the LDS analysis support a causal model that indicates that neurocognition underlies and is causally primary to social cognition, and that neurocognition and social cognition are causally primary to functional outcome. CONCLUSIONS: Social cognition and neurocognition could have independent and distinct upward causal effects on functional outcome. It is also suggested that the approaches for remediation of neurocognition and social cognition might need to be distinct.

Neurocognitive change, functional change and service intensity during community-based psychosocial rehabilitation for schizophrenia.

BACKGROUND: This study examined the magnitude of neurocognitive change during 1 year of community-based psychosocial intervention, whether neurocognitive change and functional change were linked, and how neurocognitive change combined with service intensity to facilitate functional change. METHOD: A total of 130 individuals diagnosed with schizophrenia were recruited upon admission to four community-based psychosocial rehabilitation programs. Subjects were assessed at baseline, 6 and 12 months on role functioning and symptom measures. Neurocognition was measured at baseline and 12 months. Service intensity was the number of days of treatment attendance during the study period. Latent mean difference tests and Latent Growth Curve Models (LCGMs) were used to examine the study hypotheses. RESULTS: There was statistically and clinically significant functional improvement over 12 months. Neurocognition improved significantly over time. Seventy-six (58%) of the sample showed neurocognitive improvement and 54 (42%) did not. There was a significant rate of functional enhancement in the neurocognitive improver group. There was a non-significant rate of functional change in the neurocognitive non-improver group. Neurocognitive improvers showed functional improvement that was 350% greater than neurocognitive non-improvers. Service intensity did not vary between neurocognitive improvers and non-improvers but there was a strong interaction between neurocognitive improvement, service intensity and rate of functional improvement such that service intensity was strongly related to functional improvement for neurocognitive improvers but not for neurocognitive non-improvers. Medication usage and symptomatology did not confound these findings. CONCLUSIONS: These findings suggest that neurocognitive improvement may be a foundation for functional change and treatment responsiveness during community-based psychosocial rehabilitation for individuals with schizophrenia.

Adjuvant postoperative 5-fluorouracil chemotherapy combined with pelvic radiation for rectal cancer: results from an Asian population.

Prospective randomized clinical trials have shown the effectiveness of combined adjuvant 5-fluorouracil-based chemotherapy and radiotherapy after surgical resection of rectal cancer. To assess toxicity of this therapy, prospective data were collected from 236 Asian rectal cancer patients treated with combined 5-fluorouracil-based chemotherapy and radiotherapy after surgery. Almost 82% of patients completed planned therapy. Grade 3 and 4 diarrhea, stomatitis, and granulocytopenia occurred in approximately 18-21% of patients. There were two treatment-related deaths from granulocytopenia and sepsis. With median follow-up of 3.5 years, median disease-free and overall survival was 75 and 88 months, respectively. In conclusion, combined adjuvant 5-fluorouracil-based chemotherapy and radiotherapy after surgical resection of rectal cancer is tolerable in Asian patients with moderate toxicity.

Breast reconstruction after mastectomy: a survey of general surgeons in Singapore.

BACKGROUND: Breast cancer is the leading malignancy among women in Singapore. In the West as many as 30% of eligible patients undergo some form of reconstruction, but in Singapore breast reconstruction is not often performed. METHODS: A postal survey of general surgeons in Singapore (response rate of 46%) was conducted to ascertain the factors influencing their decision to refer for reconstruction and the possible concerns they had about reconstruction. RESULTS: Age, anticipated psychosocial morbidity and the need for adjuvant therapy were the most important factors identified. The survey also found that almost 30% of respondents were unsure of whether reconstruction would mask recurrence. Despite this, almost 80% of respondents felt that reconstruction was worth the effort, but 55% (compared to less than 20% in the West) felt that patients did not want reconstruction despite being advised of its availability. CONCLUSION: Lack of information and the perception that patients would not want reconstruction may be important reasons for the low emphasis placed on the role of breast reconstruction in post-mastectomy patients.

Induction of cellular immunity by immunization with novel hybrid peptides complexed to heat shock protein 70.

Heat shock proteins 70 (hsp70) derived from tissues and cells can elicit cytotoxic T lymphocyte (CTL) responses against peptides bound to hsp70. However, peptides can markedly differ in their affinity for hsp, and this potentially limits the repertoire of peptides available to induce CTL by the hsp immunization. Hybrid peptides consisting of a high-affinity ligand for the peptide-binding site of hsp70 joined to T cell epitopes by a glycine-serine-glycine linker were constructed. Immunization with hybrid peptides complexed to mouse hsp70 effectively primed specific CTL responses in mice and were more potent than T cell peptide epitopes alone with hsp70. In vivo immunization with hsp70 and hybrid peptides led to rejection of tumors expressing antigen with greater efficacy than immunization with peptide epitope plus hsp70. Induction of CTL responses occurred independently of CD4(+) T cells, suggesting that immunization directly primed antigen-presenting cells to elicit CD8(+) cytotoxic T cell responses without T cell help. Both peptide/hsp70 complexes and mouse hsp70 alone were able to induce cultures of mouse bone marrow-derived dendritic cells (DC) to release cytokines, including DC from endotoxin-resistant C57BL/10Sc mice. Thus, hsp70/hybrid peptide complexes can activate DC for cytokine release, providing a potential adjuvant effect that could bypass T cell help.

Laparoscopic drainage of liver abscesses.

BACKGROUND: The mainstay of the management of liver abscesses has been intravenous antibiotics and radiologically guided percutaneous drainage. However, not all abscesses are treated successfully in this way, and some require surgical drainage. Laparoscopic drainage of liver abscesses may be an alternative to open surgical drainage. METHODS: Twenty consecutive patients with liver abscesses treated by laparoscopic drainage in combination with intravenous antibiotics were studied prospectively. Fifteen had had failed percutaneous drainage previously. RESULTS: There were 13 right lobe and seven left lobe abscesses ranging from 6 to 25 cm in diameter. Mean operating time was 38 min. Seventeen patients were drained successfully. Three patients developed recurrent symptoms of which two resolved with conservative measures, but one required a second laparoscopic procedure. There were no intraoperative or other postoperative complications in the 20 patients. Follow-up ranged from 5 to 12 months. CONCLUSIONS: Laparoscopic drainage of liver abscesses, in combination with systemic antibiotics, is a safe and viable alternative in all patients who require surgical drainage following failed medical or percutaneous treatment, and in those with large abscesses.

Evidence for recycling of the resident medial/trans Golgi enzyme, N-acetylglucosaminyltransferase I, in ldlD cells.

ldlD cells, which lack the UDP-Gal/UDP-GalNAc 4-epimerase, were stably transfected with a Myc-tagged version of N-acetylglucosaminyltransferase I (Myc-Glc-NAc-T I). In the absence of GalNAc and Gal, newly synthesized GlcNAc-T I did not acquire O-linked oligosaccharides but was catalytically active and was transported to the Golgi region as defined using both immunofluorescence and immunoelectron microscopy. After addition of cycloheximide to prevent further synthesis, GalNAc and Gal were added, and the unglycosylated GlcNAc-T I was found to acquire mature, O-linked oligosaccharides with a half-time of about 150 min. The addition of these sugars was sensitive to N-ethylmaleimide and okadaic acid, both inhibitors of vesicle-mediated traffic. Together, these results suggest that Myc-Glc-NAc-T I undergoes retrograde transport to the early part of the Golgi apparatus where the first O-linked sugar, GalNAc, is added followed by anterograde transport back to the Golgi stack, where addition of Gal and sialic acid occurs.

An integral membrane component of coatomer-coated transport vesicles defines a family of proteins involved in budding.

We have isolated a major integral membrane protein from Golgi-derived coatomer-coated vesicles. This 24-kDa protein, p24, defines a family of integral membrane proteins with homologs present in yeast and humans. In addition to sequence similarity, all p24 family members contain a motif with the characteristic heptad repeats found in coiled coils. When the yeast p24 isoform, yp24A, is knocked out in a strain defective for vesicle fusion, a dramatic reduction in the accumulation of transport vesicles is observed. Together, these results indicate a role for this protein family in the budding of coatamer-coated and other species of coated vesicles.

Kin recognition between medial Golgi enzymes in HeLa cells.

The medial Golgi enzymes, N-acetylglucosaminyltransferase I (NAGT I) and mannosidase II (Mann II), and the trans Golgi enzyme, beta-1,4-galactosyltransferase (GalT) were each retained in the endoplasmic reticulum (ER) by grafting on the cytoplasmic tail of the p33 invariant chain. Transient and stable expression of p33/NAGT I in HeLa cells caused relocation of endogenous Mann II to the ER and transient expression of p33/Mann II had a similar effect on endogenous NAGT I. Neither of these endogenous medial enzymes were affected by transient expression of p33/GalT. These data provide strong evidence for kin recognition between medial Golgi enzymes and suggest a role for them in the organization of the Golgi stack.

Kin recognition. A model for the retention of Golgi enzymes.

The surprising result that the spanning domain causes retention of proteins in the Golgi stack poses the question as to the actual mechanism. Here we present a simple model that might have general applicability.

Role of oligosaccharides in the processing and function of human transferrin receptors. Effect of the loss of the three N-glycosyl oligosaccharides individually or together.

When the coding sequence for human transferrin receptors was expressed in a Chinese hamster ovary cell line lacking endogenous transferrin receptors, 86-kDa molecules containing three N-glycosidically linked oligosaccharides were synthesized. These rapidly dimerized to form 172-kDa molecules which increased in size to 190 kDa. After site-directed mutagenesis of all three N-glycosylation sites, 80-kDa receptors were synthesized and only a few dimers were formed. 84-kDa monomers were synthesized in the absence of the oligosaccharide attached to Asn727 or Asn317. Dimerization and maturation through the Golgi body of the Asn727 mutant receptors were much slower than the wild type whereas the Asn317 mutant receptors behaved more similarly to the wild type. Lack of the oligosaccharide at Asn251 gave rise to 73-kDa monomers because of proteolytic processing (Hoe, M. H., and Hunt, R. C. (1992) J. Biol. Chem. 267, 4916-4923), but a second mutation at a potential cleavage site allowed the formation of 84-kDa receptors. These also dimerized at a similar rate to wild type receptors. The three-site mutant receptors were degraded in the endoplasmic reticulum but all three 84-kDa single site mutant receptor species migrated to the cell surface. However, receptors lacking the oligosaccharide at Asn727 bound and internalized little transferrin as a result of reduced affinity.

Overlapping distribution of two glycosyltransferases in the Golgi apparatus of HeLa cells.

Thin, frozen sections of a HeLa cell line were double labeled with specific antibodies to localize the trans-Golgi enzyme, beta 1,4 galactosyltransferase (GalT) and the medial enzyme, N-acetylglucosaminyltransferase I (NAGT I). The latter was detected by generating a HeLa cell line stably expressing a myc-tagged version of the endogenous protein. GalT was found in the trans-cisterna and trans-Golgi network but, contrary to expectation, NAGT I was found both in the medial- and trans-cisternae, overlapping the distribution of GalT. About one third of the NAGT I and half of the GalT were found in the shared, trans-cisterna. These data show that the differences between cisternae are determined not by different sets of enzymes but by different mixtures.

Loss of one asparagine-linked oligosaccharide from human transferrin receptors results in specific cleavage and association with the endoplasmic reticulum.

The coding sequence for the human transferrin receptor gene has been mutated in order to abolish the attachment of the oligosaccharide closest to the transmembrane sequence. Expression of the mutant receptor in Chinese hamster ovary cells resulted, after analysis under nonreducing conditions, in an 85- and a 73-kDa receptor species. After reduction, the 85-kDa receptors were mostly converted to 73 kDa, although with short labeling periods some 85-kDa receptor remained suggesting that the mutated gene was capable of coding for the entire polypeptide which was then proteolytically processed. This was supported by in vitro translation of mRNA from either wild type or mutant cells which in both cases yielded an 80-kDa protein, the full size of the nonglycosylated protein. The solubility characteristics of the mutant receptor suggest that it contains the COOH-terminal extracellular domain but not the transmembrane sequence. This is supported by the endoglycosidase H sensitivity of the 73-kDa protein which is compatible with the retention of two of the original three high mannose oligosaccharides. The receptor that lacks one oligosaccharide is unable to form intermonomer disulfide bridges or to migrate to the cell surface and is located in the endoplasmic reticulum where it is further degraded after a lag period of about 30 min.

Problems in the identification of potential organ donors. Misconceptions and fallacies associated with donor cards.

A survey of organ procurement programs and district attorneys' offices was undertaken in all 50 states and the District of Columbia to determine to what extent organ donor cards were effective in obtaining organs for purposes of transplantation. Results of the survey revealed that all 50 states and the District of Columbia have adopted some form of the Uniform Anatomical Gift Act (UAGA), but in 47 states, even when a signed donor card is available, surgeons still require family approval for removal of organs despite the fact that the provisions of the UAGA do not require this. In addition, it was found that while 44 states have a provision on their permanent drivers' licenses for organ donation, no state requires drivers to indicate whether they want to donate organs. While there is little information on the number of persons who actually carry donor cards, four states indicated that between 1.7% and 8.5% of their drivers were designated as donors. In Colorado, however, it was reported that 60% of all drivers are designated as donors. Nevertheless, in all states it was determined that few actual donors were carrying donor cards at the time of their death. It must therefore be concluded that while donor cards are an excellent educational medium and certainly facilitate the activities of transplant coordination, they are not an effective means of substantially increasing the supply of organs for transplantation.

KIE: A survey of organ procurement programs and district attorneys' offices in every state and the District of Columbia was conducted to determine how effective donor cards were in obtaining organs for transplantation. The authors discovered that, although all jurisdictions have adopted some form of the Uniform Anatomical Gift Act and most have provisions for donor documentation on driver's licenses, there has been no substantial increase in the organ supply. Organ procurement appears to be hampered by current methods of card distribution, problems with maintaining referral networks, and uncertainties about the legal status of donor cards which have led hospitals to add a requirement for next-of-kin consent.