Visualization and quantification of myocardial mass at risk using three-dimensional contrast echocardiography

To investigate possible biochemical mechanisms underlying the "toxic gain of function" associated with polyglutamine expansions, the ability of guinea pig liver tissue transglutaminase to catalyze covalent attachments of various polyamines to polyglutamine peptides was examined. Of the polyamines tested, spermine is the most active substrate, followed by spermidine and putrescine. Formation of covalent cross links between polyglutamine peptides and polyamines yields high-M(r) aggregates--a process that is favored with longer polyglutamines. In the presence of tissue transglutaminase, purified glyceraldehyde-3-phosphate dehydrogenase (a key glycolytic enzyme that binds tightly to the polyglutamine domains of both huntingtin and dentatorubral-pallidoluysian atrophy proteins) is covalently attached to polyglutamine peptides in vitro, resulting in the formation of high-M(r) aggregates. In addition, endogenous glyceraldehyde-3-phosphate dehydrogenase of a Balb-c 3T3 fibroblast cell line overexpressing human tissue transglutaminase forms cross-links with a Q60 polypeptide added to the cell homogenate. Possibly, expansion of polyglutamine domains (thus far known to occur in the gene products associated with at least seven neurodegenerative diseases) leads to increased/aberrant tissue transglutaminase-catalyzed cross-linking reactions with both polyamines and susceptible proteins, such as glyceraldehyde-3-phosphate dehydrogenase. Formation of cross-linked heteropolymers may lead to deposition of high-M(r) protein aggregates, thereby contributing to cell death.     

Lobectomy combined with volume reduction for patients with lung cancer and advanced emphysema

Methanol-induced conformational transitions of hen egg white lysozyme were investigated with a combined use of far- and near-UV CD and NMR spectroscopies, ANS binding and small-angle X-ray scattering. Addition of methanol induced no global change in the native conformation itself, but induced a transition from the native state to the denatured state which was highly cooperative, as shown by the coincidence of transition curves monitored by the far- and near-UV CD spectroscopy, by isodichroic points in the far- and near-UV CD spectra and by the concomitant disappearance of individual 1H NMR signals of the native state. The ANS binding experiments could detect no intermediate conformer similar to the molten globule state in the process of the methanol denaturation. However, at high concentration of methanol, e.g., 60% (v/v) methanol/water, a highly helical state (H) was realized. The H state had a helical content much higher than the native state, monitored by far-UV CD spectroscopy, and had no specific tertiary structure, monitored both by near-UV CD and NMR spectroscopy. The radius of gyration in the H state, 24.9 angstroms, was significantly larger than that in the native state (15.7 angstroms). The Kratky plot for the H state did not show a clear peak and was quite similar to that for the urea-denatured state, indicating a complete lack of globularity. Thus we conclude that the H state has a considerably expanded, flexible broken rod-like conformation which is clearly distinguishable from the "molten globule" state. The stability of both N and H states depends on pH and methanol concentration. Thus a phase diagram involving N and H was constructed.     

Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects

CONTEXT: Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population. OBJECTIVE: To investigate the molecular changes present in HIV-associated lung tumors and compare them with those present in lung carcinomas arising in HIV-indeterminate subjects ("sporadic tumors"). DESIGN: Convenience sample. SUBJECTS: Archival tissues from 11 HIV-positive persons and from 35 persons of indeterminate HIV status. SETTING: University-based medical centers and affiliated hospitals. MAIN OUTCOME MEASURES: Analysis of frequency of loss of heterozygosity (LOH) and microsatellite alteration (MA) using polymerase chain reaction and 16 polymorphic microsatellite markers at 8 chromosomal regions frequently deleted in lung cancer. Presence of HIV and human papillomavirus (HPV) sequences. RESULTS: The overall frequency of LOH at all chromosomal regions tested and the frequencies at most of the individual regions were similar in the 2 groups. Frequency of MA present in the HIV-associated tumors (0.18) was 6-fold higher than in sporadic tumors (0.03) (P<.001). At least 1 MA was present in 10 (91%) of 11 HIV-associated tumors vs 17 (48%) of 35 sporadic tumors (P=.02). Molecular changes were independent of tumor stage and gender. HIV and HPV sequences were not detected in the HIV-associated lung carcinomas. CONCLUSIONS: Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated lung carcinomas. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated tumors.     

The Cartwright Report ten years on: the obligations and rights of health consumers and providers

It is ten years since the Cartwright report was published, three years since the code of health and disability services consumers' rights was promulgated and two years since the code came into force which makes it due for review next year. This paper reviews the issues identified by Cartwright and the effect that her investigation into the "Unfortunate Experiment" has had on the provision of health services. Issues of clinical freedom, peer supervision and informed consent are discussed in relation to the Health and Disability Commissioner Act, the Privacy Act and concepts of partnership in health care. Some comments on the present state of the relationships between consumers and providers in the health system are included.     

Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl

We have generated transgenic mice over-expressing human apolipoprotein CI (apo CI) using the native gene joined to the downstream 154-bp liver-specific enhancer that we defined for apo E. Human apo CI (HuCI)-transgenic mice showed elevation of plasma triglycerides (mg/dl) compared to controls in both the fasted (211 +/- 81 vs 123 +/- 52, P = 0.0001) and fed (265 +/- 105 vs 146 +/- 68, P < 0.0001) states. Unlike the human apo CII (HuCII)- and apo CIII (HuCIII)-transgenic mouse models of hypertriglyceridemia, plasma cholesterol was disproportionately elevated (95 +/- 23 vs 73 +/- 23, P = 0.002, fasted and 90 +/- 24 vs 61 +/- 14, P < 0.0001, fed). Lipoprotein fractionation showed increased VLDL and IDL + LDL with an increased cholesterol/triglyceride ratio (0.114 vs 0.065, P = 0.02, in VLDL). The VLDL apo E/apo B ratio was decreased 3.4-fold (P = 0.05) and apo CII and apo CIII decreased in proportion to apo E. Triglyceride and apo B production rates were normal, but clearance rates of VLDL triglycerides and postlipolysis lipoprotein "remnants" were significantly slowed. Plasma apo B was significantly elevated. Unlike HuCII- and HuCIII-transgenic mice, VLDL from HuCI transgenic mice bound heparin-Sepharose, a model for cell-surface glycosaminoglycans, normally. In summary, apo CI overexpression is associated with decreased particulate uptake of apo B-containing lipoproteins, leading to increased levels of several potentially atherogenic species, including cholesterol-enriched VLDL, IDL, and LDL.     

Laminar and columnar patterns of geniculocortical projections in the cat: relationship to cytochrome oxidase

We examined the laminar and columnar arrangement of projections from different layers of the lateral geniculate nucleus (LGN) to the visual cortex in the cat. In light of recent reports that cytochrome oxidase blobs (which in primates receive specific geniculate inputs) are also found in the visual cortex of cats, the relationship between cytochrome oxidase staining and geniculate inputs in this species was studied. Injections of wheat germ agglutinin-conjugated horseradish peroxidase were made into the anterior "genu" of the LGN, where isoelevation contours of the geniculate layers are distorted due to the curvature of the nucleus. Consequently, anterograde labeling from the various LGN layers was topographically separated across the surface of the cortex, and labeling in a particular isoelevation representation of the cortex could be associated with a specific layer of the LGN. Labeling from the A layers, which contain X and Y cells, was coextensive with layers 4 and 6 in both area 17 and area 18, as previously reported. Labeling from the C layers, which contain Y and W cells, occupied a zone extending from the 4a/4b border to part way into layer 3 in area 17. The labeling extended throughout layer 4 in area 18. There was also labeling in layer 5a and layer 1 in both area 17 and area 18. Except in layer 1, labeling from the C layers was patchy. In the tangential plane, adjacent sections stained for cytochrome oxidase showed that the patches of labeling from the C laminae aligned with the cytochrome oxidase blobs. The cytochrome blobs were visible in layers 3 and 4a, but not in layer 4b in both areas 17 and 18. These results suggest that W cells project specifically to the layer 3 portion of the blobs, while Y cells, at least those of the C layers, project specifically to the layer 4a portion of the blobs in area 17. The heavy synaptic drive of the Y cells is probably the cause of the elevated metabolism, and thus, higher cytochrome oxidase activity, of the blobs.     

HLA-DRB1 genes and disease severity in rheumatoid arthritis. The MIRA Trial Group. Minocycline in Rheumatoid Arthritis

OBJECTIVE: To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated in the minocycline in RA (MIRA) trial. METHODS: Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosions were used to assess disease severity and new erosions at the last visit served as a proxy for progression. RESULTS: At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-treated, but not the minocycline-treated, patients. A treatment group/HLA-DR4 epitope interaction was demonstrated in multivariate analyses. Approximately two-thirds of African-American patients did not have the rheumatoid epitope. CONCLUSION: HLA-DRB1 oligotyping may be useful in predicting the progression of disease in some Caucasian patients. Our study corroborates the infrequency of the epitope among African-American patients with RA.     

Progressive subretinal fibrosis and blindness in patients with multifocal granulomatous chorioretinitis

Since women with a first-degree relative with breast cancer are at increased risk for breast cancer, it is of special importance that they adhere to early detection programs. In this study, women with (389) and without (3295) a family history of breast cancer were compared with respect to risk perception, breast cancer anxiety, and early detection behavior. Special attention was paid to the role of knowing that family history is a breast cancer risk factor. It was found that 46% of "family history positives" did not know that their risk was increased by their family history. Still, family history positives had increased risk perception; our results suggest that this was partly caused by their knowing they belonged to a risk group and partly by their having experienced the disease at close range. Although family history positives had higher risk perceptions, no differences in early detection behavior were found. This could not be attributed to high anxiety levels. Implications for health education are discussed.     

Pancreatic xanthomatous neuropathy associated with hyperlipidemia: a cause of abdominal pain mimicking chronic pancreatitis

"Hyperlipidemic crisis" is a term used to describe episodic abdominal pain in patients with hyperlipidemia. The morphologic correlates of this phenomenon have not been investigated and the etiology of the disorder is uncertain. We report a unique histologic finding in the pancreas of a 34-year-old woman with a 17-year history of episodic abdominal pain, sometimes accompanied by hyperamylasemia. At the age of 18 years, grossly elevated cholesterol and triglyceride levels were documented and type V hyperlipidemia was diagnosed. At the age of 34 years, subtotal pancreatectomy was performed for intractable abdominal pain. Histologic examination identified an increased number of enlarged pancreatic nerves that were infiltrated by foamy macrophages and encircled by fibrous tissue; endoneurial infiltration with macrophages occasionally split nerves into individual fascicles. Otherwise, the pancreas had only minimal fibrosis, nesidioblastosis, mucinous metaplasia of some pancreatic ducts, and scattered small collections of chronic inflammatory cells, subtle features suggesting very mild chronic pancreatitis. We propose that this novel xanthomatous neuropathy mimicked pancreatitis and was one of the underlying pathophysiologic mechanisms of abdominal pain in this patient. Further studies are necessary to document the prevalence of this new entity in patients with hyperlipidemia and to correlate its occurrence with "hyperlipidemic crisis" in those individuals.