Epitope specificity of CD44 for monoclonal antibody-dependent facilitation of marrow engraftment in a canine model

Primary graft rejection after marrow transplantation occurs more frequently in patients receiving HLA-haploidentical compared with HLA-identical sibling transplants. Both human and experimental animal data suggest that the cells responsible for this phenomenon are either host natural killer (NK) cells, T cells, or both. To investigate the mechanisms of graft rejection, we have developed a canine model of marrow transplantation, which uses DLA-nonidentical unrelated donors in the absence of postgrafting immunosuppression. In this model most animals rejected their marrow grafts after a preparative regimen of 9.2 Gy total body irradiation (TBI). However, engraftment of DLA-nonidentical marrow can be facilitated when the recipients are pretreated with monoclonal antibody (MoAb) S5, which recognizes CD44. In this report, we extended these observations by first cloning the canine CD44 and, next, mapping the epitope recognized by S5, which was located in a region conserved among human and canine CD44 and was distinct from the hyaluronan binding domain. However, in vitro binding of S5 caused a conformational change in CD44, which allowed increased hyaluronan binding. Then, we reexamined the in vivo model of marrow transplantation and compared results with MoAb S5 to those with two other anti-CD44 MoAbs, IM7 and S3. Only MoAb S5 significantly increased the engraftment rate of DLA-nonidentical unrelated marrow, whereas the two other anti-CD44 MoAbs were ineffective. The enhanced in vivo effect was not related to differences in the MoAbs' avidities, since both S5 and IM7 had equivalent binding to CD44, but most likely related to the specific epitope that S5 recognizes. Thus, this study shows that the effect of the anti-CD44 MoAb S5 in facilitating engraftment is epitope specific and if one is to use an anti-CD44 to facilitate engraftment of marrow in humans, one cannot assume that any anti-CD44 would work.     

Apoptosis in the failing human heart

BACKGROUND: Loss of myocytes is an important mechanism in the development of cardiac failure of either ischemic or nonischemic origin. However, whether programmed cell death (apoptosis) is implicated in the terminal stages of heart failure is not known. We therefore studied the magnitude of myocyte apoptosis in patients with intractable congestive heart failure. METHODS: Myocardial samples were obtained from the hearts of 36 patients who underwent cardiac transplantation and from the hearts of 3 patients who died soon after myocardial infarction. Samples from 11 normal hearts were used as controls. Apoptosis was evaluated histochemically, biochemically, and by a combination of histochemical analysis and confocal microscopy. The expression of two proto-oncogenes that influence apoptosis, BCL2 and BAX, was also determined. RESULTS: Heart failure was characterized morphologically by a 232-fold increase in myocyte apoptosis and biochemically by DNA laddering (an indicator of apoptosis). The histochemical demonstration of DNA-strand breaks in myocyte nuclei was coupled with the documentation of chromatin condensation and fragmentation by confocal microscopy. All these findings reflect apoptosis of myocytes. The percentage of myocytes labeled with BCL2 (which protects cells against apoptosis) was 1.8 times as high in the hearts of patients with cardiac failure as in the normal hearts, whereas labeling with BAX (which promotes apoptosis) remained constant. The near doubling of the expression of BCL2 in the cardiac tissue of patients with heart failure was confirmed by Western blotting. CONCLUSIONS: Programmed death of myocytes occurs in the decompensated human heart in spite of the enhanced expression of BCL2; this phenomenon may contribute to the progression of cardiac dysfunction.     

The importance of geriatrics to family medicine: a position paper by the Group on Geriatric Education of the Society of Teachers of Family Medicine

The role of geriatrics and geriatricians in family medicine remains unsettled. Despite a rapidly aging population, a tremendous shortage now exists of faculty with interest and expertise in geriatrics. Relatively few family practice residents choose to enter geriatric fellowship programs, and federal funding for such programs has been reduced. Despite accreditation requirements, residency programs are not always able to provide the range of geriatric experiences needed to properly prepare graduates to provide care for the broad range of older patients. Medical students' exposure to geriatrics remains limited. The Group on Geriatric Education of the Society of Teachers of Family Medicine believes that family medicine faculty must recognize and be committed to the notion that geriatrics is integral to family medicine. Both undergraduate and residency training programs should emphasize experience with geriatric patients in multiple settings. In particular, the nursing home should not be the main focus of geriatric training. The small number of certified geriatric faculty will be able to provide leadership, but a broad range of faculty must become involved in teaching geriatrics. Faculty development activities and continuing education programs to foster the necessary expertise will be essential to the accomplishment of this task.     

Silicon bipolar chipset for SONET/SDH 10 Gb/s fiber-opticcommunication links

High-speed multiplexers, demultiplexers, frequency dividers, mixers, and amplifiers are key electronic components in high-speed fiber-optic communications systems such as SONET/SDH. In this paper, we present several important digital and analog integrated circuits (IC) which have been developed for use in SONET/SDH 10 Gb/s optical communication links. The circuits have been fabricated in MOSAIC 5E, an advanced silicon bipolar technology (f_T=26 GHz). The resulting chipset which amounts to a total of 10 IC's consists of multiplexers, demultiplexers, a regenerative frequency divider (2:1), a dual output limiting amplifier, and two different types of mixers for clock extraction. Specifically, the design and performance of these IC's and a hybrid clock recovery module are discussed. The high performance and potential low cost of this research chipset show that advanced silicon bipolar circuit technology can play an important role in future multigigabit fiber-optic communication systems     

Pitfalls and complications of esophageal prosthesis, laser therapy, and dilation

Although often diagnosed and treated by gastroenterologists, thoracic surgeons should be skilled partners in the management of esophageal obstruction. Knowledge of pitfalls and complications of any procedure is a prerequisite to success. This article focuses on problems encountered in dilatation, laser ablation, and stenting of esophageal strictures. Dilatation of both benign and malignant strictures requires knowledge of the different types of dilators and the ability to adapt to different stricture characteristics. Although lower morbidity makes laser ablation of malignant obstruction attractive, this author finds its use to be restrictive. The advent of expandable metal stents offers the potential for fewer early complications when compared with plastic protheses but, as discussed, morbidity may be different rather than less.     

XIV. Yeast sequencing reports. Sequence of MKT1, needed for propagation of M2 satellite dsRNA of the L-A virus of Saccharomyces cerevisiae

MKT1 is required for m aintenance of K₂ above 30°C in strains with the L-A-HN variant of the L-A double-stranded RNA virus of Saccharomyces cerevisiae. We report that MKT1 encodes a 92 979 Da protein with serine-rich regions and the retroviral protease signature, DTG, but with no substantial homology to proteins presently in the databases. This sequence is available from GenBank under Accession Number U09129.     

Laboratory evaluation of the XR-Bond Dentin/Enamel Bonding System

The shear bond strengths of the XR-Bonding System used in conjunction with Herculite composite, to the dentine of forty extracted human permanent first and second molars were determined after the test specimens were stored in physiological saline at 37 degrees C for 48 hours, one week, two weeks and four weeks, respectively. A shear load was applied to the base of the bonded composite cylinders with a knife-edged rod at a crosshead speed of 0.5 mm/minute. The shear bond strengths were expressed in megapascals (MPa). The quantitative microleakage of Class V preparations in dentine (cementum) in forty-eight extracted human maxillary permanent canines restored with the same dentinal bonding system and after storage in physiological saline at 37 degrees C for the same time intervals as for the shear bond strength tests, was determined. On the final day of each time interval the teeth were thermocycled X 500 in a 2 per cent methylene blue solution between 8 degrees C and 50 degrees C with a dwell time of 15 seconds. Microleakage was determined by a spectrophotometric dye-recovery method and expressed in microgram dye/restoration. There was a significant trend for the shear bond strengths to increase with duration of storage (p = 0.01) but the quantitative microleakage was not significantly different (p = 0.75).     

Temperament and attention: Orienting toward and away from positive and negative signals.

Two studies used a target detection task to examine temperament-related attentional biases toward and away from significant stimuli. Pretarget cues were used to orient attention to locations carrying a positive incentive value (where points could be gained) or a negative value (where points could be lost). Under both involuntary and voluntary conditions, extraverts were slow to shift attention away from positive locations, whereas introverts were slow to shift from negative locations. These biases were enhanced on trials following negative feedback and tended to be strongest in Ss high in Neuroticism. The findings support models proposing that Extraversion reflects the combined activity of positive (strongest in extraverts) and negative (strongest in introverts) incentive motivational processes. They further suggest that incentive processes regulate the ability to shift attention away from, rather than toward, significant stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)