Hydrogen bond integrity between MHC class II molecules and bound peptide determines the intracellular fate of MHC class II molecules.

MHC class II molecules associate with peptides through pocket interactions and the formation of hydrogen bonds. The current paradigm suggests that the interaction of side chains of the peptide with pockets in the class II molecule is responsible for the formation of stable class II-peptide complexes. However, recent evidence has shown that the formation of hydrogen bonds between genetically conserved residues of the class II molecule and the main chain of the peptide contributes profoundly to peptide stability. In this study, we have used I-A(k), a class II molecule known to form strong pocket interactions with bound peptides, to probe the general importance of hydrogen bond integrity in peptide acquisition. Our studies have revealed that abolishing hydrogen bonds contributed by positions 81 or 82 in the beta-chain of I-A(k) results in class II molecules that are internally degraded when trafficked through proteolytic endosomal compartments. The presence of high-affinity peptides derived from either endogenous or exogenous sources protects the hydrogen bond-deficient variant from intracellular degradation. Together, these data indicate that disruption of the potential to form a complete hydrogen bond network between MHC class II molecules and bound peptides greatly diminishes the ability of class II molecules to bind peptides. The subsequent failure to stably acquire peptides leads to protease sensitivity of empty class II molecules, and thus to proteolytic degradation before export to the surface of APCs.

Energetic asymmetry among hydrogen bonds in MHC class II*peptide complexes.

Comparison of crystallized MHC class II*peptide complexes has revealed that, in addition to pocket interactions involving the peptide side chains, peptide binding to MHC class II molecules is characterized by a series of hydrogen bonds between genetically conserved amino acid residues in the class II molecule and the main chain of the peptide. Many class II*peptide structures have two sets of symmetrical hydrogen bonds at the opposite ends of the class II antigen-binding groove (beta-His-81, beta-Asn-82 vs. alpha-His-68, alpha-Asn-69). In this study, we alter these peripheral hydrogen bonds and measure the apparent contribution of each to the kinetic stability of peptide* II complexes. Single conservative amino substitutions were made in the I-A(d) protein to eliminate participation as a hydrogen bonding residue, and the kinetic stability of a diverse set of peptides bound to the substituted I-A(d) proteins was measured. Although each hydrogen bond does contribute to peptide binding, our results point to the striking conclusion that those hydrogen bonds localized to the amino terminus of the peptide contribute profoundly and disproportionately to the stability of peptide interactions with I-A(d). We suggest that the peripheral hydrogen bonds at the amino terminus of the bound peptide that are conserved in all class II*peptide crystal structures solved thus far form a cooperative network that critically regulates peptide dissociation from the class II molecule.

Metallic fragments on mammography after intraoperative deployment of radiopaque clips.

OBJECTIVE: Our objective was to report the occurrence and determine the frequency of metallic fragments in the breast after placement of surgical clips that are used to delineate the margins of the biopsy cavity. CONCLUSION: Metallic fragments are commonly present in patients who have surgical clips placed during breast biopsy for both benign and malignant disease. Awareness of this phenomenon may prevent the misidentification of these fragments as microcalcifications and thus avert unnecessary concern or biopsy.

Invariant chain and DM edit self-peptide presentation by major histocompatibility complex (MHC) class II molecules.

We have studied the consequences of invariant chain (Ii) and DM expression on major histocompatibility complex (MHC) class II function. Ii has a number of discrete functions in the biology of class II, including competitive blocking of peptide binding in the endoplasmic reticulum and enhancing localization in the endocytic compartments. DM is thought to act primarily in endosomes to promote dissociation of the Ii-derived (CLIP) peptide from the class II antigen-binding pocket and subsequent peptide loading. In this study, we have evaluated the functional role of Ii and DM by examining their impact on surface expression of epitopes recognized by a large panel of alloreactive T cells. We find most epitopes studied are influenced by both Ii and DM. Most strikingly, we find that surface expression of a significant fraction of peptide-class II complexes is extinguished, rather than enhanced, by DM expression within the APC. The epitopes antagonized by DM do not appear to be specific for CLIP. Finally, we found that DM was also able to extinguish recognition of a defined peptide derived from the internally synthesized H-2Ld protein. Thus, rather than primarily serving in the removal of CLIP, DM may have a more generalized function of editing the array of peptides that are presented by class II. This editing can be either positive or negative, suggesting that DM plays a specifying role in the display of peptides presented to CD4 T cells.

T cell receptor recognition of MHC class II alloantigens is highly cell type dependent.

According to some models of T cell education, tolerance, and autoimmunity, recognition of MHC molecules by T cells may depend on the nature of the APC expressing the MHC/Ag complex. To examine this, a panel of 23 I-Ad-restricted, alloreactive T cells were used to probe MHC class II molecules expressed on established lines representing different lineages. Surprisingly, we observed cell type-specific reactivity in the majority of the T cells. In all, 18 different reactivity patterns were identified. The patterns observed suggests that MHC reactivity can be organized into a hierarchical pattern for both the APC and the T cells. Experiments assessing T cells' avidities for allogeneic targets, ability to produce lymphokines, and expression of accessory molecules revealed no predictive correlation with the hierarchical reactivity pattern, nor did experiments measuring allogeneic target cells' expression of known accessory molecules and ability to stimulate Ag-specific hybridomas. These results suggest that the differential reactivity cannot be accounted for by accessory molecule discrepancies among the APC, but rather might reflect deficiencies in the ability of the various APC to engage the Ag-specific T cell receptor. Collectively, these data indicate that a significant fraction of allorecognition of MHC class II is cell-type dependent and that cell-type-specific recognition may relate to peptide-specific recognition requirements by the Ag receptor of alloreactive T cells.

Kaposi's sarcoma involving the thyroid in a patient with AIDS.

A 30-year-old man with acquired immune deficiency syndrome (AIDS) and Kaposi's sarcoma had a palpable thyroid mass and cervical lymphadenopathy. Nuclear medicine and ultrasound scans revealed multiple thyroid nodules. Results of biopsy showed Kaposi's sarcoma metastatic to the thyroid.

Normal uterine activity on a 99mTc-glucoheptonate renal scan.

Uterine radioactivity uptake has previously been reported for a variety of radionuclide agents in the presence of uterine pathological disorders, such as leiomyomata as well as uterine and cervical neoplasma and infections. Activity within the normal uterus has also been reported in Meckel's scans using 99mTc-pertechnetate, but this has not been reported for other radionuclide agents. We report a case exhibiting radioactivity uptake within a normal uterus on a 99mTc-glucoheptonate scan of a renal transplant. Awareness of the possibility of radioactivity uptake in a normal uterus is important in order to avoid potential confusion with abnormal pelvic masses or fluid accumulations.

Subintimal dissection of peritoneovenous shunt tubing. Demonstration with radionuclide study.

A case report is presented in which malfunction of a peritoneovenous shunt was caused by subintimal dissection of the venous end of the shunt tubing. The radionuclide shunt patency study demonstrated a collection of radioactivity at the venous end of the tubing, representing the abnormal intramural collection of peritoneal fluid. Scintigraphic demonstration of this complication of a peritoneovenous shunt has not been reported previously.

Thyroid nodules: sonographic-pathologic correlation.

Sonographic patterns of thyroid disease were correlated with pathologic findings. Twenty-eight cadaver thyroid glands were prospectively examined with a high-resolution real-time ultrasound scanner. Ultrasound findings were correlated in detail with gross and microscopic findings. Ultrasound is very accurate in detecting architectural variation, adenomatous goiter, and solitary nodules. Ultrasound cannot distinguish benign from malignant nodules, but it can be used to measure changes in nodule size. Glandular asymmetry and multiple solid nodules must be present for confident diagnosis of adenomatous goiter; hemorrhage, necrosis, and calcific spherules may be present in varying amounts. Fibrous septae, dilated follicles, and vascular calcification are found in normal aging thyroid glands. Using these criteria, ultrasonography is very accurate in the diagnosis of adenomatous goiter.

Growth recovery zones.

Growth arrest lines and zones have been reinvestigated. Sequential studies after dietary deprivation reveal transformations of the physis with diminution in formation of the zone of cell columns, resorption of previously formed bone, and cessation of new bone formation. At 6 weeks post diet restriction, the physis is prominently narrowed with transversely oriented, thin bone plaque sealing it from the subjacent marrow. Initially, restoration of stock diet thickens the bony plaque, creating a growth arrest line. Later the zone of osteogenesis adds new bone as a dense metaphyseal band.

Spontaneous correction of angulational deformity of the proximal femoral epiphysis after cervical and trochanteric fracture.

This case report of a 5-year-old girl describes a severely comminuted fracture of the cervical and trochanteric areas of the left proximal femur which required open reduction and internal fixation for stable realignment. At 7 months follow-up, angulational deformity was recognized due to partial growth arrest leading to valgus tilt of the proximal femoral epiphysis. After persisting 1 year, gradual spontaneous improvement occurred leading to total realignment with a normally wide growth plate at 36 months following injury. It is hypothesized that the valgus deviation of the femoral head, by causing a medial shift of the weight bearing axis, led to relative unloading of the lateral margin of the growth plate. It is suggested that this mechanical element contributed to the spontaneous release of the epiphyseal tether.

Tissue antibiotic levels with tourniquet use in orthopedic surgery.

Ten adult mongrel dogs were given 500 mg of cefazolin intravenously, before and after tourniquet cuff inflation. Muscle tissue antibiotic levels were comparable to the control side when the antibiotic was administered prior to tourniquet inflation. Muscle tissue antibiotic levels were markedly diminished compared to the control limb when the antibiotic was given after the tourniquet was inflated. The low level of antibiotic appeared slowly and peaked at 60 minutes as a reflection of minimal limb blood flow. It was questionable whether the small antibiotic concentration in the latter situation served adequate protective cover.

Nonarticular osteochondroses.

Nonarticular osteochondroses represent disordered enchondral ossification of epiphysis or apophysis at specific sites of muscle/tendon insertions or ligament attachments. Traditionally, osteochondroses have been identified by eponymic proper names. A generic classification is based upon the relationship of excessive or repetitive traction in occasional combination with direct pressure at discrete anatomical sites. The following are models of the several varieties: Osgood-Schlatter syndrome, typifying muscle/tendon stress on the tibial tuberosity; medial epicondylosis (Adams), resulting from forearm and elbow stress generated by muscles and creating traction through the ulnar collateral ligament attachment; and Sever's syndrome (calcaneal apophysis), associated with tension at either end of the calcaneal apophysis in combination with direct impact pressure. The general characteristics of this group include symptoms of pain or tenderness, timed appearance coincident with the developmental sequence of the apophysis, and generally symptomatic management.

Which books are perceived as helpful in the training of psychotherapists?

Psychotherapy and Clinical Fellows responded to a survey that requested them to recommend books they thought were of substantial help in training the prospective clinician to do psychotherapy. Responses indicated that there was little agreement among clinicians with regard to which books are helpful. Also, a minority of clinicians felt that no books were helpful. Those books found most helpful are referenced.