HLA class-II-mediated homotypic aggregation: involvement of a protein tyrosine kinase and protein kinase C.

Homotypic aggregation of B-lymphocytes, B-cell lines and class-II-positive T cells via HLA class II molecules was examined. Signaling via DR antigens induced rapid aggregation in a dose- and time-dependent manner, maximum and stable aggregation was induced within 20 minutes. On the contrary, rapid signaling via DP or DQ required prestimulation with either PMA or anti-sIg. Aggregation was temperature and energy dependent. [Ca2+] and [Mg2+] concentrations and an intact cytoskeleton were required while neither mRNA or protein synthesis were required. Furthermore, FACS analysis revealed that aggregation was not directly correlated with cell surface expression of HLA class II molecules. Our results demonstrate that aggregation was mediated through a protein tyrosine kinase (PTK)-dependent pathway that preceded activation of protein kinase C (PKC) and failure to generate either the PTK signal or the PKC signal prevented aggregation. The contribution of a tyrosine kinase was further demonstrated by the total inhibition of aggregation following treatment with an anti-CD45 mAb.


Production and characterization of murine monoclonal antibodies recognizing HLA-DQ polymorphisms obtained by immunizing mice with transfected L cells.

Two polymorphic anti-HLA-DQB1 mAbs, TM 902 and TM 903, have been produced by immunizing F1 mice (Balb/C x C3H) with HLA-DQ-transfected mouse L cells. Cytotoxic analysis on a panel of HLA-typed cell lines has shown that TM 902 reacts with all the DQB1* alleles except DQB1*0501, *0502, and *0503, and DQB1*0601, *0602, *0603, and *0604, whereas TM 903 reacts with the DQB1*0501, *0502, and *0503, DQB1*0601, *0602, *0603, and *0604, and DQB1*0401 and *0402 alleles. The same reactivity pattern has been confirmed by cytofluorimetric analysis. Indirect immunofluorescence with various class-II-transfected cell lines showed no binding of both mAbs to the DR or DP products, suggesting their reactivity to the DQ products. The use of transfectants expressing HLA-DR/DQ heterodimers demonstrates that TM902 and TM903 mAbs are both specific for the DQ-beta chain. Comparison of the amino acid sequences of the DQ-beta chain suggests the involvement of residues 84-90 (QLELRTT) in the formation of TM902 epitope and of residues 54-55 (GR) in the formation of TM903 epitope.


Analysis of HLA DP, DQ, and DR alleles in adult Italian rheumatoid arthritis patients.

We analyzed the distribution of DRB1, DQA1, DQB1, and DPB1 allelic variants in 48 rheumatoid arthritis (RA) patients, compared with 109 Italian random controls, using PCR amplification and hybridization with specific oligonucleotides. We confirm the previously reported increase of DR4 specificity, in comparison with healthy Italian individuals. In particular, we find a statistically significant positive association of DRB1*0401 and DRB1*0404 alleles with RA. However, when we compare the DR4+ groups, none of the DRB1*04 alleles is increased in the RA group. By sequence analysis, performed on 10 patients, we demonstrate that the DRB1*04 genes of RA show no difference from the DRB1*04 sequences previously published. From the molecular analysis of the other DRB1 polymorphic variants, we find a trend of positive association of DRB1*0101 in DR4-negative patients versus DR4-negative healthy controls and, in the group of DR4-negative and/or DR1-negative patients, a similar increase of DRB1*06. Also, we observe in RA patients a statistically significant increase of DQA1*0301 and DQB1*0302 accompanied by a significant decrease of DQA1*0201, DQA1*0501 and DQB1*0201. Finally, from the analysis of DPB1 gene, it can be assessed that the distribution of DPB1 alleles does not differ significantly between RA patients and healthy controls.


Relative contribution of HLA-DQA and -DQB alleles to predisposition to insulin-dependent diabetes mellitus.

The presence of DQA and DQB alleles conferring protection or susceptibility was assessed in a panel of 39 insulin-dependent diabetes mellitus patients and 39 healthy control subjects from the central highland of Ethiopia. The results were grouped into three entities: a combination of alleles conferring susceptibility, a group conferring protection, and a group without any apparent HLA-DQ or -DR predisposition to insulin-dependent (type 1) diabetes mellitus (IDDM). Statistical analysis revealed that the relative risk of the first group is 64.1. If a similar approach is applied to the data on a study in caucasoid IDDM patients and controls of Kahlil and colleagues, the pattern is fully consistent with the data presented here, with an extraordinarily high relative risk (RR 258.2). It will be of interest to study whether this subdivision is reflected or supported by clinical or etiologic differences of the disease. The predictive value of susceptibility phenotypes appears to be more accurate by the proposed subdivision. Furthermore, in combination with islet-cell antibody analysis, assessment of genotype will permit more accurate identification of prediabetic individuals to be entered in clinical trials.


Contribution of a single DQ beta chain residue to multiple sclerosis in French Canadians.

Putative disease susceptibility and resistance HLA class II alleles were studied in 78 French Canadian multiple sclerosis (MS) patients and 79 controls by using sequence-specific oligonucleotide probes to analyze in vitro amplified DNA (PCR-SSOP) typing). In this relatively homogeneous ethnic group, MS was positively associated with DRB5*0101, DQB1*0602, and DQA1*0102 and negatively associated with DQB1*0301. The strongest disease association was with DQB1*0602. Complete DQB1 typing of these individuals, plus RFLP DQ beta typing of an additional five patients showed that 98% of patients compared with 73% of controls carry DQB1 alleles encoding leucine at residue 26. In contrast, 16% of patients compared with 38% of controls carry DQB1 alleles encoding tyrosine at the same residue, and 22% of patients versus 44% of controls carry DQB1 alleles encoding glycine at residue 26. The positive disease correlation was confirmed with SSO probes designed to hybridize to codons for amino acids 22-27 of DQB1*0602, 0603, 0604, 0302, 0303 or to codons for amino acids 25-31 of DQB1*0201; all of these alleles encode Leu 26. These findings suggest that DQ beta chain polymorphisms at a single residue contribute to the development of MS in the French Canadian population.


Apparent HLA DR triplet due to the coexpression of a DRB5-encoded molecule on a DR1 haplotype.

HLA DR1 molecules are coded by a single polymorphic DRB1 gene. We have observed rare DR1 cells in one Caucasoid family and three unrelated individuals that also reacted with some anti-DR2 sera. Since the second DR antigen was normally expressed, these cells appeared as triplets. Contrary to serology, the cells were not typed by HTCs defining Dw2, Dw12, and Dw21. Further investigations on these unusual DR1+2* haplotypes were conducted by DNA oligotyping and by sequencing of the DRB first-domain exon. The results showed that these DR1 haplotypes, besides their DRB1*0101 allele, carried also a DRB5*0101 allele.


HLA class II expression on human epidermal Langerhans cells in situ: upregulation during the elicitation of allergic contact dermatitis.

An immunoelectron-microscopic technique was applied to investigate the localization of molecules that are involved in the elicitation of allergic contact dermatitis in human epidermal cells in situ. Langerhans cells in the epidermis of lesions showed a strongly increased cell surface expression of HLA class II molecules as compared with normal skin. In addition, a high number of intracellularly located HLA class II molecules were present in Langerhans cells of lesional epidermis, suggesting increased biosynthesis of these molecules during the elicitation process. In contrast, no differences in the expression of CD1a by Langerhans cells was observed between normal and lesional skin. Frequently, the Langerhans cells were found in close apposition to mononuclear cells, which also exhibited a strong cell surface HLA class II expression. The number of Birbeck granules that are characteristic intracellular Langerhans cells organelles was increased in lesional Langerhans cells as compared with normal-skin Langerhans cells, which may correlate with the activated state of lesional Langerhans cells. These Birbeck granules were always HLA class II or CD1a negative. The increased synthesis and expression of HLA class II molecules on the cell surface of Langerhans cells suggests a direct role for these HLA class II molecules in the elicitation process of allergic contact dermatitis.


HLA-DR,DQ sequence polymorphisms in Polynesians, Micronesians, and Javanese.

The origins of the Polynesians remain an enigma. Linguistic reconstructions of proto-Austronesian languages suggest a shared origin for Polynesians, Micronesians, and Javanese with dispersal from northern Borneo and Sulawesi. Analysis of 810 chromosomes for nucleotide sequence polymorphism at HLA-DRB1, DRB3, DRB5, DQA1, and DQB1 loci in Polynesian (Rarotonga, Western Samoa, and Niue), Micronesian (Nauru and Kiribati), and Javanese populations showed virtually no overlap of HLA class II haplotypes between contemporary Polynesians and Javanese. Further, there were marked differences in population distributions of some HLA-DRB1 alleles that could not be distinguished in earlier serologic or restriction fragment length polymorphism (RFLP) studies, e.g., for DR12, DRB1*1201 had a frequency of 15%-30% in Polynesians (1% in Micronesians and Javanese), whereas DRB1*1202 had a frequency of 28%-38% in Micronesians and 51% in Javanese (1% in Polynesians). A novel DR6-related allele, DRB1*1408, was found in all three Polynesian study populations. The Polynesian HLA class II genetic repertoire is not readily derived from the island Southeast Asian gene pool.


Sequence variation in Japanese HLA-DRw8 specificity.

There are four DRw8 haplotypes with different DQ alleles in Japanese: DRw8-DQw6 (w1), DRw8-DQw4, DRw8-DQw8(w3), and DRw8-DQw7 (w3). We previously reported the nucleotide sequence of DRB1 gene of DRw8-DQw6(w1) and it was named DRB1*08032. The nucleotide sequences of the other DRw8 DRB1 alleles and their correspondence to internationally recognized DRw8 subspecificities were still unclear. We have cloned these DRB1 genes and determined the nucleotide sequences. The comparison of the sequences with the published sequences revealed that the differences were occurred at two amino acid positions, and these four haplotypes are classified in two groups: (a) DRw8-DQw6(w1) and DRw8-DQw7(w3), and (b) DRw8-DQw4 and DRw8-DQw8(w3). The DRB1 molecules of DRw8-DQw6(w1) and DRw8-DQw7(w3) have Ser57 and Ile67, and those of DRw8-DQw4 and DRw8-DQw8(w3) have Asp57 and Phe67. The former has the same sequence as that of DRB1*08032, and the latter is same as that of DRB1*0802. The classification corresponds to the serologic subtyping, which divides DRw8 into DR8.1 and DR8.2, reported in the 10th Japan HLA Workshop.


Transplantation tolerance in heart transplant recipients as demonstrated by unresponsiveness in cell-mediated lympholysis.

Transplantation tolerance or adaptation to an allograft is associated with unresponsiveness to donor-specific transplantation antigens measured in in vitro cell-mediated lympholysis (CML). We here demonstrate in a longitudinal follow-up that CML nonreactivity develops in seven of ten patients following heart transplantation. The first manifestation of this nonreactivity manifested between 3 and 27 months after transplantation. CML nonreactivity correlated with time after transplantation and the percentage of activated lymphocytes in peripheral blood. CML nonreactivity was also associated with good graft function, i.e., in condition of nonresponsiveness patients did not manifest acute rejection. The only exception was seen in one patient in whom the immunosuppressive therapy was strongly reduced. A more detailed evaluation of this patient indicated that the underlying mechanism for CML nonreactivity is clonal anergy or active suppression of the alloreactive cells.


Peptide-induced proliferation and lymphokine production in human T cells in the absence of antigen-presenting cells: role of T-cell activation state and costimulatory signals.

The role of T-lymphocytes as antigen-presenting cells (APCs) for other T cells was investigated. Activated rabies-virus-specific human T-cell clones were shown to present peptide to class II major histocompatibility complex (MHC)-restricted T cells of a different fine specificity, resulting in lymphokine production and cell proliferation. Furthermore, purified and activated antigen-specific T cells could produce lymphokines and proliferate as a result of the addition of antigenic peptide in the absence of APC. The functional response of T cells to peptide in the absence of APC was amplified by the addition of phorbol ester (PMA) and was inhibited with antibodies specific to class II MHC or to the CD2 molecule. Experiments performed in single-cell suspension cultures using semisolid medium prepared with 1% agar demonstrate that T-cell proliferative and lymphokine responses to peptide both in the presence and absence of APC require the interaction of T-cell antigen receptor (TCR) molecules with class II MHC-peptide complexes on different cell surfaces (cell-cell contact). On the other hand, peptide self-presentation, which occurs by the binding of TCR with class II MHC-peptide complexes on the same cell surface (at the single-cell level), resulted in T-cell activation (i.e., high expression of surface CD2, CD25, and HLA-DR molecules), without proliferation or lymphokine secretion, a pattern observed in the induction of T-cell anergy by antigen. The results are discussed in terms of the role of class II MHC molecules on activated T-lymphocytes, which enable these cells to function as "professional APC" in the development of T-cell regulatory networks.


Silent allelic variants of a T-cell receptor V beta 12 gene are present in diverse human populations.

Amino acid substitutions in variable regions of the T-cell receptor (TCR) can alter T-cell reactivity; however, relatively little is known about the extent of allelic variation in human TCR coding sequences. In the present studies, coding region variation in the human TCR V beta 12.2 gene was examined in detail. Virtually the entire V beta 12.2 coding region was screened for nucleotide substitutions by single-stranded conformational polymorphism analysis. Four alleles were identified in a sample population of 90 unrelated people from diverse genetic backgrounds. Three of the alleles were common, with estimated frequencies of 0.32, 0.47, and 0.20. Sequence analyses revealed that variation between the alleles was confined to three single-base differences in codons 24, 31, and 45; none of these changes altered the amino acid sequence. No evidence for other coding region differences in this gene were found. This analysis suggests that coding region variation in V beta 12.2 is limited, and amino acid sequence is highly conserved.


Flow-cytometric analysis of immune cell populations in human decidua from various types of first-trimester pregnancy.

We undertook an investigation in which flow cytometry was used to characterize immune cell populations in the decidua of first-trimester normal pregnancies, spontaneous abortions, and ectopic pregnancies in comparison to the nonpregnant endometrium to demonstrate how the proportions of immunocompetent cell populations at the fetomaternal interface are influenced by the presence and state of a fetoplacental allograft. No significant differences were found in the decidua of the different types of first-trimester pregnancy in the proportions of the CD45+, CD14+, CD3+, CD4+, CD8+, CD19+, CD3-/CD16+ and/or CD56+, CD3+/CD16+ and/or CD56+, CD4+/Leu-8+, CD4+/Leu-8-, CD8+/CD11b+, CD8+/CD11b-, and CD3+/HLA-DR- decidual leukocyte subsets. However, the percentage of decidual CD3+/HLA-DR+ cells, which are characteristic of activated T cells, was significantly higher in spontaneous abortions than in normal pregnancies (p less than 0.05). This suggests that the accumulation of decidual leukocytes may be regulated mainly by hormones and/or cytokines rather than by the presence and state of an intrauterine conceptus and that on/off-switching of activation of decidual T cells may be associated with successful maintenance of the implanted embryo.


Autologous graft-versus-host disease: a novel approach for antitumor immunotherapy.

Autologous bone marrow transplantation (BMT) is a therapeutic option for the treatment of lymphohematopoietic malignancies and solid tumors. Despite the intensive cytoreductive therapy, however, the rates of tumor recurrence after autologous BMT remain unacceptably high. Current studies suggest that the administration of cyclosporine (CsA) disrupts the reconstitution of self-tolerance following autologous BMT leading to the induction of an autoimmune graft-versus-host disease (GVHD). Studies in a rat tumor model and preliminary clinical trials suggest that this autoimmune or autologous GVHD provides a significant antitumor effect. Moreover, the antitumor effect of autologous GVHD can be enhanced by administration of gamma-interferon, which upregulates the antigen recognized by the autoreactive effector cells of autologous GVHD. These studies indicate that the induction of an autoimmune GVHD after autologous BMT may be a promising immunotherapeutic approach for treatment of certain neoplastic diseases.


Familial glomerular disease with asymptomatic proteinuria and nephrotic syndrome: a new clinical entity.

Seventy-three members of a 100-member kindred with asymptomatic proteinuria, nephrotic syndrome, and progressive renal failure were studied. Of those studied, 11 members had progressed to end-stage renal disease and seven had significant proteinuria (greater than 1 g/24 hours) with normal renal function. The genetic mode of inheritance was autosomal dominant with variable penetrance and expressivity. Histopathologic changes were variable but included focal segmental glomerulosclerosis and diffuse glomerulosclerosis. Renal failure usually occurred in the fifth decade of life. The most consistent clinical finding was proteinuria without microscopic hematuria or other significant urinary sediment elements. This disease differed from Alport's hereditary nephritis and congenital nephrotic syndrome in age of onset, urinary findings, and associated conditions, that is, nerve deafness. The hereditary proteinuria and nephrotic syndrome described in this kindred represents another facet in the spectrum of hereditary renal disease.


Adult respiratory distress syndrome: a review for the clinician.

Adult respiratory distress syndrome is a common respiratory problem with a wide array of precipitating causes and an overall mortality rate of more than 50%. Signs on physical examination tend to be nonspecific as do laboratory findings associated with the syndrome. Because of its diverse etiology, there is no one specific treatment for adult respiratory distress syndrome. Therapy is primarily supportive and centers around the use of mechanical ventilator support. The authors discuss the pathogenesis and management of this syndrome together with some of the newer approaches to mechanical ventilation.


Therapeutic considerations: lower respiratory tract infections in smokers.

Tobacco smoke can alter both the structural and the immunologic defenses of the lungs against infection. The gases from smoke can also inhibit repair of the damages they create. Smokers have been found to have increased bacterial adherence to the respiratory tract, decreased IgA and IgG, and a decrease in vital capacity two to three times greater than that of nonsmokers. These and other respiratory tract alterations put smokers at an added disadvantage when acute lower respiratory tract infections strike. A history of smoking influences the diagnosis of respiratory tract infections because smokers are more prone than nonsmokers to infection by certain organisms. The major causes and characteristics of lower respiratory tract infections, methods of outpatient diagnosis, and the pros and cons of various modes of therapy are discussed.


Therapeutic drug monitoring: lithium levels.

Lithium has been used in the treatment of mania since 1949. Although its effectiveness is well recognized, the mechanism by which it stabilizes manic behavior is not well understood. In addition, it has some serious toxic properties combined with a narrow therapeutic range. For this reason, monitoring of serum lithium levels is mandatory. Suggested mechanisms of action and protocols for monitoring of serum levels are presented.


Evaluating an intern/residency program.

When faced with the task of program evaluation, many directors of medical education may find themselves overwhelmed. This article presents suggestions for conducting an evaluation, including the six basic elements to consider before embarking on such an undertaking. With an emphasis on selecting a model framework as a guide for conducting a program evaluation, this article examines one model--Stufflebeam's CIPP model--in depth.


Retained fetal scalp monitoring lead discovered in the wall of the jejunum.

The retention of a foreign body following surgery is a longstanding and dreaded problem. We report the retention of a fetal scalp monitoring lead that was embedded in the wall of the patient's jejunum and discovered 2 years after cesarean section. In reviewing the American medical literature, we believe this case is, perhaps, unique. The treatment of this entity is discussed as well as ways to help to prevent it.


Aortic dissection in acute pancreatitis.

Extrapancreatic fluid collections are frequently seen in acute pancreatitis. Vascular damage with life-threatening hemorrhage is also a known complication. In the case report presented, we include documentation by computed tomography of an apparent abdominal aortic wall dissection by fluid in a patient with acute pancreatitis. Conservative therapy resulted in complete resolution without hemorrhage or aneurysm formation.


Anomalous origin of the left main coronary artery from the right anterior aortic sinus.

Anomalous origin of the left main coronary artery from the right sinus of Valsalva is an uncommon problem, occurring in four distinct patterns. When the left main coronary artery passes between the aorta and the pulmonary trunk, acute myocardial ischemia or sudden death may occur. Angiography is required in establishing a diagnosis. Surgical correction or bypass surgery are sometimes indicated. The authors report two cases of anomalous origin of the left main coronary artery and discuss the anatomic variants, clinical significance, and technical considerations in both diagnosis and management.


Mirizzi syndrome (hepatic duct obstruction).

The Mirizzi syndrome is an uncommon cause of obstructive jaundice. In 1948, Mirizzi characterized a syndrome in which common hepatic duct obstruction occurs because of impacted stones in the gallbladder neck or cystic duct. The authors report a case demonstrating this syndrome. They discuss the radiographic features and report the features found on a computed tomographic cholangiogram that have not been previously described. Computed tomography-cholangiography may be helpful in evaluating patients with suspected Mirizzi syndrome.


Primary laryngeal and nasal septal lesions in pemphigus vulgaris.

Synchronous laryngeal and nasal septal lesions in pemphigus vulgaris are rare. The authors report a case of pemphigus vulgaris in an elderly man who was seen with lesions of the supraglottic larynx and nasal septum. The classic skin changes of pemphigus eventually developed, and the patient responded to daily treatments of 80 mg of prednisone. Steroids and immunosuppressive agents remain the treatment of choice, but a favorable prognosis is still dependent on early diagnosis and institution of therapy.


Male breast carcinoma: clinical experience in a suburban community.

Male breast cancer is difficult to study because it occurs infrequently, accounting for 1% of all breast carcinoma. Breast cancer occurs 10 years later in men than in women, and its presentation parallels that in women. The authors retrospectively review 13 cases of male breast cancer occurring over a 20-year period in four community hospitals. Treatment methods paralleled those used for female cancer patients. Surgery, primarily radical mastectomy, was performed in all patients. In the eight patients in whom hormone receptor assays were obtained, all tests were positive for estrogen receptors, progesterone receptors, or both. Metastases were diagnosed in five patients during follow-up. The longest disease-free survival has been 10 years. Similarities and differences regarding male and female breast cancer are discussed as are the diagnosis and management of men with this disease.


Update on monoclonal antibody therapy in the gram-negative sepsis syndrome.

Two multicenter controlled clinical trials of genetically engineered monoclonal antibodies directed against endotoxin, a potent mediator of inflammation in the gram-negative sepsis syndrome, were recently reported in the medical literature. One of these antiendotoxin antibodies was derived from a murine (mouse) source, and the other antibody was derived mainly from a human source (nebacumab [negative bacteria human monoclonal antibody]). This article reviews recent literature concerning the use of these agents in the treatment of gram-negative sepsis syndrome. It also projects economic assessment data regarding the use of nebacumab in the United States.


The lupus anticoagulant and antiphospholipid antibodies.

Antiphospholipid antibody syndromes are primarily manifested as unexplained thrombotic events. Several antiphospholipid antibodies have been identified, the lupus anticoagulant being the most recognized. Considerable confusion surrounds this "anticoagulant," which is highly correlated with an increased risk of thrombosis. Several assays have been designed for the detection of antiphospholipid antibodies. There are limitations on their efficacy and interpretation requires judgment. Treatment strategies for the clinical manifestations of the antiphospholipid antibody syndrome are being developed. The explosive rise in the volume of literature dedicated to this topic will assure new and improved modalities for evaluation and treatment.


Hepatitis testing update.

During a 25-year period, four types of hepatitis-causing virus have been identified and can now be evaluated serologically. This final article in this clinical laboratory medicine series reviews routes of virus transmission and persistence and the availability of tests.


Workup of a patient with newly diagnosed HIV infection.

This monthly series was developed from the AOA Task Force on AIDS Writers' Workshop, held August 16 to 18, 1991, in New York. The workshop was sponsored by an education grant from Burroughs Wellcome. It will provide brief clinical updates and perspectives on the human immunodeficiency virus (HIV). Readers may request tear sheets from the AOA editorial offices.


Suggestions for clinicians providing--and residents seeking--feedback.

As a form of verbal or nonverbal communication intended to promote learning, feedback plays an important role in the medical training process. More often than not, however, feedback is given--and received--inappropriately by both clinicians and residents, respectively. This article outlines common types of instructional feedback, their inherent advantages and disadvantages, and suggests ways in which clinicians and residents may incorporate feedback effectively in a residency/training program.


Invasive aspergillosis of the sphenoethmoidal sinuses in an immunocompetent host.

Fungal infections of the nose and paranasal sinuses are uncommon; Aspergillus is the most frequently isolated fungal pathogen. Invasive aspergillosis is commonly seen as an opportunistic infection in the immunocomprised, debilitated host. Whereas fulminant infection in the otherwise healthy patient is rare, in the immunocompetent host with persistent signs and symptoms of sinusitis despite appropriate medical management, aspergillosis should be considered. Treatment of paranasal sinus aspergillosis requires correction of immunologic deficits, if possible; aggressive surgical debridement to provide adequate drainage and aeration of the sinuses; and adjunctive antifungal chemotherapy. The authors present an unusual case of invasive aspergillosis of the paranasal sinuses in an immunocompetent host.


Cerebral emboli from the 'stump' of a totally occluded carotid artery: surgical management.

The obstructing thrombus in a totally occluded internal carotid artery may act as a source of cerebral emboli. These emboli traverse the external carotid and ophthalmic arteries and enter the intracranial circulation via retrograde collateral pathways. Surgical treatment can result in complete abatement of symptoms in selected patients. The authors describe internal carotid "stump" syndrome in a 47-year-old man and discuss the options for surgical management.


Clinical improvement of the myopathy in eosinophilia-myalgia syndrome with steroids and rehabilitative therapy.

The authors report a case of eosinophilia-myalgia syndrome with a progressive neuromyopathy. Progressive weakness, myalgia, and dermatitis developed in the patient described after chronic ingestion of high-dose L-tryptophan for insomnia. Laboratory, electrophysiologic, and muscle biopsy results support the diagnosis of an inflammatory myopathy consistent with that of eosinophilia-myalgia syndrome. The patient's weakness led to wheelchair dependency. A review of the literature regarding this disorder shows inconsistent results with steroid and other modes of therapy. After a course of high-dose steroids with long-term tapering and vigorous inpatient and outpatient rehabilitation, the patient was able to walk and function independently within 2 months.


Roentgenographic documentation of atlanto-occipital sidebending.

It is assumed that the atlas (C1) glides superiorly and laterally along the occipital (C0) condyle during translatory motion of the head in the opposite direction. To provide roentgenographic documentation, a translatory test of atlanto-occipital (C0-C1) motion was performed to the left and to the right on a healthy, asymptomatic volunteer subject. Roentgenographic examination was made at the extreme in each direction. The films indicate the change in atlantal position relative to the occiput and support the assumption. A translation of the head in the coronal plane to test for atlanto-occipital joint mobility is described.


The evolution of osteopathic manipulative technique: the Spencer technique.

The Spencer technique is a standardized series of shoulder treatments with broad application in diagnosis, treatment, and prognosis. The evolution of this technique is traced from 1916 to date to try to identify factors in the development of manipulative methods. Few suggestions about the basic steps to be followed in developing any new manipulative technique were seen. Of chief importance were changes in sequence, the addition of steps, and the combination of one technique with another, as in the addition of muscle-energy methods to each step. One change, accidentally introduced in the 1970s, displaced a critical step in the procedure. The principal element guiding the development of the Spencer technique appears to be clinical necessity interpreted in terms of anatomy and pathology.


Starting therapy for an HIV-infected patient.


Alleviating stress in residency training through enhanced communication: a practical guide.

Stress is an inherent component of residency training and its effect on healthcare provided is well documented. Although stress-related signs and symptoms are easily recognized, residents and trainers are likely to ignore them--until a crisis occurs. Based on the theory that good communication alleviates stress, the "I" Language Model, discussed in this article, is designed to enhance communication between residents and their superiors, colleagues, and families. As such, it is meant to provide one means of intervention before stress affects the resident's on-the-job performance.


Manipulation with the patient under anesthesia.

Manipulation while the patient is under anesthesia is an old, widely recognized procedure in musculoskeletal medicine. It is used for treating acute and chronic musculoskeletal conditions with significant biomechanical dysfunction unresponsive to conservative therapy. The procedure is helpful when muscle spasm and irritability preclude success without anesthetization of the patient. Safety and effectiveness are favored by appropriate selection of patients, knowledge of indications and contraindications, suitable anesthetic, and services of a qualified physician trained in structural diagnosis and manipulative technique. A team approach is recommended. To illustrate effective use of the procedure, a classic case is described.


Empty sella syndrome associated with partial hypopituitarism (visualized on MRI scan).

The empty sella syndrome has become a rather frequent finding in magnetic resonance imaging (MRI) scanning. The usual presentation of empty sella syndrome involves an incidental finding on a computed tomography scan or an MRI scan. It is unusual to find empty sella syndrome associated with hypopituitarism. The authors describe such an unusual finding in a 54-year-old nulliparous woman.


High activity iodine-125 interstitial implant for gliomas.

A total of 307 adult patients with glioma were treated with high-activity removable iodine-125 interstitial brain implants at the University of California at San Francisco from December 1979 to June 1990. Recurrent gliomas underwent brain implant alone whereas previously untreated (primary) tumors underwent brain implant boost after external beam radiotherapy. Of these patients, 106 had primary glioblastoma multiforme, 68 had primary non-glioblastoma glioma, 66 had recurrent glioblastoma multiforme and 67 had recurrent nonglioblastoma glioma. Median follow-up for living patients was 143 weeks. Median survival from diagnosis for primary glioblastoma multiforme and high and low grade nonglioblastoma glioma was 88 weeks, 142 weeks, and 226 weeks, respectively. Median survival measured from the date of implant for recurrent glioblastoma multiforme and high and low grade nonglioblastoma glioma was 49 weeks, 52 weeks, and 81 weeks, respectively. Ninety-two percent of patients had no toxicity or transient acute side effects. Severe acute toxicity was seen in 6% of patients, life threatening acute toxicity in 1% of patients, and fatal toxicity in less than 1% of patients. Forty percent of patients with malignant glioma underwent reoperation at a median of 33 weeks after brain implant, with tumor found in 95% of specimens at reoperation. This large experience demonstrates that interstitial implant is well-tolerated and prolongs survival in patients with primary and recurrent glioblastoma multiforme, as evidenced by the 3-year survival rates of 22% and 15%, respectively.


Interstitial brachytherapy for newly diagnosed patients with malignant gliomas: the UCSF experience.

Although interstitial brachytherapy appears to be effective in treating recurrent malignant gliomas, it has been studied less extensively in patients with newly diagnosed tumors. To examine the effect of this treatment when used at the time of primary diagnosis, we retrospectively reviewed the records of 88 patients who received temporary interstitial implants of 125I for newly diagnosed malignant gliomas. This brachytherapy was preceded by a course of external radiation therapy and followed, in some cases, by chemotherapy. The median duration of survival after the beginning of external radiation therapy was 87 weeks in patients with glioblastoma multiforme and 160 weeks in those with anaplastic gliomas. In 46% of patients with glioblastoma multiforme and 56% of those with anaplastic gliomas, a second operation was necessary to remove symptomatic radiation necrosis, recurrent tumor, or both. Our results support the conclusion that interstitial brachytherapy used at the primary diagnosis lengthens survival in selected patients with glioblastoma multiforme. However, the toxicity is significant in terms of the need for surgical resection of symptomatic necrosis. In patients with anaplastic gliomas, the toxicity associated with the treatment probably outweighs its advantages.


Hyperfractionated radiation therapy for gliomas of the brainstem in children and in adults.

Between February 1984 and September 1990, 60 patients with brainstem gliomas were treated with hyperfractionated radiotherapy in the Department of Radiation Oncology at the University of California, San Francisco. Forty-one children (< or = 18 years) and 19 adults were treated with 100 cGy twice daily with 4-8 hr between doses. Thirty-one patients (21 children and 10 adults) received total doses of 66-72 Gy and 29 patients (20 children and nine adults) received 74-78 Gy. Median follow-up was 208 weeks for all patients (214 weeks for children, 157 weeks for adults). Twenty-three patients (14 children and nine adults) were alive at the time of analysis, surviving 59-359 weeks following treatment. Median actuarial survival was 73.6 weeks overall (72 weeks for children, 190 weeks for adults; p = 0.43). Survival at 12 and 24 months was 65% and 38%, respectively (63% and 32%, for children; 68% and 53% for adults). All patients had pretreatment magnetic resonance imaging by which tumors were classified as either focal or diffuse. No significant pretreatment prognostic factors for adults were identified. In children, significant favorable prognostic factors on univariate analysis were older age (p = 0.001), tumor location in thalamus or midbrain (p = 0.002), focal appearance on MRI scan (p < 0.001) and duration of symptoms > 2 months prior to treatment (p < 0.001). Thirty-five patients had tumor biopsies, leading to a diagnosis in 33 (22 children and 11 adults). Children with moderately anaplastic astrocytomas survived significantly longer than those with glioblastoma multiforme or unbiopsied tumors (p < 0.001). Only duration of symptoms > 2 months remained significant as a favorable prognostic indicator for children on multivariate analysis (p < 0.001). Survival was not significantly different for patients receiving < or = 72 Gy and those receiving > 72 Gy (p = 0.18). No subgroup of patients showed significantly better survival with the higher dose. These findings indicate that hyperfractionated radiotherapy is effective treatment for adults and a subgroup of better prognosis children with brainstem gliomas. There is a subgroup of pediatric patients with extremely poor prognosis for whom even this aggressive treatment does little to extend survival. We conclude that there is no benefit to increasing total dose above 72 Gy for any of the groups analyzed.


Pediatric craniopharyngiomas: long term results of combined treatment with surgery and radiation.

From 1961 to 1981, 19 pediatric patients with craniopharyngiomas were treated with external beam radiation post surgery. Twelve underwent primary treatment while seven were treated for recurrence. Median follow-up is 21 years (range 8-28 years) with an overall 20-year survival of 62%. Twenty-six percent (5/19) developed disease recurrence following radiation. Of the multiple patient and treatment parameters analyzed, only initial disease status (i.e., primary vs recurrence), surgical extent, radiation dose, and treatment prior to routine use of CT scans (1961-1974) appeared to have major influence on patient outcome. The 20-year survival for those treated for primary disease was 78% versus 25% for those treated for recurrence. Fifty percent (3/6) of patients receiving tumor doses of < or = 5400 cGy developed recurrences versus 15% (2/13) in those receiving > 5400 cGy. Four of the five recurrences occurred in patients treated during the pre-CT era. Long term effects of treatment were analyzed. Surgical morbidity correlated strongly with extent of surgery. All patients who underwent total resection developed surgical sequelae. Radiation morbidity correlated strongly with radiation dose. The incidence of vascular or neurologic complications attributable to radiation were minimal, occurring in only two patients. Both received doses higher than that given with modern therapy. Long-term results from this series are better than those reported with surgery alone. Use of modern surgical and radiation equipment/technique along with CT/MRI imaging should yield improved treatment results both in terms of lower recurrence and lower toxicity rates.


Defining the role of radiosurgery in the management of brain metastases.

The role of stereotactic radiosurgery in the management of recurrent and newly diagnosed brain metastases was evaluated prospectively. From December 1988 to March 1991, 58 lesions in 40 patients were treated with accelerator-based stereotactic radiosurgery. All patients were followed for a minimum of 6 months or to death. The primary purpose was to determine the impact of radiosurgery on local control and its subsequent effects on quality of life. An overall tumor control rate of 82% with a complete response rate of 43% were achieved. As anticipated, the response rate for smaller tumors was substantially better than that for larger tumors (78% for lesions < 2 cm3; 50% for lesions > or = 10 cm3). Although the overall in-field progression rate was 18.5%, only 1/23 (4%) complete responders subsequently recurred. The in-field failure rate is highly comparable with recently published surgical data. Progression outside the brain was noted in two-thirds of patients. One quarter of the deaths were neurologic. The median survival for this minimally selected patient population was 6.5 months. Stereotactic radiosurgery was also associated with improved quality of life as measured by Karnofsky score, neurologic function, and steroid dependence. Long-term steroid dependence was encountered in only four patients. We conclude that stereotactic radiosurgery can be used effectively in patients with brain metastases. In this series, a high tumor response rate was achieved which was associated with improved quality of life.


The role of laminectomy in the combined treatment of metastatic spinal cord compression.

A retrospective analysis of clinical data concerning 140 patients with spinal cord compression is presented. Treatment consisted of a surgical decompressive laminectomy followed by radiation therapy in 127 cases. Primary radiation therapy supported by steroids was applied in only 26 cases. A dose of 30-40 Gy in 15-20 fractions was delivered to all patients. Treatment outcome was analyzed by comparing motor function (categories: no deficit, mild deficit ambulatory, paraparetic not ambulatory, paraplegic), sphincter function, and pain relief before and after treatment in both modalities. Following laminectomy and radiation therapy, 82% of paraparetic patients regained their ability to walk, sphincter function improved in 68%, pain relief was achieved in 88%. Following radiation therapy alone, 64% of paraparetic patients became ambulatory, 33% showed a normalization of sphincter function, and 72% became pain free. Our results indicate that laminectomy should play a major role in the treatment of patients with metastatic spinal cord compression. The decision as to the treatment of choice has to be made individually for each patient taking into consideration his general condition, life expectancy, and origin of the primary.


Patterns of failure following combined modality therapy for esophageal cancer, 1984-1990.

From 1984-1990, 143 patients with squamous cell or adenocarcinoma of the esophagus were enrolled in a Phase I/II study of neoadjuvant chemotherapy followed by concurrent chemotherapy plus radiotherapy with or without subsequent esophagectomy. Patients received one cycle of Cisplatin or Carboplatin plus Etoposide for squamous cell carcinoma, or Cisplatin or Carboplatin plus 5FU for adenocarcinoma, followed by two cycles of the same chemotherapy given concurrently with 44-46 Gy over 5 weeks. Operable patients then underwent esophagectomy. Inoperable patients and those with positive surgical margins received additional irradiation (16-18 Gy). Twelve percent of the surgical group received preoperative radiotherapy doses > or = 50 Gy. Seventy-two percent (103) had clinical Stage I-III tumors and 28% (40) were clinical Stage IV (1983 American Joint Committee on Cancer criteria). Only clinical Stage I-III patients were analyzed with respect to patterns of failure. Isolated local failure occurred in 19/103 (18%) of clinical Stage I-III patients. Both local and distant relapse occurred in 15/103 (15%), and distant metastases alone occurred in 25/103 (24%). The 3-year actuarial rates of local and distant failures were 45% and 60%, respectively. Among the clinical Stage I-III patients who underwent surgery (n = 58) versus those who did not (n = 45), the 3-year actuarial local and distant failure rates were 30% versus 60% and 45% versus 45%, respectively. Multivariate analysis was performed to identify significant predictors of local control. For all clinical Stage I-III patients, treatment with surgery (p = 0.001) and with three or more cycles of chemotherapy (p = 0.02) were significant predictors of improved local control. Patients who underwent surgery were significantly younger and had a better performance status than those who did not. The improvement in local control with surgery did not translate into better survival, likely on account of a high operative mortality rate in older patients and those receiving > or = 50 Gy preoperatively. We conclude that local control remains poor with concurrent chemotherapy + radiotherapy for esophageal cancer. The addition of surgery improved local control, but distant metastases remain a problem both in this group of patients as well as those treated without esophagectomy. Efforts to improve local control appear warranted, but it remains to be demonstrated that improved local control translates into improved survival in esophageal cancer because of a high rate of distant metastases in patients whose disease is controlled in the esophagus.


Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation.

The characteristic of malignant pleural mesothelioma is a tumor that grows by plate-like extension over the pleura, and invades adjacent tissues and organs. Radical surgical removal of the tumor is generally not possible, and most treatment regimens involve combined chemotherapy and radiotherapy, as well as debulking surgery. We have prospectively evaluated five locally-aggressive multi-modality treatment programs, using different hemithorax irradiation schedules and chemotherapy regimens. One hundred patients with confirmed malignant pleural mesothelioma entered the study between 1977 and 1989. The treatment programs, which can consecutively, were: I, 20 Gy (10 x 2 Gy) to the hemithorax + CYVADIC (cyclophosphamide 500 mg/m2 d 1, vincristine 1 mg/m2 d 1 and 5, adriamycin 40 mg/m2 d 1 and dacarbazine 200 mg/m2 d 1 and 5, several cycles before and after irradiation); II, 55 Gy (25 x 2.2 Gy) to the hemithorax + 15 Gy (6 x 2.5 Gy) to the tumor + CYVADIC (2 cycles before, 1 cycle during, and 2 cycles after irradiation); III, Mitoxantrone (14 mg/m2 q 28 d, < or = 6 cycles) followed by 70 Gy (56 x 1.25 Gy, twice a day); IV, 4-Epirubicin (110-130 mg/m2 q 28 d, < or = 6 cycles) followed by 35 Gy (28 x 1.25 Gy twice a day) to the hemithorax + 36 Gy (9 x 4 Gy every 2 days) to the tumor; V, Etoposide (150 mg/m2 1, 3, 5 q 28 d) followed by 38.5 Gy (11 x 3.5 Gy) to the hemithorax. A new system for evaluating tumor response in pleural mesothelioma was applied. None of the combined treatment programs prevented local invasive growth or the spread of mesothelioma outside the hemithorax. The median survival time was slightly increased from 8 to 12 months for those patients who completed the protocol treatments, but progressive disease was the invariable outcome. Radiation pneumonitis and fibrosis were severe and compatible with results of total loss of lung function on the irradiated side. We conclude that data relating to therapeutic responses and treatment programs in malignant mesothelioma should be better correlated internationally, if the problems associated with the evaluation of treatment and the management of patients with mesothelioma are to be improved.


Sarcoma therapy: functional outcome and relationship to treatment parameters.

To systematically assess the functional outcome of patients treated with surgery and irradiation for extremity or truncal sarcomas, and to correlate this outcome with a detailed analysis of the radiation dose distribution and surgical technique. Conservative surgery and radiation therapy (RT) are known to provide excellent local control, but the relationship of technique to functional outcome requires further study. Forty-one patients were treated for lower extremity (25 patients, 61%), upper extremity (8 patients, 19.5%), and truncal (8, 19.5%) sarcomas from 1983 to 1990. Most patients had malignant fibrous histiocytoma (15), liposarcoma (8), or aggressive fibromatosis (6). Age ranged from 13 to 85 years (median 54). All patients received RT and 39 (95%) had surgery. The mean total RT dose was 59 Gy (range 55.8-64.8 Gy). A protocol for functional assessment was devised and included a 4 point scale (0-3) for each of seven functional parameters (range of motion, fibrosis, edema, pain, skin changes, muscle strength, gait, or upper extremity performance). An aggregate score was obtained by adding the seven parameter scores and compared with both a patient and physician overall functional rating score (excellent, good, fair, poor). Based on this analysis, aggregate scores were defined as < or = 3 = excellent, < or = 8 = good, < or = 13 = fair, and > 13 = poor, with 21 as the worst possible score. The same orthopaedic surgeon and radiation oncologist independently examined and rated 22 patients. An additional 17 patients were evaluated by record review. The median time from completion of radiation therapy was 30.5 months (range 7-95 months). A computerized radiation therapy dosimetric analysis was performed on 34 patients. Local control was achieved in 39 patients (95%), including 6 with aggressive fibromatosis. The mean functional outcome score was 5.1 with a range of 0-16. 34 patients (83%) had good or excellent functional outcomes. The rating system demonstrated minimal interobserver variability. There was a positive relationship between volume irradiated to > or = 55 Gy and functional score, strength, fibrosis, and skin changes. Total dose independent of volume was significantly associated with skin changes. Increasing peak dose (hot spot dose) was associated with fibrosis and skin changes. More fibrosis developed as the volume of the peak dose increased. A portion of the joint was treated in 5/33 extremity patients and the entire joint in 24/33 (mean dose 55.8 Gy, range 45-65 Gy). Neither range of motion nor total functional score was correlated with joint dose. Edema and functional score were not related to either the volume or percent of limb spared (receiving < or = 40 Gy). The physician functional status ratings generally concurred with patient self-assessments. A system for functional assessment has been developed which is easily performed and provides detailed information about patient functional outcome. This system can be used to evaluate the morbidity of combined modality sarcoma therapy. Doses up to 65 Gy, even over joint spaces, are not associated with significant morbidity. Only a small volume treated to < or = 40 Gy is required to maintain good outcome. The most important parameter appears to be the volume treated to > or = 55 Gy.


Treatment of malignant gliomas with interstitial irradiation and hyperthermia.

A Phase I study of interstitial thermoradiotherapy for high-grade supratentorial gliomas has been completed. The objective of this trial was to test the feasibility and toxicity of hyperthermia induced by ferromagnetic implants in the treatment of intracranial tumors. The patient population consisted of 16 males and 12 females, with a median age of 44 years and a median Karnofsky score of 90. Nine patients had anaplastic astrocytoma while 19 had glioblastoma multiforme. Twenty two patients were treated at the time of their initial diagnosis with a course of external beam radiotherapy (median dose 48.4 Gy) followed by an interstitial implant with Ir-192 (median dose 32.7 Gy). Six patients with recurrent tumors received only an interstitial implant (median dose 40 Gy). Median implant volume for all patients was 55.8 cc and median number of treatment catheters implanted per tumor was eighteen. A 60-minute hyperthermia treatment was given through these catheters just before and right after completion of brachytherapy. Time-averaged temperatures of all treatments were computed for sensors located within the core of (> 5 mm from edge of implant), and at the periphery of the implant (outer 5 mm). The percentage of sensors achieving an average temperature > 42 degrees C was 61% and 35%, respectively. Hyperthermia was generally well tolerated; however, there have been 11 minor toxicities, which resolved with conservative management, and one episode of massive edema resulting in the death of a patient. In addition, there were three major complications associated with the surgical implantation of the catheters. Preliminary survival analysis shows that 16 of the 28 patients have died, with a median survival of 20.6 months from diagnosis. We conclude that interstitial hyperthermia of brain tumors with ferromagnetic implants is feasible and carries significant but acceptable morbidity given the extremely poor prognosis of this patient population.


Hyperthermia enhances mitoxantrone cytotoxicity on human breast carcinoma and sarcoma xenografts in nude mice.

In this preclinical in vivo study, we measured antitumor response, local side effects and systemic toxicity of locally applied water-bath hyperthermia given alone or simultaneously with mitoxantrone (3 mg/kg b.w. i.v.; LD 10) on a human derived breast carcinoma (MX 1) or a human sarcoma (S 117) transplanted to female athymic (nude) mice. A single hyperthermia treatment at a tumor temperature up to 43 degrees C for 1 hr caused in both tumor lines only minor tumor regressions and transient tumor growth delay. However, the antitumor effect of mitoxantrone was significantly enhanced by local hyperthermia at 42 degrees C and particularly at 43 degrees C. In both tumor lines complete tumor regressions were achieved only if mitoxantrone was combined with hyperthermia. Undesired side effects and drug toxicity were not enhanced by hyperthermia. According to in vitro data and the results of the present in vivo study mitoxantrone seems to be a good candidate for clinical trials in combination with locoregional hyperthermia.


Radiosensitivity testing of human malignant gliomas.

Radiotherapy remains the main treatment modality for patients with malignant gliomas and is the only treatment which significantly prolongs survival. Clonogenic and tetrazolium based colorimetric assays (MTT) of early passage cultures have been performed following 2 Gy doses of x-rays in order to determine if in vitro radiosensitivity is a factor in response to treatment. Of 47 biopsies received, 39 were established in primary culture. A value of surviving fraction to 2 Gy (SF2) was obtained in 85% of growth assays and 64% of clonogenic assays. The mean SF2 value for the MTT was 0.56 which was significantly higher than the 0.42 obtained for the clonogenic assay. There was, however, reasonable qualitative agreement in assessing relative radiosensitivity/radioresistance (r = 0.7). Mean SF2 values for grade 3 tumors were 0.52 (MTT) and 0.35 (clonogenic) as against mean SF2 values of 0.63 (MTT) and 0.47 (clonogenic assay) for grade 4 tumors. In 24 patients with adequate follow-up, no direct correlation was found between SF2 and survival, although mean SF2 values for patients surviving greater than 18 months was significantly less (p = 0.01) than patients surviving less than 18 months as determined by the MTT assay.


The effect of hyperfractionation on spinal cord response to radiation.

The T10-L2 level of the spinal cord of C3Hf mice was irradiated using a conventionally fractionated regimen of 2.0 Gy once daily or a hyperfractionated regimen of 1.2 Gy twice daily separated by 8 hr. After a fractionated dose of 24-60 Gy given by either regimen, a top-up dose of 15 Gy was given. Hind limb strength was then measured weekly for 15 months. The time to onset of paralysis was inversely associated with the total dose. Overall, the spinal cord was not spared by hyperfractionation to the extent predicted by the modified Ellis power law or the linear-quadratic model. The threshold dose for the development of paralysis was higher in the hyperfractionated than in the conventionally fractionated group. However, the latent period for paralysis and the dose producing hind limb paralysis in 50% of the mice (ED50) were not significantly different between the two regimens. The continuation of the process of sublethal damage (SLD) repair in the spinal cord beyond 8 hr after irradiation may have influenced these results. The slow component of SLD repair should be considered in the design of hyperfractionated or accelerated radiation therapy schedules for clinical use.


The isoquinoline sulfonamide H7 attenuates radiation-mediated protein kinase C activation and delays the onset of x-ray-induced G2 arrest.

Protein kinase C activation by ionizing radiation in human tumor cell lines participates in the transcriptional activation of genes which may be associated with the phenotypic response of cells to x-rays. We gamma-irradiated cell line RIT-3 (radiation-induced human sarcoma) and quantified the phosphorylating capacity of protein kinase C. Protein kinase C activity increased rapidly and transiently in these cells. The selective protein kinase C inhibitor H7 attenuated radiation-mediated protein kinase C activation when added to cells prior to irradiation. To determine whether protein kinase C activation is associated with radiation-induced G2 arrest, we analyzed the cell cycle distribution of cells following gamma-irradiation. Following irradiation, RIT-3 cells rapidly progressed through G1 and S and subsequently underwent a dose dependent G2 arrest. At concentrations which are selective for protein kinase C inhibition, H7 delayed the onset of radiation-induced G2 arrest. However, there was no difference in the duration of G2 arrest following the addition of inhibitor as compared to cells irradiated without inhibitor. We propose that protein kinase C activation by ionizing radiation is associated with radiation-mediated cell cycle regulation.


The relationship between apoptosis and atrophy in the irradiated lacrimal gland.

Atrophy is generally considered to be a true late effect of radiation. However, in serous glands, atrophy was thought to be a consequential late effect because serous cells die within hours of irradiation and the apparent effects of atrophy are observed contemporaneously with radiation treatment. Therefore, to determine the pathogenesis of atrophy in serous glands, it is necessary to differentiate between parenchymal loss as a result of direct radiation death of serous cells and parenchymal loss as a result of serous cell death that is secondary to fibrosis, vascular damage, or precursor cell death. The lacrimal glands of 62 rhesus monkeys have been irradiated to single doses of 2.5 to 20 Gy and examined at intervals of 4 hr to 112 days postirradiation. Serous cells (nuclei) and acini were counted in at least 30 high power fields per (dose, time) point. At each dose and time of sacrifice, the average number of nuclei per acinus and the average number of acini per high power field were calculated. Also at each dose and time, the distribution of the number of nuclei per acinus was examined to determine how the frequency of acinar sizes changed as a function of irradiation. The number of cells per acinus appears to rise initially, but this is likely a result of the degranulated cells being physically smaller, yielding an artificially higher count. Within 4 days after 12.5 Gy, the average number of nuclei per acinus approaches control values and remains within the range of controls for at least 112 days. The number of acini per high power field decreases steadily for 30 days after 12.5 Gy. From 30 to 112 days, there is some recovery of this number, but it remains well below control values. At 24 hr, the number of nuclei per acinus shows a distinct dose response up to 20 Gy. However, at 30 days there is no evidence of a dose response for this parameter. These results indicate that even though serous cells die in significant numbers within hours of irradiation, the atrophy of the lacrimal gland (and by extension, the parotid gland) is a result of the death of the serous stem cell or precursor. Consequently, protection of serous cells from radiation apoptosis will not diminish serous gland atrophy.


Sensitization processes in human tumor cells during protracted irradiation: possible exploitation in the clinic.

Recent studies documenting the response of several human tumor cell lines to protracted, continuous irradiation and to acutely delivered radiation, suggest that tumor control may be enhanced with a tumor therapy combining external beam fractionated therapy and protracted irradiation from radiolabeled antibodies. We have evaluated the cytotoxic effect of continuous, protracted irradiation (0.005 Gy/hr to 0.50 Gy/hr) and acutely delivered high-dose-rate irradiation (1.0 Gy/min) on monolayer cultures of human tumor cell lines. Colony formation in these studies was analyzed by the seven-parameter simulation model of Dillehay. Additionally, for some cell lines, cultures were challenged during irradiation with an acute dose of 2.5, 5.0, 7.5 or 10.0 Gy at high-dose-rate. Results from these various studies indicate an altered cellular radiosensitivity occurs for some cell lines during protracted irradiation. At least two mechanisms have been identified that underlie this altered radiosensitivity. One mechanism, G2B, associated with redistribution within the cell cycle, has been previously described by Mitchell and others, and is associated with the phenomenon termed "the inverse dose-rate effect". The other mechanism is only observable following a challenge by acute high-dose-rate irradiation. We have termed this phenomenon "protracted-exposure-sensitization." The characteristics of these two mechanisms are discussed from the perspective of clinical therapeutic exploitation of combined external beam fractionated therapy and radiolabeled immunoglobulin therapy.


Immunophenotype predicts radiation resistance in T-lineage acute lymphoblastic leukemia and T-lineage non-Hodgkin's lymphoma.

In the preclinical arm of our study, the radiobiologic features of primary malignant cells from newly diagnosed and relapsed T-lineage acute lymphoblastic leukemia/non-Hodgkin's lymphoma patients were analyzed using clonogenic assays. A marked heterogeneity existed relative to the intrinsic radiation sensitivity of clonogenic T-lineage ALL/NHL cells from 42 patients. The mean SF2 (surviving fraction at 200 cGy) and alpha values (initial slope of the survival curve) were 0.36 +/- 0.04, and 0.558 +/- 0.079 Gy-1. Fourteen cases had SF2 values of > or = 0.50 and alpha values of < or = 0.2 Gy-1, consistent with a marked intrinsic radiation resistance at the level of clonogenic leukemia/lymphoma cells. Of these 14 radiation resistant cases, 12 were CD3+. Furthermore, the SF2 and D0 values of the 28 CD3+ cases were significantly higher than the SF2 and D0 values of the 14 CD3- cases (SF2: 0.441 +/- 0.048 versus 0.189 +/- 0.045, p = 0.002; D0: 189.6 +/- 26.3 cGy versus 108.7 +/- 18.2 cGy, p = 0.047) and CD3+ cases had smaller alpha values than CD3- cases (0.454 +/- 0.087 versus 0.765 +/- 0.152, p = 0.06). Thus, clonogenic cells from CD3+ T-lineage ALL/NHL patients were more resistant to radiation than clonogenic cells from CD3- T-lineage ALL/NHL patients. In the clinical arm of our study, 33 T-lineage ALL/NHL patients received autologous bone marrow transplants during remission. Pretransplant conditioning consisted of total body irradiation combined with high dose chemotherapy. The expression of CD3 antigen predicted the outcome of relapsed T-lineage ALL/NHL patients undergoing autologous bone marrow transplantation following total body irradiation plus high dose chemotherapy. Overall, the Kaplan-Meier estimate and standard error of the probability of remaining in remission at 3.5 years was 11 +/- 9% with a median relapse-free interval of 102 days. The disease-free survival at 3.5 years was 8 +/- 7% with a median disease-free survival time of 96 days. Notably, the expression of CD3 antigen on T-lineage ALL/NHL cells correlated with the probability of relapse after bone marrow transplantation. While 16 of 19 CD3+ patients relapsed after bone marrow transplantation, only 3 of 8 CD3- patients relapsed. The Kaplan-Meier estimates and standard errors of the probability of remaining in remission at 1 year after bone marrow transplantation were 7 +/- 6% (median relapse-free interval = 74 days) for CD3+ patients (n = 19) and 63 +/- 17% for CD3- patients (n = 8) (p = 0.006).(ABSTRACT TRUNCATED AT 400 WORDS)


Differential radioprotection of cultured human diploid fibroblasts and fibrosarcoma cells by WR1065.

The present studies were performed to determine whether WR1065, the dephosphorylated, free-thiol active metabolite of WR2721, could provide differential radioprotection of normal and tumor cell lines in vitro and secondly to investigate potential mechanisms for the selective nature of the radioprotection at the cellular and molecular level. When 4 mM WR1065 was administered 30 min prior to and during irradiation, a protection factor of 1.9 was obtained in clonogenic assays performed with normal human diploid fibroblasts (AG1522) while no protection of fibrosarcoma cells (HT1080) was observed. Some radioprotection of fibrosarcoma cells was observed with higher drug concentrations (10-40 mM), but the increase in survival was considerably less than the plateau level reached with the diploid fibroblasts (3-fold vs 24-fold at 6 Gy). The observation of such a selective effect in vitro with WR1065 indicates that differences in tissue-specific variables such as blood flow, pH, pO2, and drug dephosphorylation cannot solely account for the selective nature of the radioprotection afforded by WR2721 in vivo. Incubation of nucleoids with increasing concentrations of the DNA intercalating dye propidium iodide was used to titrate the ability of DNA to undergo supercoiling changes. The relaxation and rewinding of supercoiled DNA loops in isolated nucleoids serves as an indicator of both the presence of DNA damage and inherent differences in DNA loop characteristics. Fibrosarcoma cells had a much larger propidium iodide-relaxable DNA loop size than fibroblasts. The rewinding phase of the DNA supercoiling response is impaired by the presence of radiation-induced DNA strand breaks. Four mM WR1065 resulted in a significant reduction in the amount of rewinding inhibition observed after a dose of 10 Gy in diploid fibroblasts (protection factor = 1.43) but did not alter the response of irradiated fibrosarcoma cells. These results, indicating that WR1065 had a preferential radioprotective effect in vitro on both survival and the manifestation of DNA damage at the nucleoid level, are consistent with the hypothesis that cell type differences in chromatin organization and DNA-drug associations could play a role in the selective radioprotection.


Intraoperative and external radiotherapy in resected gastric cancer: updated report of a phase II trial.

From September 1984 to August 1991, 48 evaluable patients with resected gastric cancer and apparent disease confined to locoregional area were treated with intraoperative electron beam boost to the celiac axis and peripancreatic nodal areas (15 Gy) and external irradiation (40 to 46 Gy in 4 to 5 weeks) including the gastric bed and upper abdominal nodal draining regions. At the time of evaluation for IORT, the disease was primary in 38 cases, recurrent but resectable in four (anastomosis), and unresectable in four (nodal). Post operative complications were reversible. Acute tolerance to the complete treatment program was acceptable. Late complications included life-threatening events: Six episodes of gastro intestinal bleeding (three of them had an arteriographic documentation of arterioenteric fistula) and nine with severe enteritis (five required reoperation). Other long-term treatment related complications were six cases of vertebral collapse. The median follow-up time for the entire group is 22 months. Locoregional recurrence/persistence of disease has been identified in five patients (three with residual and/or recurrent postsurgical tumor). Systemic tumor progression has been detected in 15 patients (11 in intra-abdominal sites). Overall actuarial survival for patients with positive or negative serosal involvement was 33% versus 56%. It is concluded that the treatment program described is able to induce a high locoregional tumor control rate (100%) when used strictly in an adjuvant setting and might control long term, a small portion of patients not amenable for curative surgery (2 out of 8 patients with confirmed residual post-surgical disease). Gastrointestinal bleeding and enteritis are findings that indicate treatment intensity at the upper limits of tissue tolerance. Assessment of long term tolerance of pancreatic parenchyma and large blood vessels (tissues included in the IRORT field) are pending for longer follow-up and the appropriate selective studies.


The frequency of translocations after treatment for Hodgkin's disease.

We studied the frequency of translocations in peripheral blood lymphocytes of patients with Hodgkin's disease to determine the extent of chromosome changes induced by radiation or radiation and chemotherapy. Comparisons were made to patients with second cancers to determine if this population is more susceptible to the effects of treatment. Group one included six patients with newly diagnosed Hodgkin's disease who were treated with radiation only. Group two included Hodgkin's disease patients who were treated 12-24 years previously and have been continuously free of disease. Five of these patients were treated with radiation only and five patients received radiation and mechlorethaminehydrochloride, oncovin, procarbazine, prednisone (MOPP) chemotherapy for six cycles. Group three included three patients who developed a second cancer after successful treatment for Hodgkin's disease. Two of these patients had a sarcoma within the radiation field and one had breast cancer. Metaphase spreads were obtained from cultured lymphocytes and hybridized with a chromosome 4 specific probe. After fluorescein staining, approximately 1000 metaphases were scored per patient. In group one only one patient in six demonstrated translocations in chromosome 4 before treatment for a mean frequency of .0009. After treatment the frequency of translocations increased to a mean of .016 (p = .036) (range .006-.034). Group two patients treated with radiation only had a mean translocation frequency of .012 (range .004-.022) in comparison to the radiation/mechlorethaminehydrochloride, oncovin, procarbazine, prednisone chemotherapy treated patients who demonstrated a mean frequency of .016 (p = .425) (range .0009-.023). The third group of second cancer patients showed inconsistent translocation frequencies of .002, .020, and .035. Of these patients, the one who demonstrated the greatest frequency of translocations (.035) was treated with mechlorethaminehydrochloride, oncovin, procarbazine, prednisone/adriamycin, bleomycin, vinblastine, decadron) and radiation. Our data demonstrates a statistically significant increase in translocations detected after radiation. When compared to combined modality therapy a greater mean frequency of translocations is observed over radiation alone; however, this was not statistically significant. In the three patients who developed second cancers in our series we saw no consistent increase in translocation frequency compared to Hodgkin's disease patients who did not develop a second cancer.


Adjuvant radiotherapy in high stage transitional cell carcinoma of the renal pelvis and ureter.

This review was undertaken to assess the influence of adjuvant radiation therapy on failure patterns and survival in high stage transitional cell carcinoma of the renal pelvis or ureter. Ninety-four patients with transitional cell carcinoma of the renal pelvis or ureter were retrospectively reviewed. Twenty-six had American Joint Commission stage T3 or T4 N0/+, M0 disease and underwent curative resections (median follow-up 13.5 months, range 3-311). Local failure was defined as recurrence in the tumor bed, regional nodes, or ureteral stump. Time to recurrence and survival were calculated from the time of pathologic diagnosis. Variables associated with local failure, distant metastasis, and survival were analyzed using univariate and multivariate analysis. Seventeen received surgery only, nine received adjuvant radiation therapy (median dose 50 Gy). Local failure occurred in 9 of 17 without and 1 of 9 with adjuvant radiation therapy (p = 0.07). Actuarial 5-year local control was 34% without and 88% with adjuvant radiation therapy. Cox step-wise regression confirmed adjuvant radiation therapy (p = 0.006) and grade (p = 0.006) as significantly associated with local failure. No patients with low grade lesions suffered local failure either with or without adjuvant radiation therapy. High grade lesions had an local failure rate of 15% with and 71% without adjuvant radiation therapy. Metastatic disease occurred in 4 of 9 and 8 of 17 with and without radiation therapy. No significant factors influencing distant failure were identified. Five-year actuarial survival was 44% with and 24% without adjuvant radiation therapy. The survival differences were not statistically significant on univariate or multivariate analysis. High staged transitional cell carcinoma of the renal pelvis or ureter has a substantial local failure risk after surgery alone. Adjuvant radiation therapy markedly reduces this risk but has no impact on distant disease which occurs in approximately 50%. Effective adjuvant therapy will require effective systemic therapy in addition to adjuvant radiation therapy.


The importance of brachytherapy technique in the management of primary carcinoma of the vagina.

This retrospective analysis of 49 cases of primary carcinoma of the vagina treated with radiation therapy alone from 1970-1988 examines the results of treatment with an emphasis on the importance of brachytherapy technique. Thirty-six patients were treated with combined external beam radiation and brachytherapy, 11 patients were treated with external beam alone, and two patients were treated with brachytherapy alone. Brachytherapy techniques used included intracavitary implants, temporary Ir-192 interstitial implants, and permanent I-125 interstitial implants. Intracavitary therapy included the use of a fractionated high dose rate intravaginal cylinder, tandem and ovoids, and a low dose rate intravaginal cylinder. The 5-year actuarial survival was 44% for Stage I (six patients), 48% for Stage II (27 patients), 40% for Stage III (10 patients), and 0% for Stage IVa and IVb (six patients). There was a significant increase in the 5-year actuarial survival for those patients who had brachytherapy as part of their treatment compared to those patients treated with external beam alone (50% vs. 9%) (p < .001). For Stages II and III, there was a trend toward improved actuarial and crude disease free survival with the use of a temporary Ir-192 interstitial implant as part of the treatment compared to the use of intracavitary brachytherapy as part of the treatment (80% vs. 45%) (p = 0.25) and (75% vs. 44%) (p = 0.08), respectively. Brachytherapy plays an important role in the management of primary vaginal cancer. A temporary interstitial implant should be used over an intracavitary form of therapy for more invasive disease.


Preliminary results in heavy charged particle irradiation of bone sarcoma.

Between 1979 and 1989, 17 patients with unfavorable bone sarcoma were treated wholly or in part with heavy charged particle irradiation (helium and/or neon ions) at the University of California Lawrence Berkeley Laboratory. The majority of tumors were located near critical structures such as the spinal cord or brain. Gross tumor was present in all but two patients at the time of irradiation. Six patients were treated for recurrent disease. Histologies included osteosarcoma, Ewing's sarcoma, and recurrent osteoblastoma. Four of the osteosarcomata were believed to have been induced by previous therapeutic irradiation for various tumors. Follow-up time since initiation of radiation ranged from 7 to 118 months (median 40 months). The 5-year Kaplan-Maier local control rate was 48%; the corresponding survival rate was 41%. Over half the patients succumbed to distant metastases despite the majority of patients receiving chemotherapy. In this preliminary study, we have shown that heavy charged particle irradiation can be effectively used for control of bone sarcoma. A Phase II trial is warranted to determine optimal treatment for unresectable or gross residual disease.


Hypofractionated accelerated radiotherapy in osteogenic sarcoma.

A method of hypofractionated accelerated radiotherapy (3 weekly fractions of 6 Gy over 2 weeks to a total tumor dose of 36 Gy) was used as single modality in 14 patients with osteogenic sarcoma for palliative treatment of the primary tumor site (six cases) or skeletal metastases (15 sites). A durable response, radiologically assessed, was obtained in 17 of the 21 (81%) irradiated sites. When this irradiation modality was combined with chemotherapy, to treat patients presenting with synchronous metastases (eight cases) or refusing amputation (five cases), a radiologically assessed response was observed in 12 of 13 (92%). In no case did a local recurrence occur before surgery or death because of progressive disease elsewhere. Of the seven patients who later had to undergo ablative surgery, a 100% and 95% tumor necrosis was observed in 6 and 1, respectively. Because of intralesional resection of primary osteogenic sarcoma after preoperative chemotherapy, seven additional patients were irradiated. None recurred at the level of the primary site. Although effective in inducing remission of osteogenic sarcoma, this irradiation method produced severe damages to normal tissues in a high proportion of patients.


The clinical utility of magnetic resonance imaging in 3-dimensional treatment planning of brain neoplasms.

Results of the clinical experience gained since 1986 in the treatment planning of patients with brain neoplasms through integration of magnetic resonance imaging (MRI) into computerized tomography (CT)-based, three-dimensional treatment planning are presented. Data from MRI can now be fully registered with CT data using appropriate three-dimensional coordinate transformations allowing: (a) display of MRI defined structures on CT images; (b) treatment planning of composite CT-MRI volumes; (c) dose display on either CT or MRI images. Treatment planning with non-coplanar beam arrangements is also facilitated by MRI because of direct acquisition of information in multiple, orthogonal planes. The advantages of this integration of information are especially evident in certain situations, for example, low grade astrocytomas with indistinct CT margins, tumors with margins obscured by bone artifact on CT scan. Target definitions have repeatedly been altered based on MRI detected abnormalities not visualized on CT scans. Regions of gadolinium enhancement on MRI T1-weighted scans can be compared to the contrast-enhancing CT tumor volumes, while abnormalities detected on MRI T2-weighted scans are the counterpart of CT-defined edema. Generally, MRI markedly increased the apparent macroscopic tumor volume from that seen on contrast-CT alone. However, CT tumor information was also necessary as it defined abnormalities not always perceptible with MRI (on average, 19% of composite CT-MRI volume seen on CT only). In all, the integration of MRI data with CT information has been found to be practical, and often necessary, for the three-dimensional treatment of brain neoplasms.


Radiosurgery target point alignment errors detected with portal film verification.

Stereotactic radiosurgery with a linear accelerator requires an accurate match of the therapeutic radiation distribution to the localized target volume. Techniques for localization of the target volume using CT scans and/or angiograms have been described. Alignment of the therapeutic radiation distribution to the intended point in stereotactic space is usually accomplished using precision mechanical scales which attach to the head ring. The present work describes a technique used to verify that the stereotactic coordinates of the center of the intended radiation distribution are in agreement with the localized target point coordinates. This technique uses anterior/posterior and lateral accelerator portal verification films to localize the stereotactic coordinates of the center of the radiation distribution with the patient in the treatment position. The results of 26 cases have been analyzed. Alignment errors of the therapeutic radiation distribution in excess of 1 mm have been found using the portal film verification procedure.


Computer systems and mechanical tools for stereotactically guided conformation therapy with linear accelerators.

An integrated system for fractionated, stereotactically guided conformation radiotherapy has been developed. The system components are a stereotactic fixation system that can be used each treatment day, a localization, and positioning unit that can be used during x-ray computer tomography, magnetic resonance imaging, positron emission tomography, and radiographical examinations as well as for treatment. Conformal precision radiotherapy is planned with a new three-dimensional treatment planning system (Voxel-Plan-Heidelberg) which comprises, among others options, a three-dimensional image correlation procedure as well as routines for the calculation of coplanar and non-coplanar irradiations with irregularly shaped fields. Two different multi-leaf collimators have been designed for precision radiotherapy in the head and neck region. A manual multi-leaf collimator is used for irradiations with stationary beams or for moving beam treatments with invariable irregularly shaped fields. This collimator system is now being used for patient treatments. The design of a computer controlled multi-leaf collimator unit for multiple fixed field irradiation techniques is discussed. All system components are aimed at conforming dose distributions for fractionated radiotherapy treatments to the target to improve sparing of adjacent normal tissues, and at achieving a sufficient geometrical accuracy in the dose application.


Three-dimensional dose distribution of total body irradiation by a dual source total body irradiator.

This study describes the three-dimensional dosimetric characteristics of total body irradiation by our dedicated irradiation unit, which consists of two modified 4-MV linear accelerators mounted opposite each other, providing a field size of 220 cm x 80 cm at the midplane. Our dose calculation algorithm considers the three-dimensional contour of the patient to evaluate the primary and scatter doses. The data base for the calculation includes tissue-to-maximum ratios measured for the large fields. The lung dose correction was calculated using the methods of Batho or ratio of TMR. The accuracy of the calculated dose distributions was verified by measurements with ionization chambers in a humanoid phantom. We also describe and verified a technique to achieve desirable midline lung doses using lead shields. The flexibility and the accuracy of the planning system offers the potential in optimizing the therapeutic ratio for total body treatments.


Dose determination in high dose-rate brachytherapy.

Although high dose-rate brachytherapy with a single, rapidly moving radiation source is becoming a common treatment modality, a suitable formalism for determination of the dose delivered by a moving radiation source has not yet been developed. At present, brachytherapy software simulates high dose-rate treatments using only a series of stationary sources, and consequently fails to account for the dose component delivered while the source is in motion. We now describe a practical model for determination of the true, total dose administered. The algorithm calculates both the dose delivered while the source is in motion within and outside of the implanted volume (dynamic component), and the dose delivered while the source is stationary at a series of fixed dwell points. It is shown that the dynamic dose element cannot be ignored because it always increases the dose at the prescription points and, in addition, distorts the dose distribution within and outside of the irradiated volume. Failure to account for the dynamic dose component results in dosimetric errors that range from significant (> 10%) to negligible (< 1%), depending on the prescribed dose, source activity, and source speed as defined by the implant geometry.


On falling in love and creativity.

This paper discusses the ego functioning and self psychological aspects of falling in love and passionate love. These universal and extraordinary phenomena are conceptualized as representing the activity of the creative imagination in solving problems related to coping with intense narcissistic and libidinal pressures. The work of other authors is reviewed and recast into a metapsychological framework involving ego and superego contributions to the experience, and focused on self cohesion. An illustrative clinical psychotherapy case is presented in an effort to understand what has traditionally appeared to be a mysterious and disjunctive life experience, and to explore the creative surge that can be generated by falling in love both in and out of the transference.


German voices about the Nazi terror: late opponents and postwar critics.

Of the dark passions that afflict mankind none has surpassed Nazism in its dimensions of evil. Descriptions of its terror abound, and many attempts have been made to understand what it was that drove an entire nation to serve an ideology of evil and madness. Many volumes have been written about the historical background of what occurred and about the socioeconomic factors that contributed to the rise of Nazism. Attempts have also been made to build psychodynamic underpinnings, so as to help us understand the inconceivable. I believe that we will never grasp it fully, yet there are sources that have remained underutilized, particularly on our side of the Atlantic. I am referring to books written by German authors. Some of them exist in English translation, most do not. For years I have read everything on the subject that came to my attention. I have been shaped by those events and cannot let go of them. So here is an occasion to share some of my thoughts with you.


Enzyme-linked immunosorbent assays for the detection of Toxoplasma gondii-specific antibodies and antigens in the aqueous humor of cats.

Serum and aqueous humor samples, collected from 14 clinically normal cats and 96 cats with clinical evidence of intraocular inflammation, were assayed with ELISA for Toxoplasma gondii-specific immunoglobulin M (IgM), T gondii-specific IgG, T gondii-specific antigens, total IgG, and total IgM. Additionally, serum was assayed with ELISA for feline leukemia virus p27 antigen and antibodies against the feline immunodeficiency virus as well as with an immunofluorescent antibody assay for antibodies against feline coronaviruses. Calculation of the Goldmann-Witmer coefficient (C-value) for the T gondii-specific antibodies detected in aqueous humor established the likelihood of local antibody production. Serologic evidence of present or prior infection by an infectious agent was found in 81.9% of the clinically affected cats from which serologic results were available (77/94 cats). Seropositive results for toxoplasmosis were found in 74.0% of the clinically affected cats. Anterior segment inflammation was found in 93.1% (81/87 cats from which information was available) of the clinically affected cats, most of which were older males. Toxoplasma gondii-specific antibodies were not detected in the aqueous humor of 6 seropositive, clinically normal cats. The C-values for aqueous T gondii antibodies were greater than 1 in 44.8% of the cats and greater than 8 in 24.0% of the cats. Response to treatment with clindamycin HCl was positive in 15/20 (75%) of the T gondii-seropositive, clinically affected cats treated with this drug. In 13/15 (86.7%) T gondii-seropositive, clinically affected cats having a C-value greater than 1, response to treatment with clindamycin HCl was positive.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of the human and canine Schiotz tonometry conversion tables in clinically normal cats.

Intraocular pressure (IOP) was measured in 73 eyes of 37 clinically normal cats with 2 applanation tonometers (Tono-Pen and Mackay-Marg) and the Schiotz indentation tonometer, using the 5.5- and 7.5-g weights. Statistically, the Tono-Pen tonometer underestimated IOP compared with the values obtained by use of the Mackay-Marg tonometer (P less than 0.0001) and the Schiotz tonometer, with either weight and either the human (P less than 0.01) or the canine (P less than 0.0001) calibration tables. Estimates of IOP using the human calibration table and either the 5.5- or 7.5-g weight were not significantly different from each other or from those obtained with the Mackay-Marg tonometer. Schiotz measurements obtained with either weight and converted using the canine calibration table were not only significantly (P less than 0.0001) different from each other, but were also clinically and significantly (P less than 0.0001) higher than measurements obtained with the Tono-Pen and Mackay-Marg tonometers or the Schiotz tonometer, using the human calibration table and either weight. Approximately three quarters of clinically normal cats had an IOP greater than or equal to 30 mm of Hg when Schiotz tonometer measurements were converted with the canine conversion table. The human calibration table was the most clinically useful table for converting Schiotz measurements from clinically normal feline eyes to estimates of IOP in mm of Hg. Normal mean (+/- SD) feline readings with the Schiotz tonometer and the 5.5-g weight was 3.9 +/- 1.4 tonometer scale units (range, 1.0 to 7.5; 95% confidence interval [CI], 1.1 to 6.7).(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of the human and canine Schiotz tonometry conversion tables in clinically normal dogs.

Intraocular pressure (IOP) was measured in 114 eyes of 57 clinically normal dogs with 2 applanation tonometers (Tono-Pen and Mackay-Marg) and the Schiotz indentation tonometer, using the 5.5- and 7.5-g weights. Significant differences were not detected between measurements obtained with the Tono-Pen and Mackay-Marg tonometers the Mackay-Marg and Schiotz tonometers using either weight and conversion with the human calibration table, or the Tono-Pen and Schiotz tonometers using the 7.5-g weight and the human calibration table. Values obtained by use of the Tono-Pen tonometer were significantly less (P less than 0.005) than values obtained with the Schiotz tonometer when a 5.5-g weight and the human calibration table were used, but the amount was clinically unimportant. Estimates of IOP using the Schiotz tonometer and the canine calibration table, and either the 5.5- or 7.5-g weight were clinically and significantly much higher (P less than 0.0001) than estimates obtained with the Tono-Pen, Mackay-Marg, or Schiotz tonometers, using the human calibration table and either weight. Sixty to 70% of clinically normal dogs had an IOP greater than or equal to 30 mm of Hg when Schiotz scale measurements were converted with the canine conversion table. For clinically normal dogs, the human calibration table was the most clinically useful table for converting Schiotz tonometer measurements to mm of Hg. Normal mean (+/- SD) canine readings with the Schiotz tonometer and the 5.5-g weight was 4.9 +/- 1.5 tonometer scale units (range, 2 to 11; 95% confidence interval, 1.9 to 7.9).(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of electrolyte solutions for oral administration on clotting of milk.

The effect of electrolyte solutions commercially formulated for oral administration on clotting of milk was investigated in vitro. Rennet or abomasal fluid was used as the clotting agent. Electrolyte solutions that contained large amounts of bicarbonate or citrate (greater than 40 mEq/L) had marked adverse effects on milk clotting, probably because bicarbonate increased pH and because citrate chelated calcium. Addition of solutions that did not contain alkalinizing agents resulted in normal or enhanced clotting, and enhancement was associated with the presence of acid phosphate salts. Electrolyte solutions that included acetate as the alkalinizing agent did not interfere with milk clotting as long as pH of the final solution was acidic and minimal amounts of citric acid salts were present (less than 10 mEq/L). Acetate-containing electrolyte solutions can be used for oral administration in calves in which alkalinization of blood without interference with milk clotting is desired.


Seroprevalence of antibodies to Borrelia burgdorferi in a population of horses in central Texas.

Four hundred sixty-nine serum samples were obtained from horses admitted to the internal medicine service of the Texas Veterinary Medical Center between Jan 1 and Dec 31, 1990. Serum samples were tested by ELISA for antibody to Borrelia burgdorferi. Of these 469 samples, 1 (0.2%) was repeatedly seropositive for the organism by ELISA. Confirmatory testing by protein immunoblot was negative. The observed seroprevalence was 0%; the upper bound of the 95% confidence interval was 0.6%. These findings indicate the evidence of infection with B burgdorferi is presently uncommon in horses in central Texas.


Removal of nasogastric tube fragments from three horses.

Three horses were admitted for retrieval of polyurethane nasogastric tube fragments. The fragments were removed from the esophagus or stomach of 2 horses by manipulation of a snare introduced through the biopsy port of an endoscope. The fragments were surgically removed from the stomach of the third horse.


Postsurgical ventricular tachycardia in a horse.

A 2-year-old Thoroughbred racehorse developed ventricular tachycardia after elective laryngoplasty and ventriculectomy were performed while anesthesia was maintained with halothane. During surgery, the horse became febrile and developed transient mild hypercarbia. The horse was treated with an IV infusion of quinidine gluconate. Continuous electrocardiographic monitoring was used to evaluate cardiac rhythm during treatment, and conversion was achieved after 12 hours of IV infusion. The inciting cause for the arrhythmia was not determined.


Conservative management of fourth tarsal bone fracture in a draft horse.

A fourth tarsal bone fracture was treated conservatively in an adult draft horse. Seven months after the injury, the horse had no evidence of lameness and was able to compete in athletic events. It has been suggested that conservative management of these fractures be considered for brood animals or animals used for less strenuous activities. The outcome of this case suggests that fourth tarsal bone fractures can be successfully treated in athletic animals with conservative management.


Ovarian mass in three mares with regular estrous cycles.

Three mares with regular estrous cycles and a large ovary were examined. In each case, the ovary was composed of a single, fluid-filled cavity with a thick capsule. The ovarian mass was surgically removed from each mare. Histologic diagnosis of each mass was different.


Correction of cervical esophageal stricture in a dog by creation of a traction diverticulum.

A cervical esophageal stricture was corrected in a dog by creation of a traction diverticulum. Although abnormal esophageal motility persisted in the portion of the esophagus cranial to the stricture, the clinical effects of the stricture were ameliorated by the simple surgical procedure.


Multiple cardiac anomalies in a cat.

A 7-week-old domestic shorthair cat was examined because of congestive heart failure. Echocardiography and angiography were used to identify multiple cardiac anomalies. Because of the uncorrectable nature of the defects, the cat was euthanatized. Necropsy revealed persistent left vena cava, patent foramen ovale, and a right atrial/left ventricular canal. The right atrioventricular valve was replaced by a small ostium, and no chordae tendinae or papillary muscles were observed around the ostium. The pulmonary trunk originated from the right atrium. The right ventricular free wall was approximately 1 mm thick.


Subconjunctival cyst associated with Thelazia gulosa in a calf.

A large subconjunctival cyst of 4 weeks' duration was surgically excised from the left eye of a 7-month-old Simmental calf. Two white, partially mineralized, approximately 1-cm-long, fertile female nematodes subsequently identified as Thelazia gulosa were found embedded in the cyst wall. Thelazia spp are generally regarded as nonpathogenic or mildly pathogenic in cattle in North America, despite reported infection rates ranging from 12.2 to 34.2%. Additionally, parasitic subconjunctival nodules associated with Thelazia spp rarely have been reported in the past, and cyst formation has not been described. It was postulated that in this calf, immature or adult worms may have penetrated normal tissue barriers, or entered via an earlier conjunctival wound, and created an inflammatory response with subsequent cyst formation.