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Biomedical subjects

J P Leddy

Publications and source records attributed to J P Leddy.

At least 19 recordsLinked to original sources
PubMed2000

Closed flexor tendon disruption in athletes.

Closed tendon injuries of the hand and wrist are very common in the athletic population. Most of these injuries, especially those involving the extensor tendons, can be treated successfully with nonoperative management if seen acutely. Acute closed flexor tendon injuries, however, usually require operative intervention for the best result. Although evaluation and diagnosis of flexor tendon injuries are relatively straightforward, diagnosis is still commonly delayed secondary to both delayed presentation and missed diagnoses. If diagnosis is delayed, operative intervention becomes less optimal and the patient may have a permanent disability regardless of treatment. Generally, athletes are able to return to their pre-injury level of participation regardless of treatment. This is a product of both the finger involved--usually ring or little--and the extent of the disability. In many instances, the athlete may even continue participation during treatment with protective splinting.

Athletic Injuries↗
PubMed1998

Closed tendon injuries of the hand and wrist in athletes.

Closed-tendon injuries of the hand and wrist are very common in the athletic population. Most of these injuries, if seen acutely, can be treated successfully with nonoperative management, although some do require operative treatment. It is those injuries, however, that go undiagnosed until the end of the season, which may result in permanent disability.

Athletic Injuries↗
PubMed1996

Allergic reactions to cyclophosphamide: delayed clinical expression associated with positive immediate skin tests to drug metabolites in five patients.

BACKGROUND: Cyclophosphamide (CP) is one of the relatively few drugs implicated in systemic allergic reactions for which the metabolites are well known. Formation of CP metabolites is a multistep, time-dependent process (hours) with significant interindividual differences. Although allergic reactions to CP have been recorded in 17 previous reports, skin testing with CP or its metabolites has been included in only five. We now describe five patients receiving monthly cycles of intravenous CP whose allergic reactions included clinical features of type I hypersensitivity but were atypical in their markedly delayed onset (i.e., 8 to 16 hours in patients 1 to 4 and 10 days in patient 5). OBJECTIVE: The objective was to investigate these late-developing clinical reactions by skin testing with CP and two of its major metabolites. METHODS: The five patients and a control group receiving intravenous CP uneventfully were studied by the same skin test protocol. RESULTS: The four individuals in the control group were unreactive to CP or its metabolites. All five patients with late-onset allergic reactions had positive immediate skin test results to CP metabolites but not to CP itself. We propose that the allergic reactions in patients 1 to 4 were mediated, wholly or in major part, by IgE antibodies reactive with allergens derived from time-dependent drug metabolites. The 10-day lag time in patient 5 is unexplained. Immunomodulation by the underlying malignancies or by the immunosuppressive drugs could have contributed. CONCLUSION: IgE-mediated allergic drug reactions may have a delayed onset if the allergen is a time-dependent drug metabolite, illustrated in this study by CP.

Adult↗
PubMed1995

Inherited human complement C5 deficiency. Nonsense mutations in exons 1 (Gln1 to Stop) and 36 (Arg1458 to Stop) and compound heterozygosity in three African-American families.

Hereditary C5 deficiency has been reported in several families of different ethnic backgrounds and from different geographic regions, but the molecular genetic defect causing C5 deficiency has not been delineated in any of them. To examine the molecular basis of C5 deficiency in the African-American population, the exons and intron/exon boundaries of the C5 structural genes from three C5-deficient (C5D) African-American families were sequenced, revealing two nonsense mutations. The nonsense mutations are located in exon 1 (C84AG to TAG) in two of the C5D families (Rhode Island and North Carolina) and in exon 36 (C4521GA to TGA) in the third C5D family (New York). The exon 1 and 36 mutations are contained in codons that encode the first amino acid of the C5 beta-chain (Gln1 to Stop) and residue 1458 in the alpha-chain (Arg1458 to Stop), respectively. Allele-specific PCR and sequence analyses demonstrated that the exon 1 mutation is present in only one of the C5 null genes in both the Rhode Island and North Carolina families, and the exon 36 mutation is contained in only one C5 null gene in the New York family. Neither of the nonsense mutations was found in the European or Caucasian-American C5D individuals examined. Collectively, these data indicate that: 1) C5 deficiency is caused by several different molecular genetic defects, 2) C5 deficiency in the African-American population can be explained in part by two distinct nonsense mutations in exons 1 and 36, and 3) compound heterozygosity exists in all of the reported African-American C5D families.

Alleles↗
PubMed1994

Erythrocyte membrane proteins reactive with IgG (warm-reacting) anti-red blood cell autoantibodies: II. Antibodies coprecipitating band 3 and glycophorin A.

In our initial immunochemical study of the red blood cell (RBC) membrane proteins targeted in 20 cases of warm-antibody autoimmune hemolytic anemia (AHA), RBC eluates of 6 patients mediated immunoprecipitation (IP) of both band 3 and glycophorin A (GPA). This dual IP pattern had previously been observed with murine monoclonal antibodies (MoAbs) against the high frequency blood group antigen, Wrb (Wright), suggesting that the Wrb epitope may depend on a band 3-GPA interaction. Earlier, anti-Wrb had been identified serologically as a prominent non-Rh specificity of AHA autoantibodies. In the present study, 6 autoantibody eluates immunoprecipitating band 3 and GPA from common Wr(b+) RBCs were retested, in parallel with murine anti-Wrb MoAbs, against very rare Wr(a+b-)En(a+)RBCs. One patient's autoantibodies were unreactive with the Wr(b-) RBCs by either IP or indirect antiglobulin test (IAT) and were judged to have "pure" anti-Wrb specificity. Two other patients' autoantibodies displayed both IP and serologic evidence for anti-Wrb as a major component in combination with one or more additional specificities. However, among 3 other patients whose autoantibodies coprecipitated band 3 and GPA, there was no reduction in IP or IAT reactivity with Wr(b-) RBCs in 2 and only slight reduction in the third. We conclude (1) that human anti-Wrb autoantibodies, like their murine monoclonal counterparts, coprecipitate band 3 and GPA from human RBCs; but (2) that not all antibodies with this IP behavior have anti-Wrb serologic specificity, as defined by this donor's Wr(b-) RBCs. The possibility of an additional (non-Wrb) RBC epitope dependent on a band 3-GPA interaction is raised.

Animals↗
PubMed1994

Mononeuritis multiplex and vasculitis. Association with anti-neutrophil cytoplasmic autoantibody.

Mononeuritis multiplex is known to occur in many illnesses including certain types of systemic vasculitis. Anti-neutrophil cytoplasmic autoantibody (ANCA) has been described in association with Wegener's granulomatosis, polyarteritis nodosa, pauci-immune necrotizing crescentic glomerulonephritis, and so-called ANCA-associated vasculitis. We describe three patients who presented with mononeuritis multiplex and positive tests for ANCA. A careful search revealed underlying vasculitis in two of the three patients. Whereas both respiratory and renal involvement are well known in ANCA-associated vasculitis, to our knowledge the relationship of mononeuritis multiplex and ANCA positivity has not previously been described. The three patients were treated with steroids and oral cyclophosphamide. All demonstrated marked clinical improvement, as well as a decrease or disappearance of the ANCA. Since mononeuritis multiplex may be a presenting symptom of many illnesses, a serological marker may be helpful for early diagnosis and prompt treatment.

Aged↗
PubMed1993

Chronic lunotriquetral instability: diagnosis and treatment.

Fourteen patients with chronic lunotriquetral instability were evaluated. Forced wrist extension was the most common mechanism of injury. Fourteen patients underwent lunotriquetral arthrodesis. Arthrograms were positive in 9 of the 12 performed. In three cases abnormalities not identified by arthrography were demonstrated by arthroscopy. The follow-up period averaged 27 months. X-ray films showed fusion in 12 cases. One pseudarthrosis was asymptomatic. A second pseudarthrosis required a rearthrodesis that became solid 8 weeks after surgery. One patient had persistent wrist pain. Wrist motion compared to the contralateral side averaged 85%, 88%, 83% and 80%, respectively, for flexion, extension, ulnar deviation, and radial deviation. Grip strength compared to the contralateral side averaged 93%. Lunotriquetral instability is a clinical diagnosis confirmed by arthrography or arthroscopy. Lunotriquetral fusion reliably relieves pain while maintaining functional wrist motion and grip strength. The long-term effects of lunotriquetral fusion on carpal kinematics and wrist function are unknown.

Adult↗
PubMed1993

Erythrocyte membrane proteins reactive with human (warm-reacting) anti-red cell autoantibodies.

Immunoglobulin G (IgG) autoantibodies of 20 patients with autoimmune hemolytic anemia (AHA) were used in immunoaffinity assays with surface-radioiodinated human red blood cells (RBCs), and detergent-solubilized products were analyzed by SDS-PAGE/autoradiography. Four membrane proteins were identified as candidate autoantigens: a nonglycosylated polypeptide with an apparent molecular mass of 34 kD (p34) that was expressed in all available RBC phenotypes except Rhnull but differed consistently in apparent molecular mass from the 32-kD Rh(D) polypeptide co-isolated by IgG allo-anti-D; a heterogenous 37-55-kD glycoprotein, also deficient in Rhnull RBCs, which disappeared after deglycosylation by N-glycanase, with the appearance of a sharp, new approximately 31-kD band distinct from p34 and from Rh(D) polypeptide; a approximately 100-kD major membrane glycoprotein identified by immunoblotting as the band 3 anion transporter; and glycophorin A (GPA), also confirmed by immunoblotting. GP37-55 was not seen in the absence of p34, and both proteins are likely to be members of the Rh family. Indeed, a 34-kD polypeptide band and 37-55-kD poly-disperse "smear," isolated concurrently from the same labeled RBCs by IgG allo-anti-e, were indistinguishable from their autoantibody-isolated counterparts and may well be the same protein identified at different epitopes by the auto- and allo-antibodies. Individual AHA patients' autoantibodies isolated p34 and gp37-55, alone or in combination with band 3 (nine cases); strong band 3 alone (five cases); and combinations of band 3 with GPA (six cases). The autoantibodies of three additional patients whose AHA had been induced by alpha-methyldopa also isolated p34 and gp37-55.

Anemia, Hemolytic, Autoimmune↗
PubMed1993

Shoulder strength with rotator cuff tears. Pre- and postoperative analysis.

Twenty-five patients with rotator cuff tears had bilateral isokinetic shoulder strength evaluations after a pain-relieving subacromial lidocaine injection. Shoulder strength testing was repeated at six months and again at 12 months after rotator cuff surgery. Strength was recorded as a ratio of peak torques comparing the operative with the nonoperative shoulder. Preoperative strength averaged 37%, 36%, and 33% for abduction, external rotation, and forward flexion. Six-month postoperative strength increased to 68%, 76%, and 66% for abduction, external rotation, and forward flexion, respectively. Twelve-month postoperative strength increased to 104%, 142%, and 97% for abduction, external rotation, and forward flexion. Shoulders with rotator cuff tears demonstrate major objective signs of weakness. Shoulder pain obscures objective evaluation of weakness. Preoperative strength can be accurately measured after subacromial lidocaine injection. Shoulder strength is significantly improved by rotator cuff repair.

Biomechanical Phenomena↗
PubMed1989

Secretion of the terminal complement proteins, C5-C9, by human platelets.

The terminal complement components, C8 and C9, and to a lesser extent C5, C6, and C7, but minimal amounts of C3, were shown to be associated with washed human platelets. In unactivated platelets, the complement components were detected in the platelet pellet by hemolytic assays after centrifugation and disruption of the platelets by freeze-thawing. However, after platelets had been activated by collagen, thrombin, or aggregated IgG to induce aggregation, the complement components were released into the supernatant. The rank order of hemolytic activity of C9, C8, C7, C6, and C5 detected in the supernatants of activated platelets was quite different from that found in serum from the same donors, in the same assays. In particular, the serum C7 hemolytic titer was more than twice the serum C9 hemolytic titer, whereas the activity of C9 detected from platelets was more than twice that of C7. This argues against a purely nonspecific uptake of these proteins by platelets from plasma. The functional role of terminal complement components released from platelets during activation is unknown, but it is tempting to speculate that these proteins may have a role in platelet-dependent immunological tissue injury. Because the C5b-9 membrane attack complex activates platelets, it is possible that release of terminal complement proteins serves to amplify platelet activation and may also play a role in diseases in which complement membrane attack complexes have been implicated.

Blood Platelets↗
PubMed1987

Human Fc gamma receptors: stable inter-donor variation in quantitative expression on platelets correlates with functional responses.

Evidence has recently been presented that a 40,000 dalton membrane sialoglycoprotein (p40) shared by monocytes and granulocytes serves as the human platelet receptor for aggregated IgG. We now report that the platelets of normal donors exhibit stable quantitative differences in the expression of this receptor molecule, as determined by flow cytometry using fluorescent staining with murine monoclonal antibody to p40 (mab IV.3). These inter-donor differences were reproducible on repeated testing over at least 4 mo. In concurrent assays, the binding of mab IV.3 to each donor's platelets was highly correlated with the binding of heat-aggregated human IgG, also assayed by flow cytometry. The biological relevance of this quantitative variation in IV.3 binding is suggested by its reproducible correlation with platelet responsiveness to aggregated IgG measured by aggregometry. Such stable quantitative variation in platelet Fc receptor expression among individual humans could contribute to differences in severity of certain pathologic processes initiated by IgG-containing immune complexes.

Antibodies, Monoclonal↗
PubMed1986

Enhanced reactive lysis of paroxysmal nocturnal hemoglobinuria erythrocytes. Studies on C9 binding and incorporation into high molecular weight complexes.

As part of a broader analysis of the mechanism(s) by which the most sensitive (type III) paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes are excessively sensitive to reactive lysis by isolated C5b6, C7, C8, and C9, we have compared type III PNH (PNH-III) and normal human E in respect to both total specific binding of 125I-C9 and the proportion of cell-bound C9 appearing in high molecular weight (HMW) complexes. In a previous report, we found that after exposure to purified C5b6 and 125I-C7, specific C7 binding and, by implication, EC5b-7 formation were equal for PNH-III E and normal E. In the present study, C8-dependent binding of 125I-C9 to PNH-III EC5b-7 and normal EC5b-7 was also similar, although lysis of the PNH-III E was up to five times greater; that is, PNH-III E required fewer bound C9 molecules to produce an effective lytic site than did normal E. To quantify radioactivity in monomeric and HMW forms of membrane-bound C9, lysed and unlysed E were subjected to low ionic strength buffers to convert all E to ghosts. These ghosts were solubilized in 0.1 or 2% SDS (without reduction) and electrophoresed on 2.4-11% polyacrylamide gradient gels followed by autoradiography and densitometric scanning. With 0.1% SDS, broad, heterodisperse zones of HMW C9 were recovered from both PNH and normal ghosts; the amounts of C9 incorporated into the HMW complexes were similar for PNH-III E and normal E. In selected experiments, 125I-C7 could be shown in these same HMW bands. When membranes were solubilized in 2% SDS, the overall proportion of HMW C9 complexes compared with dimer and monomer C9 was reduced on both PNH and normal membranes. In many, but not all experiments, more of the highest mol wt C9 complexes were detected from PNH-III E membranes solubilized in 2% SDS than from normal or PNH-II E membranes similarly treated. When antibody-sensitized E were lysed by purified C1-C9, PNH-III EA bound far more C9 than did normal EA, and both lysis and C9 incorporation into HMW complexes were markedly and proportionately increased over normal; however, lytic efficiency of 125I-C9 bound to PNH EA was equal to or less than that bound to normal EA.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗
PubMed1985

High-density lipoprotein and its apolipoproteins inhibit cytolytic activity of complement. Studies on the nature of inhibitory moiety.

Human high-density lipoprotein (HDL) and its apolipoproteins A-I and A-II inhibit complement-mediated lysis of human and sheep erythrocytes. This inhibitory activity under study is exerted after C9 is bound to membrane-associated C5b-8 complexes but prior to completed assembly and insertion of the C5b-9 complex. In this paper, we define some structure-activity relationships of the inhibitory moiety. With the exception of weak lytic inhibitory activity found in LDL/VLDL pools and in some unconcentrated minor fractions of plasma obtained by hydrophobic chromatography, all inhibitor activity was found in fractions which contained either apolipoprotein A-I, apolipoprotein A-II, or both. Intact HDL has a high level of inhibitor activity but delipidation by chloroform-methanol extraction was associated with an increase in activity on a protein-weight basis. Purified apolipoprotein A-I and apolipoprotein A-II exhibited equal inhibitory activity, greater than that exhibited by intact HDL. Nevertheless, ultracentrifugal fractions in which no free apolipoproteins could be demonstrated still possessed inhibitory activity. These experiments suggest that delipidation of HDL is not necessary for expression of inhibitor activity, although we could not rule out the possibility that apolipoproteins in dynamic equilibrium with HDL are responsible for the inhibitor activity observed in whole serum and plasma and in HDL preparations. Limited proteinase digestion completely abolished the inhibitory activity of partially delipidated HDL. Phospholipase C had little or no effect on the inhibitory activity of delipidated HDL, apolipoprotein A-I or apolipoprotein A-II, but reduced the inhibitory activity of intact HDL. These data suggest that the phospholipid polar headgroups are not necessary for inhibitory activity. However, the loss of these headgroups is associated with decreased activity, possibly due to increased hydrophobicity of HDL, or increased association among HDL micelles, and subsequent decrease in effective molar concentration of the inhibitory moiety.

Apolipoprotein A-I↗
PubMed1985

Human platelet Fc receptor for immunoglobulin G. Identification as a 40,000-molecular-weight membrane protein shared by monocytes.

We have recently shown that human monocytes and U937 cells possess two molecular classes of Fc gamma receptor. One, a 72,000-mol-wt sialoglycoprotein, has high affinity for certain subclasses of human and murine monomeric IgG. The other is a 40,000-mol-wt protein (p40) with low affinity for monomeric IgG but with the capacity to bind IgG aggregates or IgG-coated particles. In the present study, a 40,000-mol-wt single chain protein, apparently identical to p40 from U937 cells, was isolated from surface-radioiodinated human platelets by affinity purification using a murine IgG2b monoclonal antibody to p40. This 40,000-mol-wt protein was not seen when control IgG2b or unrelated murine monoclonal antibodies were employed in place of anti-p40. The same 40,000-mol-wt protein was also recovered from an IgG-Sepharose affinity adsorbent, but not from ovalbumin-or myoglobin-Sepharose. The 72,000-mol-wt Fc gamma receptor of monocytes was not identified on platelets. Monoclonal anti-p40 and Fab fragments derived from this antibody blocked platelet aggregation by heat-aggregated human IgG, whereas a control murine IgG2b protein had little or no inhibitory effect at 500-1,000-fold higher concentrations. A murine IgG1 monoclonal antibody, reactive with an unrelated platelet-specific membrane antigen, did not inhibit platelet responses to aggregated IgG. Anti-p40 did not affect platelet aggregation by thrombin, collagen, or fibrinogen plus ADP. Although anti-p40 did not directly aggregate platelets in the concentrations employed, cross-linking with F(ab')2 goat anti-murine Ig induced apyrase-sensitive aggregation of anti-p40-treated platelets. This indicates that p40 possesses transmembrane linkage for platelet activation and secretion. These observations strongly suggest that this newly recognized 40,000-mol-wt platelet membrane protein serves as an Fc gamma receptor.

Antibodies, Monoclonal↗