Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium,plasma 1,25-dihydroxyvitamin D concentrations,and fractional calcium excretion in healthy human volunteers

PTH and PTH-related protein (PTHrP) cause primary hyperparathyroidism and humoral hypercalcemia of malignancy (HHM), respectively. These syndromes are similar in several important ways, but differ in several characteristic, yet unexplained, ways. Two of the unresolved questions in HHM and hyperparathyroidism involve renal physiology. 1) Why does renal proximal tubular production of 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] differ between the two syndromes? 2) Do distal tubular calcium responses to PTH and PTHrP differ in the two syndromes? To address these questions, we compared the two peptides, human PTH-(1-34) and PTHrP-(1-36), in a direct, head to head study using a continuous, steady state infusion of each peptide at the same dose in normal human volunteers for 46 h. We had previously described such methods as applied to PTHrP, but a direct multiday comparison of PTHrP to PTH has not previously been reported. In two groups (seven subjects each) of healthy young (25- to 35-yr-old) normal volunteers, PTH and PTHrP infused at 8 pmol/kg.h displayed similar calcemic effects, although PTH was slightly more potent in this regard. Both peptides also displayed similar phosphaturic effects. In addition, both peptides had similar effects on renal tubular calcium handling, yielding fractional calcium excretion values of approximately 3.5%, some 50% below the values (6.5%) observed in subjects rendered similarly hypercalcemic by the infusion of calcium. In contrast to these several quantitatively similar effects of PTH and PTHrP, PTH tended to be selectively more effective than PTHrP in stimulating renal production of 1,25-(OH)(2)D. These studies indicate that renal tubular calcium reabsorption is likely to contribute to hypercalcemia in patients with HHM. In addition, PTH may be selectively more effective than PTHrP in stimulating 1,25-(OH)(2)D production, in contrast to its phosphaturic, calcemic effects and its effects to stimulate nephrogenous cAMP excretion and renal tubular calcium reabsorption.     

Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated

Glycoprotein (GP) IIb/IIIa antagonists are effective therapeutic agents, but elicit thrombocytopenia with a frequency that approaches 2%. Here, we provide evidence that thrombocytopenia in humans treated with the GP IIb/IIIa antagonist roxifiban is immune mediated. Two patients underwent conversion to a highly positive drug-dependent antibody (DDAB) status temporally associated with thrombocytopenia. Despite the continued presence of DDABs, the fall in platelet count was reversed by discontinuation of drug treatment, pointing to the exquisite drug dependency of the immune response. DDABs appear to bind to neoepitopes in GP IIb/IIIa elicited on antagonist binding. This information was used to develop an enzyme-linked immunosorbent assay (ELISA) for DDAB using solid-phase GP IIb/IIIa. A high level of specificity is indicated by the observation that DDAB binding is dependent on the chemical structure of the GP IIb/IIIa antagonist and that only 2% to 5% of human blood donors and 5% of chimpanzees present with pre-existing DDABs. Furthermore, none of 108 nonthrombocytopenic patients from the phase II roxifiban study showed an increase in antibody titer. Absorption of thrombocytopenia plasma with platelets reduced the DDAB ELISA signal, indicating that the test detects physiologically relevant antibodies. Screening patients for pre-existing or increasing DDAB titer during treatment with GP IIb/IIIa antagonists may reduce the incidence of drug-induced thrombocytopenia.     

Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients

Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%).     

Relapsing illness due to Rochalimaea henselae in immunocompetent hosts: implication for therapy and new epidemiological associations.

Two previously healthy, immunocompetent men had persistent Rochalimaea henselae bacteremia with clinical relapses after courses of antibiotics to which the isolates were ultimately demonstrated susceptible in vitro. Both had sustained tick bites prior to their illnesses, thus demonstrating an association not previously identified, although suspected. The first patient had relapsing fever, constitutional symptoms, and an episode of aseptic meningitis despite therapy with amoxicillin, then with doxycycline, and then with ceftriaxone. Thereafter, he spontaneously became asymptomatic during a span of 2 months of persistent bacteremia. Finally, after 2 weeks of therapy with ceftriaxone plus gentamicin, followed by 4 weeks of therapy with oral ciprofloxacin, his bacteremia was cured. The second man had relapsing fever and constitutional symptoms after courses of tetracycline, then of chloramphenicol, and then of doxycycline. He became permanently asymptomatic after serial 2-week courses of chloramphenicol and erythromycin. The greater efficacy of lysis-centrifugation blood cultures in the recovery of R. henselae was noted.     

Nontypable Haemophilus influenzae (biotype 4) as a neonatal, maternal, and genital pathogen

Between 1976 and 1981 Haemophilus influenzae was identified in 16 women with postpartum bacteremia and 36 neonates with bacteremia or meningitis. H. influenzae was also recovered from neonatal or genital cultures of 50 additional patients. By counter-immunoelectrophoresis 17% of neonatal isolates from blood or cerebrospinal fluid (CSF) were type b. All remaining strains (94% overall) were nontypable (NT). Of the NT blood or CSF isolates, 38% belonged to biotype 4. Of all the NT biotype 4 isolates referred to the Centers for Disease Control during the study, 82% were of genital, neonatal, or maternal origin, a finding that suggests that this isolate is a genital biotype. Clinical disease was similar to that observed in patients infected with group B Streptococcus except for the infrequent (11%) occurrence of meningitis. Maternal bacteremia resulted in mild febrile illness, while neonatal bacteremia was associated with a high incidence of shock, respiratory distress (50%), and death (30%). H. influenzae bacteremia in these two patient groups was rare in Houston before 1976, but since then it has been responsible for 2.5% of cases of significant bacteremia. NT H. influenzae should be recognized as a definite neonatal, maternal, and genital pathogen.     

Antibodies against oxidized low-density lipoproteins in systemic sclerosis

OBJECTIVE: To investigate whether circulating concentrations of antibodies against oxidized low-density lipoproteins (LDL) are increased in patients with systemic sclerosis (SSc). METHODS: Oxidation of LDL and anti-oxidized LDL antibodies were measured in 26 patients with limited cutaneous SSc (LCSSc), in eight patients with diffuse cutaneous SSc (DCSSc) and in 24 healthy control subjects. Results were adjusted for age, sex and smoking. RESULTS: Binding to oxidized LDL was increased in patients with both limited and diffuse cutaneous disease (geometric mean 0.35 and 0.39 optical density units respectively) compared with controls (0.28) (P=0.03 and P=0.01 respectively). Circulating concentrations of anti-oxidized LDL were increased only in patients with diffuse SSc (geometric mean 0.22 optical density units) compared with controls (geometric mean 0.16, P=0.02). CONCLUSION: These preliminary findings lend further weight to the concept that oxidation of LDL contributes to the vascular pathology of SSc, particularly in patients with diffuse cutaneous disease. Prospective longitudinal studies are required to investigate whether anti-oxidized LDL antibodies may be a marker of vascular damage in SSC.     

Brain metastases from papillary thyroid carcinomas

Brain metastasis from papillary thyroid carcinoma (PTC) is extremely rare and carries a poor prognosis. We report nine cases (five females and four males) of brain metastasis of PTC. The age of patients ranged from 46 to 87 years old. The patients presented with nonspecific symptoms such as headaches. Brain metastasis was the first clinical presentation in three of nine patients; two of which had the aggressive tall cell variant of PTC. Six patients had prior history of PTC (four classic, one oncocytic variant, and one columnar cell variant) for 2 to 17 years with a median of 12 years. Gross total resection of brain metastasis was achieved for eight of our patients. Eight patients were treated with radioactive iodine. The median follow-up time was 12 months, ranging from 1 month to 4 years. Three patients died of their disease in 6 months, 21 months and 4 years, respectively after their first presentation of brain metastasis. It seems that these rare aggressive variants of PTC, such as tall cell variant, not only have higher propensity to develop brain metastasis, but also more frequently present with brain metastasis as their first clinical presentation than classic PTC. Furthermore, patients with PTC can develop brain metastasis even after many years.     

Posterior Soft Tissue Repair After Primary THA is Durable at Mid-term Followup: A Prospective MRI Study

Background

The enhanced posterior soft tissue repair has reduced the frequency of dislocation after primary THA performed through the posterolateral approach. However, the long-term integrity of the repair is unknown and could influence surgeon choice regarding surgical technique and THA approach.

Questions/Purposes

We asked: (1) What is the durability of the enhanced posterior soft tissue repair at a minimum of 49 months using MRI to evaluate soft tissue to bone integrity? (2) How does the appearance of the posterior soft tissues change during this time? (3) Are there patient characteristics associated with the long-term imaging appearance of the posterior repair?

Methods

All patients without a contraindication for MRI who were undergoing unilateral primary uncemented THA through a posterior approach between February and May 2005 were eligible for inclusion. Ninety percent consented to participate (36 of 40 patients), and 30 patients were followed prospectively with MRI postoperatively and again at 3 months; of those, 22 (73%; 12 men, 10 women) completed the study by having another MRI study at a minimum of 49 months (mean, 51 months; range, 49–59 months). Each patient underwent metal-artifact–reduction sequence MRI to evaluate the integrity of the posterior soft tissues, which had been repaired anatomically during primary THA at a minimum of 4 years earlier. The results were compared with those of prior MR images obtained immediately after surgery and at 3 months postoperatively. All patients were given a self-reported modified Harris hip score at the time of the most recent MRI study (maximum score = 81).

Results

At latest followup, 21 of 22 (96%) patients had a posterior capsule in contact with bone, and 21 of 22 (96%) had an intact quadratus femoris. Twenty-one patients (96%) had soft tissue or a scar from the piriformis and conjoined tendons in continuity with bone. In these cases, the interface between the piriformis and conjoined tendons and the greater trochanter observed immediately postoperatively and at 3 months postoperatively became filled with hypointense tissue, with signal characteristics similar to tendon. Time from surgery was most associated with changes in native tendon-to-bone distances (p < 0.001) and MRI signal intensity of the repair (p < 0.001).

Conclusions

At followup of just more than 4 years, the posterior capsule and quadratus femoris most often were healed to bone. In the majority of patients, scar tissue between the piriformis and conjoined tendons and bone matured to achieve orientation and signal intensity resembling native tendon. We believe the enhanced posterior soft tissue repair facilitates this process. Our results provide a plausible explanation for improved postoperative stability observed in patients receiving an enhanced soft tissue repair compared with those in whom a repair is not performed.

Level of Evidence

Level IV, therapeutic study.