Successful treatment by cyclooxyenase-2 inhibitor of refractory hypokalemia in a patient with Gitelman's syndrome.

Gitelman's syndrome is manifested by hypokalemic alkalosis, hypomagnesemia, hypocalciuria, normotensive hyperreninemia and hyperaldosteronism. Hypokalemia can at times be refractory to treatment. We present a patient refractory to a variety of drugs including indomethacin, the nonspecific COX inhibitor. Rofecoxib, a specific COX 2 inhibitor, promptly elevated serum potassium concentration with normalization of plasma aldosterone and near normalization of renin without a change in serum magnesium. Our patient also had rhabdomyolysis, a rarely reported complication, which was also ameliorated by COX 2 inhibition.

S-nitrosoderivative of a recombinant fragment of von Willebrand factor (S-nitroso-AR545C) inhibits thrombus formation in guinea pig carotid artery thrombosis model.

Antiplatelet drugs are the mainstays of therapy for acute and chronic cardiovascular diseases. S-nitroso-AR545C - an S-nitrosoderivative of a recombinant von Willebrand factor fragment AR545C spanning Ala 444 to Asp 730 and containing an Arg 545 Cys mutation, was previously found to inhibit ristocetin- and ADP-induced platelet aggregation and the interaction of platelets with extracellular matrix (ECM). In the current study we tested the antithrombotic properties of S-nitroso-AR545C on guinea pig platelets and in a platelet-rich thrombosis model in the guinea pig. Preincubation of guinea pig platelets with 0.1 microM of S-nitroso-AR545C decreased ristocetin-induced agglutination by 40% (p = 0.009) and completely abolished ADP-induced aggregation (p <0.0001). At concentration of 1.0 microM, S-nitroso-AR545C completely inhibited platelet adhesion (represented by surface coverage - SC) and decreased aggregate formation (represented by average aggregate size - AS) by more than 50%. Treatment of guinea pigs with 1.0 mg/kg S-nitroso-AR545C resulted in a significantly delayed time to arterial occlusion (31.7+/-6.0 min vs. 13.9+/-3.2 min, p <0.02). Similarly, total patency time was longer in the group injected with S-nitroso-AR545C compared to the control group. However, the difference was not statistically significant (33.8+/-6.3 min vs. 20.2+/-3.3 min, p = 0.07). No change in platelet count, hematocrit and bleeding time was observed 60 min after injection compared to baseline. In contrast, a significant decrease in SC (p <0.0001) and AS (p <0.01) were observed 60 min after the injection of S-nitroso-AR545C, whereas no change in these parameters was observed in the control group. These observations indicate that S-nitroso-AR545C exhibits significant antiadhesive and antiaggregating effects in-vitro and inhibits clot formation in-vivo suggesting that this compound may have potential therapeutic advantages.

Effect of implantable cardioverter-defibrillator shocks on QT dispersion.

Following transvenous implantable cardioverter defibrillator shocks, a significant increase in QT dispersion was observed. We suggest shock-induced increased dispersion of myocardial repolarization as one of the mechanisms of shock-induced proarrhythmia.

Multiple adverse events with a dual chamber pacemaker.

The aim of the study was to evaluate our experience with Physiocor 400T, a dual chamber unipolar pacemaker manufactured by Sorin Biomedica. Between March 1993 and December 1994, 63 units of that model were implanted at our center. Patients were followed for 46 +/- 16 months. By the end of follow-up, 15 patients had died, 1 patient was lost to follow-up, and two units had been replaced for unrelated reasons. During follow-up the following phenomena had been observed: (1) Spontaneous backup reversion (VOO, 80 ppm) in 6 (9.5%) of 63 patients. In three patients this phenomenon was accompanied by concomitant ineffective pacing artifacts at 130 beats/min with very low pulse widths. (2) Unexpected battery depletion (EOL) occurred in 3 (5%) of 63 patients; two of the three occurred within weeks of routine evaluation that confirmed normal battery status. (3) Early elective replacement time (ERT) unpreceded by a gradual drop in magnet rate in 2 (3.2%) of 63 patients. (4) Total loss of telemetry without change in pacing mode in 1 (1.6%) of 63 patients. The estimated event-free 5-year survival of this model was 46%. In conclusion, 12 (19%) of 63 patients had adverse events with Physiocor 400T pacemakers. The potential risk of asynchronous pacing for prolonged periods and the risk of unexpected EOL warrants consideration of elective replacement of all remaining units.

Clinical profile and long-term prognosis of women < or = 50 years of age referred for coronary angiography for evaluation of chest pain.

A significant lack of information exists regarding risk factors, preventive strategies, diagnostic testing, and treatment of women with coronary artery disease (CAD), especially in the young age group. We studied the clinical profile, angiographic results, and long-term follow-up of 135 women aged < or =50 years referred for coronary angiography because of chest pain. The most prominent risk factor was hyperlipidemia (60%), followed by a family history of coronary disease (44%), systemic hypertension (40%), cigarette smoking (31%), postmenopausal state (23%), and diabetes mellitus (21%). Angiographically significant CAD was demonstrated in 79 of 135 patients (58%), most of whom (61%) had 1-vessel CAD. Women with compared to those without significant CAD had a higher prevalence of hyperlipidemia (71% vs 45%; p = 0.002) and of the post-menopausal state (30% vs 16%; p = 0.028). There was no difference in the incidence of positive noninvasive evaluation (ergometry or thallium scan) before catheterization between women with or without significant coronary lesions. At a follow-up period of 2 to 7 years, 3 women had acute myocardial infarction, all of whom demonstrated coronary lesions on prior angiography. No difference was found regarding the recurrence of chest pain on follow-up between women with or without significant CAD. Mortality and congestive heart failure were observed more frequently in women with CAD (6% vs 0%; p = 0.0516 and 12% vs 2%; p = 0.047, respectively).

Unique antiplatelet effects of a novel S-nitrosoderivative of a recombinant fragment of von Willebrand factor, AR545C: in vitro and ex vivo inhibition of platelet function.

The recombinant fragment of von Willebrand factor (vWF) spanning Ala444 to Asp730 and containing an Arg545Cys mutation (denoted AR545C) has antithrombotic properties that are principally a consequence of its ability to inhibit platelet adhesion to subendothelial matrix. Endothelial-derived nitric oxide (NO) can also inhibit platelet function, both as a consequence of inhibiting adhesion as well as activation and aggregation. Nitric oxide can react with thiol functional groups in the presence of oxygen to form S-nitrosothiols, which are naturally occurring NO derivatives that prolong the biological actions of NO. Because AR545C has a single free cysteine (Cys545), we attempted to synthesize the S-nitroso-derivative of AR545C and to characterize its antiplatelet effects. We successfully synthesized S-nitroso-AR545C and found that it contained 0.96 mol S-NO per mole peptide. S-nitroso-AR545C was approximately 5-fold more potent at inhibiting platelet agglutination than was the unmodified peptide (IC(50) = 0.02 +/- 0. 006 micromol/L v 0.1 +/- 0.03 micromol/L, P =.001). In addition and by contrast, S-nitroso-AR545C was a powerful inhibitor of adenosine diphosphate-induced platelet aggregation (IC(50) = 0.018 +/- 0.002 micromol/L), while AR545C had no effect on aggregation. These effects were confirmed in studies of adhesion to and aggregation on extracellular matrix under conditions of shear stress in a cone-plate viscometer, where 1.5 micromol/L S-nitroso-AR545C inhibited platelet adhesion by 83% and essentially completely inhibited aggregate formation, while the same concentration of AR545C inhibited platelet adhesion by 74% and had significantly lesser effect on aggregate formation on matrix (P

Recombinant von Willebrand factor fragment AR545C inhibits platelet aggregation and enhances thrombolysis with rtPA in a rabbit thrombosis model.

Platelet adhesion to exposed subendothelium is mediated by platelet receptor glycoprotein Ib and polymeric von Willebrand factor (vWF). To improve the results of coronary arterial thrombolysis, fragments of vWF with enhanced glycoprotein Ib binding competitive with native vWF have been proposed as adjuvants to recombinant tissue-type plasminogen activator (rtPA). We designed a recombinant vWF fragment spanning Ala444 to Asp730 that contains the Arg545Cys mutation (named AR545C) and analyzed its antiplatelet properties in vitro and in vivo. AR545C-platelet interaction was assessed by ristocetin or botrocetin-induced platelet agglutination, or interaction with extracellular matrix under arterial flow conditions. AR545C showed enhanced reactivity with platelet glycoprotein Ib at low concentrations of ristocetin, and 60% bound spontaneously to platelets. AR545C inhibited ristocetin-induced platelet agglutination in a dose-dependent manner, with a concentration necessary to inhibit 50% of agglutination of 0.16+/-0.04 micromol/L. The inhibitory effect of AR545C on rabbit botrocetin-induced platelet agglutination was also dose dependent, with a concentration necessary to inhibit 50% of agglutination of 0.3 to 0.5 micromol/L. AR545C also completely inhibited aggregate formation and decreased the adhesion of platelets to extracellular matrix by 62.5%. The effect of AR545C on thrombolysis with rtPA was evaluated using a modified rabbit femoral thrombosis model. Local injection of AR545C into the thrombosed segment of rabbit femoral artery significantly shortened the time to reperfusion with rtPA (60+/-17.3 versus 103+/-15.2 minutes, P=.05) and significantly prolonged the total patency time (175 versus 21 minutes, P=.04). No significant difference was found in the reperfusion rate or time to reocclusion. AR545C is a potential antithrombotic agent that enhances the thrombolytic effect of rtPA in the rabbit model.

Multiple spurious laboratory results in a patient with hyperlipemic pancreatitis treated by plasmapheresis.

Hyperlipidemia is a known cause for acute pancreatitis. Hyperlipidemia may also produce multiple spurious laboratory results that may complicate the diagnosis and management of pancreatitis. We encountered such a patient who had the following spurious laboratory results: normal serum amylase activity, hyponatremia, and high hemoglobin levels. These laboratory artifacts were previously described, mostly separately. In addition, our patient had artifactual thrombocytopenia. The patient improved dramatically following plasmapheresis, which enhanced reduction of serum lipids.

Bone-related matrix proteins expression in vitro and in vivo by marrow stromal cell line.

MBA-1, a bone marrow stroma-derived cell line, was transplanted in an ectopic site and formed endochondral bone. The ossicle developed through stages of cell proliferation, differentiated into a zone of hypertrophy and formed a chondroid-like area which further developed to primary mineralized bone. We explored the expression of various matrix proteins by MBA-1 cells in vitro and in the ossicle formed in vivo. MBA-1 cells constitutively expressed mRNAs encoding for collagen I, non-collagenous proteins and alkaline phosphatase. RNA extracted from the ossicle formed by these cells was expressed in a different pattern. The in vivo maturation of MBA-1 cells was accompanied by low expression of mRNA for procollagen alpha 2(I) and a marked increase in osteonectin and osteopontin mRNA levels. Thus, the ability to follow expression of these genes through bone formation in vivo has been demonstrated.

Cryptococcus neoformans vertebral osteomyelitis.

A 67-year-old previously healthy woman presented with low back pain of 2 months duration and daily fever of 39 degrees C for 3 weeks. CT scan showed a lytic lesion in the third lumbar vertebra and a small right lower lobe lung infiltrate with mediastinal lymphadenopathy. Culture of material obtained from open biopsy of the vertebra grew Cryptococcus neoformans var. neoformans, which was also demonstrated on histology. Cryptococcal antigen was detected in the patient's serum. Treatment with amphotericin B (1000 mg total dose) and oral 5-fluorocytosine, resulted in complete recovery and resolution of the chest X-ray findings with a follow-up of 2 years. Since this case, as well as most of the previously described cases of cryptococcal osteomyelitis, were in normal hosts, cryptococcal osteomyelitis should be considered in the differential diagnosis even in a normal host, and therefore, prior to possible invasive diagnostic procedures, cryptococcal antigen in the serum should be determined.