Gretta H. Jacobs

Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis

Prolylcarboxypeptidase (PRCP) activates prekallikrein to plasma kallikrein, leading to bradykinin liberation, and degrades angiotensin II. We now identify PRCP as a regulator of blood vessel homeostasis. β-Galactosidase staining in PRCP(gt/gt) mice reveals expression in kidney and vasculature. Invasive telemetric monitorings show that PRCP(gt/gt) mice have significantly elevated blood pressure. PRCP(gt/gt) mice demonstrate shorter carotid artery occlusion times in 2 models, and their plasmas have increased thrombin generation times. Pharmacologic inhibition of PRCP with Z-Pro-Prolinal or plasma kallikrein with soybean trypsin inhibitor, Pro-Phe-Arg-chloromethylketone or PKSI 527 also shortens carotid artery occlusion times. Aortic and renal tissues have uncoupled eNOS and increased reactive oxygen species (ROS) in PRCP(gt/gt) mice as detected by dihydroethidium or Amplex Red fluorescence or lucigenin luminescence. The importance of ROS is evidenced by the fact that treatment of PRCP(gt/gt) mice with antioxidants (mitoTEMPO, apocynin, Tempol) abrogates the hypertensive, prothrombotic phenotype. Mechanistically, our studies reveal that PRCP(gt/gt) aortas express reduced levels of Kruppel-like factors 2 and 4, thrombomodulin, and eNOS mRNA, suggesting endothelial cell dysfunction. Further, PRCP siRNA treatment of endothelial cells shows increased ROS and uncoupled eNOS and decreased protein C activation because of thrombomodulin inactivation. Collectively, our studies identify PRCP as a novel regulator of vascular ROS and homeostasis.

Effect of corticosteroid therapy on human immunodeficiency virus-associated nephropathy

PURPOSE Human immunodeficiency virus-associated nephropathy (HIV-AN) occurs predominantly in blacks and is characterized histologically by focal segmental glomerulosclerosis or mesangial proliferation and a lymphohistiocytic tubulointerstitial infiltrate. Patients manifest heavy proteinuria and, once azotemia occurs, progress rapidly to end-stage renal disease within 2 to 6 months. No treatment has been shown to be useful for HIV-AN. The purpose of this study was to determine the effect of corticosteroid agents on the progression of HIV-AN. PATIENTS AND METHODS Four consecutive HIV-infected adults with fewer than 200 CD4 cells/microL, moderate to severe renal insufficiency, proteinuria greater than 2 g per 24 hours, and HIV-AN demonstrated by renal biopsy were treated with 60 mg of prednisone daily for 2 to 6 weeks. Patients were followed with respect to serum creatinine level, 24-hour protein excretion, adverse drug reactions, and the occurrence of opportunistic infections. RESULTS CD4 counts ranged from 30 to 80 cells/microL before therapy with steroids. The mean (+/- SD) pretreatment serum creatine concentration was 9.1 +/- 5.7 mg/dL and decreased to 3.3 +/- 1.8 mg/dL (P < 0.05) after 2 to 6 weeks of corticosteroid therapy. Twenty-four hour protein excretion did not change (5.2 +/- 2.4 g pretreatment versus 4.6 +/- 4.1 g posttreatment). One patient was able to discontinue dialysis after 10 days. Two patients developed Mycobacterium avium-complex infections and steroid-associated psychosis. One of these patients developed a recurrence of genital herpes, and the other developed dermatomal zoster. None of the four required dialysis during a 1.5- to 5.5-month period of follow-up after cessation of steroid treatment. CONCLUSION In selected patients with HIV-AN, short-term treatment with corticosteroid agents improves renal function and prevents the development of end-stage renal disease during a 1.5- to 5.5-month period of observation, but may be associated with an increased risk of opportunistic infection.

Molluscum contagiosum and the acquired immunodeficiency syndrome: clinical and immunological details of two cases

We report here the clinical and immunological findings in two patients with molluscum contagiosum poxvirus infection and the acquired immunodeficiency syndrome (AIDS). These cases support earlier evidence that the molluscum contagiosum virus may act as an opportunistic pathogen. There is now evidence that members of all five families of double stranded DNA‐containing human viruses have been associated with unusual clinical manifestations in AIDS patients, and the significance of DNA virus infections in patients with AIDS is discussed.

Central nervous system Whipple's disease: Relapse during therapy with trimethoprim-sulfamethoxazole and remission with cefixime

The central nervous system (CNS) is frequently involved in patients with Whipples disease and is the most common site of disease relapse. Antibiotics such as trimethoprim-sulfamethoxazole (TMP-SMX) that have reliable CNS penetration, are therefore recommended as first-line therapy. We report a patient with Whipples disease who was treated with TMP-SMX and presented 14 months after initiation of therapy with visual decline and severe headaches. The patient was also treated concurrently with low-dose weekly methotrexate for severe psoriasis. Evaluation by magnetic resonance imaging revealed bilateral posterior white matter abnormalities that pathologically were consistent with Whipples disease. He was ultimately treated with cefixime, an orally administered third-generation cephalosporin. Visual function improved on this regimen and follow-up magnetic resonance imaging showed regression of the lesions. This case represents the first report of both CNS relapse during therapy with TMP-SMX and successful treatment with cefixime. We also speculate that methotrexate, which impairs cell-mediated immunity, may have contributed to the relapse.

Infectious crystalline keratopathy associated with topical anesthetic abuse

Two patients with infectious crystalline keratopathy associated with topical anesthetic abuse are described. No previously reported predisposing factors existed, including topical corticosteroid use during active Herpes simplex or Acanthamoeba keratitis, or following penetrating keratoplasty. Cultures from corneal biopsies of both patients grew Streptococcus viridans. Both infections resulted in corneal scarring with vascularization. Ultimately, corneal transplantation was performed in one case.

Sarcoidosis associated with nephrocalcinosis in young children

Three patients with nonpulmonary sarcoidosis had chronic erythema nodosum within the first 2 years of life. Each subsequently had renal sarcoidosis and nephrocalcinosis; hypercalcemia was documented in each patient and hypercalciuria in two patients. Treatment with prednisone was not uniformly successful in normalizing creatinine clearance. Nephrocalcinosis may be more common than previously reported in patients with sarcoidosis.

Cardiomyopathy in Coffin–Lowry syndrome

Coffin–Lowry syndrome (CLS) is a rare but well‐documented X‐linked disorder characterized by small size, developmental delay/mental retardation, and characteristic facial and skeletal findings in affected males. The phenotype in affected females is far more variable and can include developmental differences, obesity, and characteristic facial and skeletal differences. Cardiac anomalies are reported in less than 20% of affected males, with cardiomyopathy being one of the rare but reported complications of this disorder. However, cardiomyopathy is not well characterized in CLS. Here, we report on a 14‐year‐old boy with physical and developmental findings consistent with CLS who presented with a relatively sudden onset of signs of congestive heart failure due to a restrictive cardiomyopathy; an endomyocardial biopsy demonstrated non‐specific hypertrophic myocyte alterations consistent with cardiomyopathy. This is the first description of the histology and electron microscopy of cardiomyopathy in CLS.

Resolution of Hepatitis B Viremia in a Renal Transplant Recipient Treated with Alpha-2b Interferon

A renal transplant patient developed symptomatic hepatitis after withdrawal from corticosteroids. Tests for hepatitis B e antigen and hepatitis B viral DNA were both positive prior to treatment with 1 million units alpha interferon three times weekly for 3 weeks followed by an increase to 3 million units alpha interferon three times weekly for a total of 16 weeks. At the end of treatment, hepatitis had clinically resolved with conversion to a hepatitis B e antibody positive and hepatitis B e antigen and viral DNA negative state. The renal allograft function remained excellent throughout the course of therapy with interferon.

Light microscopic and ultrastructural findings in failed epikeratoplasty.

Corneal buttons from two patients with failed epikeratoplasties requiring penetrating keratoplasty were examined by light and transmission electron microscopy. Penetrating keratoplasty was performed for lenticule scarring in the first case (adult aphakia) and inadequate best corrected visual acuity in the second case (keratoconus). Findings included decreased lenticule keratocytes and electron-dense, fibrillogranular material associated with either lenticule or recipient keratocytes in both corneas and defects in Bowmans layer in one cornea. In addition, light and electron microscopic evidence consistent with recipient keratocyte migration into the lenticule was demonstrated in one case. These findings were compared with three previous cases.