Long-term treatment of lupus nephritis with cyclosporin A

We evaluated the efficacy and safety of long-term treatment with cyclosporin A (CSA) in type IV lupus nephritis. Seventeen patients with biopsy-proven WHO type IV lupus nephritis were enrolled in a prospective, open study. Twelve of the 17 completed 48 months of treatment with CSA and prednisolone. Three patients required the addition of azathioprine, at 12, 38 and 47 months, respectively, for cutaneous disease flare with refractory rashes. One patient was lost to follow-up at 40 months. The mean +/- SD duration of treatment was 43.2 +/- 10.1 months (range 15.7-48 months). A significant reduction of proteinuria and a significant rise in serum albumin were noted 1 month after initiation of treatment. Improvement was maintained throughout the study except for three patients who relapsed with recurrence of nephrotic syndrome. There were no significant changes in serum creatinine level or creatinine clearances throughout the study. Repeat renal biopsy at 12 months following treatment with CSA showed histological improvement, with WHO type II changes in all 17 patients accompanying significant reduction in activity indices. Patients with baseline haemoglobin (Hgb) levels < 12 g/dl showed significant improvement. Serum C3 and C4 levels were not changed significantly. Corticosteroid-sparing effects were noted. Side-effects included hypertension, gum hypertrophy and mild hirsuitism, but were not serious. Combination therapy using CSA and prednisone is effective and safe for long-term treatment in lupus patients with WHO type IV nephritis.     

Schwann cells proliferate at rat neuromuscular junctions during development and regeneration

Terminal Schwann cells (TSCs) cover neuromuscular junctions and are important in the repair and maintenance of these synapses. We have examined how these cells are generated at developing junctions and how their number is regulated during repair of nerve injury. At birth, approximately half of the junctions in rat soleus and extensor digitorum longus muscles have one TSC soma. Somata are absent from the remainder, although Schwann cell (SC) processes arising from somata along the preterminal axon cover almost all of these synapses. By 2 months of age, junctions have gained an additional two to three TSCs. Most of this gain occurs during the first 2 postnatal weeks and largely precedes the expansion of endplate size. Although the initial addition is caused by cell migration, mitotic labeling shows extensive division of TSCs at junctions. A slower addition of TSCs occurs in adult muscles, and TSC number in the adult is correlated with endplate size. During repair of nerve injury, TSC number is regulated by a combination of signals from motor neurons and denervated tissue. As shown previously (Connor et al., 1987), denervation of adult muscles did not, in itself, cause TSC mitosis. However, TSCs became mitotic during reinnervation. Partial denervation induced division of TSCs at innervated but not denervated endplates. A disproportionate number of these mitotic cells were found at endplates contacted by TSC processes extended from nearby denervated endplates, contacts known to promote nerve sprouting. These results show an association between TSC mitotic activity and alterations in synaptic structure during development, sprouting, and reinnervation.     

Colonic atresia associated with Hirschsprung''s disease: it is not a diagnostic challenge

OBJECTIVES: Osteoporosis is a major cause of morbidity and cost. Patients sustaining one osteoporotic fracture are at increased risk of having another fracture. The objective of this study was to examine the use of "bone drugs" for the prevention of further osteoporotic fractures among patients who have had a "typical" osteoporotic fracture. METHODS: This study took a random sample of 300 women aged 50 and over who had sustained either a vertebral, hip or Colles fracture in 1995 from the General Practice Research Database (GPRD) and compared their use of bone drugs with 300 age and practice matched controls. RESULTS: Compared with age and practice matched control patients only vertebral fracture patients showed a statistically significant increase in the use of bone drugs in the year after fracture (39% and 2% for cases and controls respectively; 95% CI of difference 27% to 47%). Etidronate was the most commonly used compound. CONCLUSION: The majority of patients sustaining an osteoporotic fracture are not prescribed any pharmaceutical agents for the secondary prevention of fracture one year after a primary fracture.     

Postpneumonectomy syndrome: recognition and management

STUDY OBJECTIVE: Postpneumonectomy syndrome (PPS) results from extreme shift and rotation of the mediastinum after pneumonectomy producing symptomatic proximal airway obstruction and air trapping. Herein, we review our experience in the treatment of PPS. PATIENTS: Five patients with PPS were treated at our institution between 1991 and 1997. Four patients had previous right pneumonectomy; one patient had left pneumonectomy. Dyspnea was the presenting symptom in all five patients. The time interval to onset of symptoms and to surgical correction ranged from 6 months to 9 years (median: 6 months) and 9 months to 29 years (median, 21 months) after pneumonectomy, respectively. INTERVENTION: The clinical diagnosis of PPS was confirmed with chest radiograph, two-dimensional echocardiography, pulmonary function tests, CT scan, and awake fiberoptic bronchoscopy. Correction of PPS required reexploration of the pneumonectomy space followed by anterior pericardiorrhaphy and insertion of a saline solution-filled Silastic prosthesis (Dow Corning; Midland, MI) for the purpose of correcting the overshift of the mediastinum. There was no morbidity or mortality. RESULTS: All patients had relief of dyspnea. Corrective repositioning of the mediastinum was confirmed by chest radiograph, CT scan, and awake fiberoptic bronchoscopy. There was a mean increase in the cross-sectional diameter, as measured by CT scan, of the obstructed bronchus by 166.7% (range, 100 to 300%) in four patients. One patient had no change in the measured diameter. Postoperatively, the peak expiratory flow rate increased by a mean of 44.2% (range, 40 to 49%) in all five patients. CONCLUSION: The presence of PPS should be considered in all patients presenting with progressive dyspnea after pneumonectomy. Repositioning of the mediastinum with a saline solution-filled prosthesis and anterior pericardiorrhaphy is easily performed and provides immediate and lasting symptomatic relief.     

A stringent test for the nucleotide switch mechanism of carbamoyl phosphate synthetase

Carbamoyl phosphate synthetase (CPS) catalyzes the formation of carbamoyl phosphate from bicarbonate, glutamine, and two molecules of MgATP. The X-ray crystal structure of the enzyme has revealed that the two nucleotide binding sites are separated by approximately 35 A. Isotopic oxygen exchange of 18O and 16O between solvent water and [13C]bicarbonate was measured using 13C NMR spectroscopy during substrate turnover in the presence and absence of glutamine as a nitrogen source. In the absence of added glutamine, CPS catalyzed the exchange of one oxygen atom from bicarbonate with solvent water during every turnover of the bicarbonate-dependent ATPase reaction. In the presence of added glutamine, there was no exchange of solvent water with bicarbonate during the enzymatic synthesis of carbamoyl phosphate, indicating that any carbon-containing intermediate in the reaction mechanism is committed to the formation of carbamoyl phosphate and is not subject to hydrolysis. These results are fully consistent with a chemical mechanism that requires the physical migration of the carbamate intermediate from the site of its formation within one of the nucleotide binding domains to the other nucleotide binding domain for subsequent phosphorylation by the second MgATP. These results are not compatible with a nucleotide switch mechanism. The nucleotide switch mechanism includes the synthesis of carbamoyl phosphate entirely within a single nucleotide binding domain and concurrent conformational changes driven by the bicarbonate-dependent hydrolysis of MgATP at the second nucleotide binding domain.     

The effect of gentamicin on acetylsalicylic acid-induced platelet antiaggregatory action in mouse pial arterioles

Proton nuclear magnetic resonance (1H-NMR) spectroscopy is used to identify a preferred binding site for uncharged hydrophilic polymers on the surface of hen egg-white lysozyme. Chemical shift titrations show that exchangeable proton signals from amino acids Arg-61, Trp-62, Trp-63, Arg-73, Lys-96 and Asp-101 are selectively perturbed upon binding of poly(ethylene oxide), poly(ethylene glycol) and poly(ethylene-co-propylene oxide). The greatest binding-induced chemical shift changes are observed for Trp-62, Arg-61 and Arg-73 at the edge of the active site cleft of the protein, consistent with a predominantly hydrophobic interaction mode involving the polymer ethylene moieties. The more hydrophilic species poly(dihydroxypropyl methacrylate) causes similar but substantially smaller chemical shift effects than the other polymers, confirming the nature of the interaction. A dissociation constant of 76+/-5 mM is determined for the poly(ethylene glycol)-lysozyme complex. The relatively low affinity of the protein-polymer interactions compared to oligosaccharide substrate binding suggests that lysozyme activity is minimally affected by these materials.