Non-immune therapy of IgA glomerulonephritis

Summary: The involvement of the IgA immune system and complement components in IgA glomerulonephritis (IgAGN) has prompted the use of immunosuppressive drugs in therapy, but none has so far been shown to alter the natural course of the disease. Because most patients with IgAGN present during the chronic phase of their illness, at the time when the initiating immune events may no longer be active, nonimmune therapy which targets the common pathway of progressive renal injury is likely to be more useful. There is increasing evidence that angiotensin-converting enzyme inhibitors (ACEI) reduce proteinuria and renal injury in patients with IgAGN, and this effect may be observed in both normotensive and hypertensive patients. Yet to be determined is whether this effect is specific for ACEI and whatever other effective antihypertensive drugs may achieve a similar result. Fish oil has recently been shown to retard the progression of renal failure in patients with aggressive IgAGN, but a narrow therapeutic window appears to exist for this form of treatment. Antiplatelet agents on their own appear to be ineffective but in combination with anticoagulation (low dose warfarin) have been shown to have an antiproteinuric effect and may preserve renal function in patients with progressive disease. Future directions of non-immune therapy of IgAGN include evaluation of the renoprotective effect of angiotensin II receptor antagonists, free-radical scavengers and antilipid drugs. More work should also be done to identify factors which put the patients at risk of developing progressive disease and which predict therapeutic response, as has been done recently with the identification of the deletion polymorphism of the angiotensin-converting enzyme gene as a marker of progressive disease and therapeutic response to ACEI in patients with IgAGN.     

Surveillance of resistance in bacteria causing community-acquired respiratory tract infections

Bacterial resistance to antibiotics in community-acquired respiratory tract infections is a serious problem and is increasing in prevalence world-wide at an alarming rate. Streptococcus pneumoniae , one of the main organisms implicated in respiratory tract infections, has developed multiple resistance mechanisms to combat the effects of most commonly used classes of antibiotics, particularly the β -lactams (penicillin, aminopenicillins and cephalosporins) and macrolides. Furthermore, multidrug-resistant strains of S. pneumoniae have spread to all regions of the world, often via resistant genetic clones. A similar spread of resistance has been reported for other major respiratory tract pathogens, including Haemophilus influenzae , Moraxella catarrhalis and Streptococcus pyogenes . To develop and support resistance control strategies it is imperative to obtain accurate data on the prevalence, geographic distribution and antibiotic susceptibility of respiratory tract pathogens and how this relates to antibiotic prescribing patterns. In recent years, significant progress has been made in developing longitudinal national and international surveillance programs to monitor antibiotic resistance, such that the prevalence of resistance and underlying trends over time are now well documented for most parts of Europe, and many parts of Asia and the Americas. However, resistance surveillance data from parts of the developing world (regions of Central America, Africa, Asia and Central/Eastern Europe) remain poor. The quantity and quality of surveillance data is very heterogeneous; thus there is a clear need to standardize or validate the data collection, analysis and interpretative criteria used across studies. If disseminated effectively these data can be used to guide empiric antibiotic therapy, and to support—and monitor the impact of—interventions on antibiotic resistance.     

Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB

Usher syndrome is recognized as the most frequent cause of hereditary deaf-blindness. Usher syndrome type I (USH1), the most severe form of the disease, is characterized by profound congenital sensorineural deafness, constant vestibular dysfunction, and retinitis pigmentosa of prepubertal onset. This form is genetically heterogeneous and five loci (USH1A-E) have been mapped thusfar. However, only the gene responsible for USH1 B (which accounts for approximately 75% of USH1 cases) has been characterized. It encodes a long-tailed unconventional myosin, myosin VIIA, with a predicted 2215 amino acid sequence. Primers covering the complete myosin VIIA coding sequence as well as the 3' non coding sequence were designed, allowing direct sequence analysis of each of the 48 coding exons and flanking splice sites in seven patients affected by USH1. Four novel mutations were thereby identified. The possibility should now be considered of a sequence-based prenatal diagnosis in some of the families affected by this very severe form of Usher syndrome.      

Urinary tract infection withCorynebacterium urealyticum in South Africa

Corynebacterium urealyticum has been well documented as a urinary pathogen in Europe. The purpose of this study was to investigate the incidence and clinical relevance ofCorynebacterium urealyticum as a urinary pathogen in a predominantly Third World population (South Africa) and to attempt to increase the isolation rate by culturing urine specimens on a selective medium. Two methods were used to isolateCorynebacterium urealyticum from urine specimens. Blood agar plates from routine urine cultures of 7,912 urine specimens were incubated for 48 hours and 1,281 specimens were cultured on a selective medium as well as on routine media. The antimicrobial susceptibility of all isolates ofCorynebacterium urealyticum was tested. The yield ofCorynebacterium urealyticum on blood agar was three isolates in three patients (0.038% of 7,912), all of whom had pyuria, alkaline urine and risk factors forCorynebacterium urealyticum infection. Use of selective media increased the yield ofCorynebacterium urealyticum to 15 of 1,281 specimens (1.17%), however 73% of these urine samples yielded other pathogens and none had an alkaline pH which could not be attributed to the presence of another urealytic pathogen. All isolates were susceptible to vancomycin and 92.6% susceptible to norfloxacin. The pathogenic potential ofCorynebacterium urealyticum was confirmed in South African patients, but the incidence of infection was low. The use of a selective medium is therefore not cost-effective in all cases but could be used selectively on the basis of typical urine findings and patient criteria.     

Ciprofloxacin treatment failure in a patient with resistant Streptococcus pneumoniae infection following prior ciprofloxacin therapy

Reported here is the case of a patient with underlying chronic obstructive pulmonary disease (COPD) in whom ciprofloxacin treatment of a lower respiratory tract infection failed subsequent to ciprofloxacin treatment of an exacerbation of COPD several weeks earlier. During the second course of ciprofloxacin therapy, the patients condition continued to deteriorate, and she was admitted to the intensive care unit. Bilateral pneumonia was diagnosed. Streptococcus pneumoniae, serotype 11A, resistant to ciprofloxacin was isolated from the sputum. Sequencing revealed a S79F mutation in parC and there was evidence of an efflux pump. The patient improved rapidly after administration of azithromycin and ampicillin/sulbactam. This report of treatment failure due to ciprofloxacin-resistant Streptococcus pneumoniae shows that fluoroquinolones should be avoided when treating patients who have recently received this class of antibiotics.     

Sequence of the structural gene (rmpM) for the class 4 outer membrane protein of Neisseria meningitidis, homology of the protein to gonococcal protein III and Escherichia coli OmpA, and construction of meningococcal strains that lack class 4 protein

The structural gene (rmpM) of the class 4 outer membrane protein of Neisseria meningitidis has been cloned and sequenced. The derived amino acid sequence reveals a 218-amino-acid protein following a 22-amino-acid signal peptide. The protein shows 94.2% homology with protein III of Neisseria gonorrhoeae and shares its two potential disulfide loops. The protein also shares limited homology with Escherichia coli OmpA. N. gonorrhoeae protein III has been shown to elicit blocking antibodies that prevent the killing of serum-resistant strains by immune sera (P. A. Rice, H. E. Vayo, M. R. Tam, and M. S. Blake, J. Exp. Med. 164:1735-1748, 1986). The very close homology of meningococcal class 4 protein with gonococcal protein III suggests that meningococcal outer membrane preparations containing class 4 protein may similarly stimulate blocking antibodies. In order to investigate the role of the class 4 protein in the pathogenesis of meningococcal infection, we have used an erythromycin resistance gene in developing two meningococcal strains that lack class 4 protein.     

Differentiation of ischemic from non-ischemic central retinal vein occlusion during the early acute phase

We investigated prospectively in 128 patients (140 eyes) the role of six routine clinical tests in the differentiation of ischemic central retinal vein occlusion (CRVO) from non-ischemic CRVO during its early acute phase. There were fourfunctional tests [visual acuity, visual fields, relative afferent pupillary defect (RAPID), electroretinography (ERG)] and twomorphologic tests (ophthalmoscopy and fluorescein fundus angiography). We found that none of the six tests had 100% sensitivity and specificity in such a differentiation during the early, acute phase, so that no one test can be considered a gold standard; however, combined information from all six is almost always reliable. Overall, the four functional tests proved far superior to the two morphologic tests in differentiating ischemic from non-ischemic CRVO: RAPID was most reliable in uniocular CRVO (with a normal fellow eye), followed closely by ERG in all cases; combined information from RAPID and ERG differentiated 97% of cases; perimetry was the next most reliable, followed by visual acuity. The two morphologic tests performed worst; fluorescein angiography provided either no information at all on retinal capillary nonperfusion (in at least one-third of the eyes during the early, acute phase) because of multiple limitations, or sometimes provided misleading information. Ophthalmoscopic appearance is the least reliable, most misleading parameter.A preliminary summary of this was presented at the Macula Society Meeting, Cannes, France (June, 1987) and at the XVIth Meeting of the Club Jules Gonin, Bruges, Belgium, 4–8 September 1988. This investigation was supported by grant EY-1151 from the National Institutes of Health and, in part, by unrestricted grants from Research to Prevent Blindness, Inc., and from Alcon Research Institute