A novel locus for autosomal dominant, non-syndromic hearing impairment (DFNA18) maps to chromosome 3q22 immediately adjacent to the DM2 locus

Investigating a large German pedigree with non-syndromic hearing impairment of early onset and autosomal dominant mode of inheritance, linkage to known DFNA loci was excluded and in a subsequent genomic scan the phenotype was mapped to a 10-cM interval on chromosome 3q22; a maximum two-point lod score of 3.77 was obtained for the marker D3S1292. The new locus, DFNA18, is excluded from neighbouring deafness loci, DFNB15 and USH3, and it overlaps with the recently described DM2/PROMM locus. As hearing loss has been described as one feature of the PROMM phenotype, the DFNA18 gene might also be responsible for hearing loss in DM2/PROMM.     

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.     

Invasive potential of "noninvasive" human bladder carcinoma. An electron microscopy study

In classification systems for bladder tumors, a clear distinction between superficial noninvasive and urothelial carcinoma invasive to the lamina propria is of prognostic and therapeutic significance. However, a subset of tumors classified as noninvasive is characterized by increased recurrence and progression rates. This study was done to look for ultrastructural characteristics in histopathologically noninvasive urothelial bladder carcinomas that might predict an unfavorable prognosis. In 10 (83%) of 12 bladder tumors studied extensively, electron microscopy revealed the presence of different degrees of lamina propria penetration by individual tumor cells (microlesions and microinvasions). In 10 (77%) of 13 "normal" control tissues, no such lesions or microinvasions were detected. These findings indicate that ultrastructural analysis may contribute to more precise staging of superficial bladder carcinoma. Undetected microinvasions may explain more aggressive biologic behavior in a subset of bladder tumors classified as noninvasive by conventional histopathologic assessment.     

Contrast rectification and distributed encoding By ON-OFF amacrine cells in the retina.

The encoding of luminance contrast by ON-OFF amacrine cells was investigated by intracellular recording in the retina of the tiger salamander (Ambystoma tigrinum). Contrast flashes of positive and negative polarity were applied at the center of the receptive field while the entire retina was light adapted to a background field of 20 cd/m(2). Many amacrine cells showed remarkably high contrast gain: Up to 20-35% of the maximum response was evoked by a contrast step of only 1%. In the larger signal domain, C50, the contrast required to evoke a response 50% of the maximum, was often remarkably low: 24 of 25 cells had a C50 value of < or =10% for at least one contrast polarity. Across cells and contrast polarity, the dynamic ranges varied from extremely narrow to broad, thereby blanketing the range of reflectances associated with objects in natural environments. Although some cells resembled "contrast rectifiers," by showing similar responses to contrasts of opposite polarity, many did not. Thus for contrast gain and C50, individual cells could show a strong preference for either negative or positive contrast. In the time domain, the preference was strong and unidirectional: for equal contrast steps, the latency of the response to negative contrast was 20-45 ms shorter than that for positive contrast. The present results, when compared with those for bipolar cells, suggest that, on average, amacrine cells add some amplification, particularly for negative contrast, to the high contrast gain already established by bipolar cells. In the time domain, our data reveal a striking transformation from bipolar to amacrine cells in favor of negative contrast. These and further observations have implications for the input and output of amacrine cell circuits. The present finding of substantial differences between cells reveals a potential substrate for distributed encoding of luminance contrast within the ON-OFF amacrine cell population.     

Morphological evidence of reduced bone resorption in the osteosclerotic (oc) mouse

Osteopetrosis, a metabolic bone disease characterized by a generalized sclerosis of the skeleton, is inherited as an autosomal recessive in a number of mammalian species. The pathogenesis of congenital osteopetrosis is mediated by a reduction in bone resorption as a result of decreased osteoclast function. This hypothesis is based on both functional and structural evidence of reduced bone resorption in all mutations examined to date. The present study examined the histology of cartilage and bone, the ultrastructure of osteoclasts, and the morphology of mineralized bone surfaces in a lethal osteopetrotic mutation, the osteosclerotic (oc) mouse. Histologically, epiphyseal cartilage growth plates, especially the hypertrophic zone, are markedly thickened in oc mice and metaphyses contain excessive osteoid, features characteristic of rickets. Transmission electron microscopy revealed that less than one-quarter of osteoclasts in oc mice demonstrated evidence of ruffled border formation compared with three-quarters of the osteoclasts in normal littermates. In mutants, ruffled borders were less elaborate and cytoplasmic processes penetrated into bone surfaces, suggesting that bone may be removed by mechanical rather than by enzymatic means. There was little morphological evidence of cartilage degradation and broad laminae limitantes persisted in mutants. Mineralized surfaces that undergo resorption in normal mice showed no evidence of bone resorption by scanning EM in mutants. The presence of a rachitic condition, the observations of reduced bone resorption, and the possible contribution of undermineralized matrices to decreased bone resorption are charcteristics of the osteosclerotic mutation which suggest that it is a unqiue csteopetrotic mutant in which to study both the development and regulation of skeletal metabolism.     

Identification of a major antigenic epitope on CNBr-fragment 11 of type II collagen recognized by murine autoreactive B cells.

Immunization of certain strains of mice with native type II collagen (CII) induces both development of arthritis and an antibody response to autologous CII. The autoantibody response in a high-responder strain, the DBA/1 mouse, has been described earlier, and a number of monoclonal antibodies have been characterized for arthritogenicity and autoreactive binding to cartilage in vivo and in vitro. Here we map the antigenic epitope of one of these arthritogenic monoclonal antibodies (CII-C1). It belongs to a group of antibodies recognizing the CNBr fragment alpha 1(II)-CB11 of CII. Using the enzyme-linked immunosorbent assay technique, we show that the antibody reacts only with native, triplehelical CII, but not with other collagens. The antibody is able to stain specifically the CB11 fragment by immunoblotting, suggesting some partial renaturation of the CNBr fragment into triple-helical structures after blotting. The binding site of CII-C1 on CB11 was further focused by rotary shadowing of antibody-labeled CII to a site 89 +/- 8 nm from the amino end of CII, corresponding to the middle of CB11. This location was confirmed by cleavage of CB11 with trypsin, separation of the tryptic peptides by high-performance liquid chromatography and dot-blot analysis of the antigenic peptides with the CII-C1 antibody. Sequencing of the single positive peptide located the antigenic epitope within the sequence GFAGQAGPAGATGAPGRP (residues 316-333). Assuming 0.29 nm per residue, this corresponds to a position within 92-96.5 nm from NH2 terminal end of CII. Apart from glycine residues, which are not exposed on the triple-helical structure, only two amino acid residues (F-x-y-Q) are conserved in CII from different species but are not found in the triple-helix of other collagens except type IV collagen. Therefore, this structure is likely to be of critical importance for the binding of the CII-C1 antibody. Of potential importance is that this structure is also found in certain other arthritogenic proteins such as 65-kDa mycobacterial protein, in CMV and EBV.     

Terpene hydrocarbons in Pimpinella anisum L.

The essential oil of anise (fruits and shoots) was investigated focusing on the composition of the hydrocarbon fraction. Several sesquiterpenes were identified by GC-MS and the relative composition of the fractions was established by GC analysis. -Himachalene and the diterpene neophytadiene were isolated by TLC and column chromatography at low temperatures. Their structures were determined by MS and NMR including¹H-¹H correlated COSY and NOE experiments.     

COVID-19 in pediatric kidney transplantation: The Improving Renal Outcomes Collaborative

There are limited data on the impact of COVID-19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID-19 in pediatric KT patients. Twenty-two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS-CoV-2 by PCR. Testing indications included symptoms and/or potential exposures to COVID-19 (N = 134, 47.7%) and/or testing per hospital policy (N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID-19-positive patients, 16 were managed as outpatients, six received non-ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID-19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID-19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID-19 disease and excellent short-term outcomes.     

The regional registry of gastro-intestinal cancer North Baden (2.2 million inhabitants)

Summary The advantages of a population-based registry are discussed. It is shown that a registry for gastro-intestinal cancer in a district with expert medical care based upon histo-pathological diagnosis, has the principal advantage that it limits the sites of material collection to a few effective contributors, thus providing highly accurate data. The disadvantage of collecting data by two separate steps should be tolerated. The geographic situation and the organization of the regional registry for gastro-intestinal cancer in North Baden are described and the incidences for these cancers for the years 1971–1975 are given for the population of 2.2 million.Supported by the DFG (SFB 136)