[Management of Primary Ciliary Dyskinesia]. / Management der Primären Ciliären Dyskinesie.

Primary Ciliary Dyskinesia (PCD, MIM 242650) is a rare, hereditary multiorgan disease characterized by malfunction of motile cilia. Hallmark symptom is a chronic airway infection due to mucostasis leading to irreversible lung damage that may progress to respiratory failure. There is no cure for this genetic disease and evidence-based treatment is limited. Until recently, there were no randomized controlled trials performed in PCD, but this year, data of the first placebo-controlled trial on pharmacotherapy in PCD were published. This cornerstone in the management of PCD was decisive for reviewing currently used treatment strategies. This article is a consensus of patient representatives and clinicians, which are highly experienced in care of PCD-patients and provides an overview of the management of PCD. Treatments are mainly based on expert opinions, personal experiences, or are deduced from other lung diseases, notably cystic fibrosis (CF), COPD or bronchiectasis. Most strategies focus on routine airway clearance and treatment of recurrent respiratory tract infections. Non-respiratory symptoms are treated organ specific. To generate further evidence-based knowledge, other projects are under way, e. g. the International PCD-Registry. Participating in patient registries facilitates access to clinical and research studies and strengthens networks between centers. In addition, knowledge of genotype-specific course of the disease will offer the opportunity to further improve and individualize patient care.

Light-induced cross-linking and post-cross-linking modification of polyglycidol.

The photoinduced radical generation process has received renewed interest due to its economic and ecological appeal. Herein the light-induced cross-linking of functional polyglycidol and its post-cross-linking modification are presented. Linear polyglycidol was first functionalized with a tertiary amine in a two-step reaction. Dimethylaminopropyl functional polyglycidol was cross-linked in a UV-light mediated reaction with camphorquinone as a type II photoinitiator. The cross-linked polyglycidol was further functionalized by quaternization with various organoiodine compounds. Aqueous dispersions of the cross-linked polymers were investigated by means of DLS and zeta potential measurements. Polymer films were evaluated by DSC and XPS.

A chlorhexidine-releasing epoxy-based coating on titanium implants prevents Staphylococcus aureus experimental biomaterial-associated infection.

Prevention of biomaterial-associated infections (BAI) remains a challenging problem, in particular due to the increased risk of resistance development with the current antibiotic-based strategies. Metallic orthopaedic devices, such as non-cemented implants, are often inserted under high mechanical stress. These non-cemented implants cannot be protected by e.g. antibioticreleasing bone cement or other antimicrobial approaches, such as the use of bioactive glass. Therefore, in order to avoid abrasion during implantation procedures, we developed an antimicrobial coating with great mechanical stability for orthopaedic implants, to prevent Staphylococcus aureus BAI. We incorporated 5 and 10 wt % chlorhexidine in a novel mechanically stable epoxy-based coating, designated CHX5 and CHX10, respectively. The coatings displayed potent bactericidal activity in vitro against S. aureus, with over 80 % of the release (19 µg/cm2 for CHX5 and 41 µg/cm2 for CHX10) occurring within the first 24 h. In mice, the CHX10 coating significantly reduced the number of CFU (colony forming units), both on the implants and in the peri-implant tissues, 1 d after S. aureus challenge. The CHX10-coated implants were well-tolerated by the animals, with no signs of toxicity observed by histological analysis. Moreover, the coating significantly reduced the frequency of culture-positive tissues 1 d, and of culture-positive implants 1 and 4 d after challenge. In summary, the chlorhexidine-releasing mechanically stable epoxy-based CHX10 coating prevented implant colonisation and S. aureus BAI in mice and has good prospects for clinical development.

[Tumor of the mesosalpinx with unclear differentiation]. / Tumor der Mesosalpinx mit unklarer Differenzierung.

Female adnexal tumors of probable Wolffian origin (FATWO) are rare tumors, which are mostly localized in the broad ligament or the mesosalpinx. They show high intratumor and intertumor variability of histological patterns (e.g. solid, tubular, cribriform and cystic) with usually unremarkable cellular and nuclear morphology and a lower mitotic rate. In general, they behave in a benign fashion but there are rare cases with malignant transformation, so that careful examination and surveillance are necessary. Differential diagnoses include Sertoli-Leydig cell tumors, metastasized endometrioid carcinoma and the FATWO-like variant of the endometrioid carcinoma of the fallopian tubes. The FATWOs express pancytokeratin, CD10, vimentin, calretinin and inhibin A. Estrogen and progesterone receptors are expressed in a minority of cases, whereas epithelial membrane antigen (EMA) is not detectable.

Polyglycidol-based metal adhesion promoters.

Hydrophilic adhesion promoters that facilitate intimate binding between metals and polymers are an important class of materials with a wide variety of applications in biomedical coatings. Currently, non-poly(meth-)acrylate based hydrophilic polymeric adhesives are unavailable. Here, we report the preparation of such adhesion-promoters based on linear polyglycidol for biomedical applications. The adhesion promoting polymer is prepared from partly phosphonoethylated polyglycidol in three steps. First, the remaining hydroxyl groups of the polyglycidol backbone are reacted with acryloyl chloride; secondly, the phosphonate groups are chemoselectively dealkylated using bromotrimethylsilane. Finally, the bis(trimethylsilyl)phosphonate intermediate is converted to the phosphonic acid through ethanolysis. The reaction conditions of each synthetic step are optimized individually and the products are characterized by 1H, 31P NMR and SEC analysis. The optimized reaction conditions are applied to establish a straightforward one-pot reaction, resulting in an ethanolic formulation of the adhesion promoter, which can be used immediately for the coating application. Special attention is paid to the stability of the intermediates, the chemoselectivity of the reactions and the shelf-life of the product. 1H NMR spectroscopy reveals hydrolytic instability of the product under ambient conditions; however, the polymers are sufficiently stable in dry ethanol for at least 14 days. The combination of this hydrophilic polymer with acrylate and phosphonic acid groups constitutes a versatile platform technology for the preparation of thin primer coatings on metal substrates for biomedical applications. The phosphonic acid residues assure strong binding to stainless steel wires and the acrylates can be addressed by UV light to enable crosslinking, thus improving mechanical stability and adhesion between the substrate and a biomedical hydrogel coating. The quality of the adhesion promotion to stainless steel wires is verified by using a lubricious, hydrogel top coat and by evaluating friction and wear resistance of this total coating system. Constant values for friction and wear are obtained, proving the applicability of phosphonic acid-functionalized polyglycidols as metal adhesion promoters for biomedical applications.

Blending of reactive prepolymers to control the morphology and polarity of polyglycidol based microgels.

The compartmentalization of microgels is a challenging task for synthetic polymer chemistry. Although the complexation with low molecular weight compounds or the use of microfluidic techniques offer attractive possibilities for other length scales, it is difficult to implement compartments in the mesoscale range of 10-100 nm. Herein we show how simple blending of reactive prepolymers is suitable to design new microgel morphologies with tailored compartments. We use poly(EEGE)-block-poly(AGE) as crosslinkable, pro-hydrophilic prepolymer in blends with varying amounts of crosslinkable, yet hydrophobic poly(THF-stat-AllylEHO) or inert and hydrophobic polystyrene, and crosslink the allyl functional prepolymer(s) in a thiol-ene click-type reaction after miniemulsification. Our strategy shows how arrested versus free nanophase separation can be used to control easily the morphology and polarity of microgel particles.

Domain sizes in heterogeneous polymers by spin diffusion using single-quantum and double-quantum dipolar filters.

1H spin-diffusion experiments employing a double-quantum (DQ) dipolar filter were performed for the characterization of the microdomain structure of heterogeneous samples. For this purpose the NMR spin-diffusion process was analysed based on a model morphology of three different domains with arbitrary sizes, diffusivities, and filter efficiency. General analytical solutions for z magnetization source and sink were obtained valid for a one-dimensional lamellar morphology in the full range of spin-diffusion times. These solutions of the spin-diffusion equations were used for determining the crystalline, interface, and amorphous domain sizes in polystyrene-poly(ethylene oxide) (PS-PEO) and poly(hydroxyethylmethacrylate)-poly(ethylene oxide) (PHEMA-PEO). The DQ dipolar filter has a good efficiency for PS-PEO but is only partially efficient in filtering the signal of the mobile domains in the PHEMA-PEO diblock copolymer. The domain sizes measured by the DQ filter method are compared to those obtained using the traditional dipolar filter creating z magnetization in the mobile domains.

Postulation of the mechanism of the selective synthesis of isotactic poly(methyl methacrylate) catalysed by [Zr[(Cp)(Ind)CMe2](Me)(thf)](BPh4): a Hartree-Fock, MP2 and density functional study.

The bridged. C1-symmetric, single-component zirconocene [Zr((Cp)(Ind)CMe2](Me)(thf)](BPh4) (Ind = indenyl, Cp = cyclopentadienyl) polymerises methyl methacrylate (MMA) selectively to isotactic poly(methyl methacrylate) (PMMA) without further cocatalysts or activators. To elucidate the stereoselective steps of the polymerisation of MMA by using this catalyst we studied the propagation steps occurring with the derivative [Zr[(Cp)(Ind)CH2][-O-C(OMe)=C(Me)(Et)](MMA)]+ by ab initio calculations at the Hartree-Fock(HF) level of theory. After the initiation step, which consumes the first two MMA molecules, each new catalytic cycle begins with the stereoselective addition of a new MMA molecule at the indenyl side of the zirconocene fragment. At the same time the enolate ring undergoes a stereoselective in-plane ring shift to the side opposite to the indenyl ring. These findings are used to postulate a mechanism for the polymerisation that explains the stereoselective synthesis of isotactic PMMA.

Impact of disseminated Mycobacterium avium-complex infection on survival of HIV-infected patients.

OBJECTIVE: To determine the frequency of disseminated Mycobacterium avium-complex infections (MAC) and the impact of MAC disease on overall survival in patients with HIV disease and AIDS. METHODS: Prospective study of HIV infected patients with a CD4 lymphocyte count < 150/microliter or patients with AIDS over a 7-year period. Blood cultures of all patients presenting symptoms and signs suggestive of disseminated MAC infection were grown. Only patients who deceased at our clinic (n = 427) were included in the final analysis in order to calculate MAC disease-free survival and overall survival after first CD4 lymphocyte count < 100/microliter. RESULTS: 101 out of 427 patients (24%) developed disseminated MAC disease: The median time between first CD4 lymphocyte count < 100/microliter and MAC disease was 441 days (range 16 to 1560). The actuarial risk of MAC disease for the entire patient population was 12%, 28%, and 42% after 1, 2, and 3 years, respectively. When comparing overall survival after first CD4 lymphocyte count < 100/microliter, there was no statistically significant difference between patients who subsequently developed disseminated MAC infection and those who did not. CONCLUSION: MAC disease is a very frequent opportunistic infection in advanced AIDS, mostly in patients with less than 50 CD4 cells/microliter. In contrast to reports from the US, only 24% of our patients developed MAC disease. Survival time between patients with and without MAC infection did not differ.

Estimation of the proliferative activity of human breast cancer tissue by means of the Ki-67 and MIB-1 antibodies--comparative studies on frozen and paraffin sections.

The estimation of the Ki-67 index in human breast cancer tissue has been proven to be a useful prognostic tool. The examination can be performed, however, only on frozen sections (FS). The development of an antibody directed against parts of the Ki-67 antigen (MIB-1) has opened a new route to determine the proliferative activity on paraffin sections (PS). MIB-1 immunohistochemistry is used instead of Ki-67 immunohistochemistry if a tumour is delivered to the pathologist after formalin fixation or if that part of the tissue suspicious for breast cancer must be totally embedded in order to confirm the diagnosis. The present study compares the findings of Ki-67 (FS) and MIB-1 (FS and PS) immunohistochemistry in a total of 544 cases of human breast cancer. The findings confirm a good statistical correlation between the Ki-67 and the MIB-1 findings. The MIB-1 results are 2-2.5 times higher in FS than in PS. Good agreement exists between the Ki-67 indices determined on FS and the MIB-1 indices determined on PS. If the cut-off value for the separation of Ki-67 negative and positive cases is defined as 10%-20%, a MIB-1 index in PS of 10% permits the correct prediction of a negative Ki-67 index in 97% of the cases, and a MIB-1 index of 30% or more correctly predicts a positive Ki-67 index in 90% or more of the cases. Hence, the determination of the MIB-1 index on PS may replace the determination of the Ki-67 index on FS with a high degree of probability.

Preliminary results of an interdisciplinary survey of drug victims.

In an interdisciplinary study, 53 cases of drug-related death were investigated. Forty per cent of these cases exhibited acute or chronic hepatitis; foreign body granulomas were detected in 30%. By CT-scan of the left lung, small abscesses and pneumonic focuses could be localized. The spectrum of bacterial strains isolated from lung tissue did not differ significantly from that of a control group. Severe alterations of the testes, i.e. reduction of spermatogenesis, was present in a considerable number of cases. The high rate of myocarditis diagnosed (18%) supports the idea that besides acute intoxication, drug-related death is due to multifactorial origin.

[Epidemiology of tuberculosis in patients with HIV infection of the Frankfurt University Clinic]. / Epidemiologie der Tuberkulose bei Patienten mit HIV-Infektion der Universitätsklinik Frankfurt.

Frequency and risk of tuberculosis were studied among a large group of HIV-infected patients (n = 2556), 869 of whom had AIDS, over a period of ten years (February 1982 through February 1992) at the University Hospital Frankfurt. A total of 148 (5.8%) out of 2.556 patients had tuberculosis. With increasing immunodeficiency, the frequency of tuberculosis rose. The rate of tuberculosis in post-mortem was even higher, i.e. 17.3%. I.v. drug-addict AIDS patients were inflicted with 18.5% considerably more often than homo-/bisexual patients with 12.3%. The same holds true with 25% of tuberculosis infections for AIDS patients from endemic areas as compared with 13% for patients from countries with lower tuberculosis incidence. 18% of patients contracted tuberculosis already at > 200 CD4-positive cells/microliters before AIDS manifestation. Coming from endemic areas, drug addiction and lower number of T-cells signify a high risk for HIV-infected patients to acquire a post-primary or primary tuberculosis, respectively. HIV-infected patients represent a relevant danger of infection for partners and health-care personnel. In contrast to the United States, no increase in the tuberculosis incidence, except for some areas like Frankfurt, has been noted. Preventive measures, which include the IHN prophylaxis for patients with T-cell counts < 150/microliters, should be discussed.

A word of caution: reopening chronic coronary occlusions.

Reopening of chronically occluded coronary arteries by angioplasty, initially considered a low risk procedure, may carry similar risks at PTCA of coronary stenoses. We report 3 cases with ventricular fibrillation or sudden death 2-4 days after reopening of 1- to 5-month-old coronary occlusions.

Rapid development of giant aneurysm at the base of the brain in an 8-year-old boy with perinatal HIV infection.

An 8-year-old boy with perinatal HIV infection developed a large fusiform aneurysm in the circle of Willis two years prior to death which was confirmed by radiological studies. The postmortem examinations revealed a predominantly intimal, proliferative lesion, and partial destruction of the internal elastic lamina in the involved arteries. Within the intima hyperplasia of fibroblasts and smooth muscle cells was observed. No inflammatory alterations, no granulomas and no multinucleated giant cells could be noted in the vascular walls and in the cerebral parenchyma. A small ischemic infarct was present in the left thalamus. Cerebellum, brainstem and medulla showed multiple areas of progressive multifocal leukoencephalopathy (PML). Immunohistochemistry with anti-gp41, a monoclonal antibody against HIV envelope did not exhibit any positive results. These findings implicate that the vascular lesion might be attributed to primary infection of the brain by HIV which led to a defect of elastic lamina and consecutive intimal hyperplasia. A second hypothesis could be based on the effect of extremely high dose AZT therapy avoiding inflammatory reaction after HIV infection.

[Morphology of pulmonary complications in AIDS--a study of 208 biopsy and 231 autopsy cases]. / Morphologie pulmonaler Komplikationen bei AIDS--Eine Untersuchung an 208 Biopsie- und 231 Autopsiefällen.

In AIDS patients infectious pulmonary complications may very frequently be demonstrated by both biopsy and autopsy. Bacterial pneumonias occur much more frequently than classic opportunistic infections, e.g. P. carinii pneumonia. Usually, several complications are present concomitantly which impairs diagnosis as well as therapy. Increased survival and modern therapeutic modalities change the spectrum of AIDS-associated pulmonary complications as well as their morphology. In the present study pulmonary complications are directly responsible for the patients' death in more than 70% of the cases.

[The effect of electromagnetically produced shock waves on calcified, stenosed aortic valves]. / Der Effekt elektromagnetisch erzeugter Stosswellen auf verkalkte, stenosierte Aortenklappen.

To determine if electromagnetically generated shock-wave lithotripsy has potential application for treatment of stenotic, calcified aortic valves, 38 cusps of surgically excised human aortic valves were studied. Valves were weighed, photographed, and calcium deposition was determined by x-ray. Stiffness was determined by palpation and by measuring the pressure gradient generated in a perfusion system. Valves were exposed to shock waves at 16 or 18 kV with 200 or 400 impulses each. Twenty valves reacted to exposure to shock waves with a reduction in pressure gradient of 1.9 +/- 2 cm H2O. Calcified valve area was reduced by 3.5 +/- 1.3 mm2. Valves without changes in pressure gradient showed a reduction of 7.1 +/- 2 mm2 of calcified valve area. There was no significant difference in weight loss. Using a small focus (4 mm) there was a significant reduction in pressure gradient and calcified valve area, but not in weight; with a large focus (8 mm) reduction in calcified valve area, gradient, and weight was significant (p less than 0.05). Changes in valve stiffness were independent of weight loss and reduction in calcified valve area. In conclusion, shock-wave lithotripsy is capable of reducing stiffness of calcified aortic valves, presumably by fragmentation of tissue calcium deposits.

[The morphology and clinical significance of pathologic changes of the adrenals and hypophysis in AIDS]. / Morphologie und klinische Bedeutung pathologischer Veränderungen an Nebennieren und Hypophyse bei AIDS.

A semiquantitative morphometric technique (point counting) was applied to the pituitary and adrenals taken at necropsy from 130 AIDS patients (4 women, 126 men, mean age 39 [22-71] years) to ascertain the nature, extent and location of the pathological lesions. Abnormalities were found in 32% of the pituitaries and 76% of the adrenals. Only 17 patients had normal findings in both organs. The predominant lesions were due to opportunistic infections or infiltration by Kaposi's sarcoma or non-Hodgkin lymphoma. The commonest finding was necrotizing cytomegalovirus adrenalitis (n = 68); in one third of the cases this had caused severe destructive lesions involving over 50% of the parenchyma. The almost total destruction of the adrenals noted in some cases suggests that cytomegalovirus adrenalitis may run a progressive course; its clinical significance has hitherto been underestimated.