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Background: There is limited data on the number and distribution of academically qualified professionals in the field of Public Health at the lower level of health authorities. The aim of this study was to analyze the distribution of Public Health Professionals in Public Health Authorities in Germany., Method: An online survey was conducted with the directors of the 376 German Public Health Authorities regarding the presence of Public Health Professionals and their views on personnel needs. The term Public Health Professionals was operationalized. The survey took place starting in 06/2023 over a period of 14 weeks. The results were descriptively analyzed., Results: The participation rate in the survey was 40.4% (n=152). On average, the participating Public Health Authorities employed 2.6 (SD 3.85, MD 2) Public Health Professionals. 28.3% (n=43) of directors reported not employing any Public Health Professionals. 78.3% (n=119) of the leadership reported needing more staff. Additionally, 65.1% (n=99) expressed the need for more personnel with a degree or those with additional training in the field of Public Health., Conclusion: Personnel from the field of Public Health are not yet represented in all Public Health Authorities in Germany. Both the distribution of Public Health Professionals in the participating Public Health Authorities and the views of the department heads regarding the needs of this professional group in their own Public Health Authorities are heterogeneous. In summary, there is a clear need to strengthen collaboration between academic Public Health Professionals and the Public Health Authorities., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: To contain the coronavirus disease (COVID-19) pandemic, public life was reduced through contact restriction measures (referred to as "lockdown" in the further course for reading simplicity), among other things to make health system resources available for the treatment of COVID-19 patients. In parallel, a decrease in emergency patients was observed in the public health system., Methods: For two 10-week periods before and during the lockdown, ambulance service deployment rates were analysed in 6 ambulance service areas for 6 tracer diagnoses. Random effects were minimised by comparing the results with the corresponding 2018 and 2019 time periods and a calculated expected value., Results: For emergency ambulance service calls, there was a reduction in call numbers (-16%) during the lockdown. A 20% reduction for the categories cardiac and cerebral ischaemia was found. In the urban area, the reduction in cardiac ischaemia was less pronounced at 14% than in the surrounding area at 23%. The deployment figures for intoxications decreased by 27% and for psychiatric emergencies by 16%., Conclusion: The public ambulance service was not overwhelmed by the COVID-19 pandemic; there was a decrease in depolyments during the lockdown. For the reduction in cerebral or cardiac ischaemias, the explanatory models for the influence of the lockdown are missing. Further studies on the utilisation behaviour of the ambulance service during a lockdown appear necessary in order to detect potentially fatal reductions in utilisation for the patient outcome and to be able to counteract them through education., (© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2021.)

The introduction of requirements for a minimum intake capacity of trauma patients by the German Trauma Society (DGU) into the so-called white book of treatment of seriously injured patients, is helpful for a sufficient preparation for threats and for dealing with mass casualties for trauma centers as well as for the emergency medical services (EMS). In the hospital information database provided by the Federation of German Medical Directors of Emergency Medical Services, more than 1300 hospitals are currently listed. This information supports the allocation of trauma patients from the field to the appropriate trauma center. Currently, without any coordination requirements, the current 626 trauma centers in Germany are able to immediately handle 6260 patients. This number could be doubled by activating the local hospital action plan, where a priority plan is set up. Additionally, the implementation of a nationwide flexible standardized communication structure between the dispatch center of the ambulance service and the hospitals, would improve daily care as well as the management of threats and mass casualties. It is the obligation of the local medical director of the EMS, to maintain and update the hospital database. Providing the information in the database with the hospital resources and the flexible standard communication structure, is appropriate to improve the daily collaboration and the preparation for mass casualties.

Background: Previous studies have suggested that when using several emergency systems and air rescue prehospital and on-scene times are extended, depending on the dispatch strategy. Emergency medical services (EMS) in Germany are delivered by ambulances (AMB) staffed by paramedics alone or with physicians (EMD) and by helicopter emergency medical services (HEMS) always staffed by both. The advantages of HEMS in countries with short transport distances and high hospital density are controversial. The best dispatching strategy for HEMS has not been determined, Objective: The BoLuS study in the German state of Hessen was designed to evaluate the influence of dispatch strategy on prehospital times for responses involving both HEMS and EMS., Methods: Rescue responses involving HEMS were prospectively evaluated in 12 regions of Hessen from July 2010 to September 2011. Although all regions had access to HEMS, only one had its own service. Data from both central dispatch centers and helicopter services were collected and combined to calculate the on-scene time (OST) and correlate it with dispatch strategy., Results: A total of 2111 emergency interventions were evaluated. Internal medicine emergencies accounted for 42.9 % of cases and trauma for 36.7 %. Just one patient was involved in 87.9 % of rescues. Two services were involved in 65.3 % of rescues and three or more in 31.5 %. The most common dispatch categories were initial dispatch of EMS and HEMS (50.6 %), initial dispatch of EMS with later request for HEMS (19.7 %) and initial dispatch of both EMS and EMD with later request for HEMS (17.4 %). The OST for these categories were 31.0 ± 13.7 min, 43.7 ± 16.2 min and 54.6 ± 21.3 min (p < 0.01), respectively., Conclusion: OST varies significantly depending on the number of EMS involved and the dispatch strategy. Sequential dispatching of ground and later HEMS wastes time. Getting an emergency physician to the scene as quickly as possible, reducing transport time to an appropriate hospital and caring for more complex emergencies are the main indications for HEMS. If HEMS appears likely to be needed, it should be dispatched immediately.

Neurokinin A (NKA) causes bronchoconstriction in asthmatic patients. In vitro both NK1 and NK2 receptors can mediate airway contraction. Moreover in guinea pigs, NK3 receptors facilitate cholinergic neurotransmission. Dual tachykinin NK1/NK2 receptor antagonism results in prevention of NKA-induced bronchoconstriction. We have now examined the effect of a single dose of the triple tachykinin receptor antagonist CS-003 on NKA-induced bronchoconstriction in asthmatics. A double blind, crossover, placebo-controlled trial in 16 mild asthmatics was performed. One single dose of CS-003 (200 mg, solution in distilled water) or matched placebo was given orally on the assessment days. NKA-provocation tests were performed pre-dose and 1, 8 and 24 h after dosing. There was a significant shift to the right of the dose-response curve at 1 and 8 h after intake of CS-003. PC20 was not reached in 12/16 patients at 1h post-dose and in 5/16 patients at 8 h post-dose. This did not occur under placebo treatment. A single dose of 200 mg CS-003 protected significantly against NKA-induced bronchoconstriction at 1 and 8h post-dose in mild asthmatics.

Methicillin-resistant Staphylococcus aureus (MRSA) strains may cause serious nosocomial infections, including pneumonia and septicemia. The rate of methicillin-resistance among S. aureus isolates in Korea is over 50%. In this study, 90 MRSA isolates from Kyung Hee University Hospital were characterized employing bacteriophage typing, pulsed-field gel electrophoresis (PFGE), and antimicrobial susceptibility testing. Eighty percent of the strains could be phage-typed. The largest group or 40% of the strains belonged to lyso group III, followed by 32% of the isolates which produced a reaction with regional additional phages. Phage type 83A was most frequently encountered, followed by phage type D11. PFGE patterns confirmed the presence of two major clusters, which comprise the isolates belonging to lyso group III and the strains that were typable with regional additional phages. The latter group also contained a number of strains that were nontypable with bacteriophages. The resistance rates to ciprofloxacin, erythromycin, tetracycline, gentamicin and clindamycin were over 94%. Strains with intermediate resistance to vancomycin strains or resistance to mupirocin were not found. In conclusion, this study demonstrates that the results of phage typing are confirmed and supplemented by PFGE data.

There is an increasing interest in the role of coagulation factor XIII (FXIII) in cardio- and cerebrovascular diseases. It has recently been reported that a common G-->T point mutation in the A-subunit gene of FXIII, which codes for a valine (val) to leucine (leu) change (FXIIIVal34Leu), is protective against thrombotic diseases but seems to increase the risk of intracerebral bleeding. We developed a colorimetric incorporation assay for detection of FXIII activity based on incorporation of 5-(biotinamido) pentylamine (BAPA) into fibrin or fibrinogen. With this new assay, we studied the effects of FXIIIVal34Leu mutation, plasma fibrinogen concentration and congenital FXIII deficiency on FXIII activity. There are no data available about the ability of different FXIII assays to detect altered activity in FXIIIVal34Leu genotypes. We therefore compared our results determined by the incorporation method with a commonly used photometric method based on ammonia release after cross-linking of glycine-ethylester to a specific glutamine containing peptide substrate. We also determined FXIII A-subunit antigen (Ag) levels using enzyme-linked immunosorbent assay (ELISA) technique. The FXIIIVal34Leu genotype could not be detected either by the photometric method nor by the FXIII A-subunit ELISA. The incorporation assay showed an increased specific FXIII activity in subjects possessing the leu allele. The photometric assay and ELISA gave similar results independent from genotype. In patients with congenital FXIII deficiency before and after substitution, however, ELISA and the incorporation assay gave similar results, whereas the photometric assay showed consistently higher values. Our results show that the incorporation assay, not the photometric assay based on ammonia release, can be used for detection of elevated activity in subjects with FXIIIVal34Leu. Because of specificity and over a wide range sensitivity, the assay can also be used for determination of FXIII deficiency and monitoring of FXIII substitution therapy.

Nitric oxide (NO) is a reactive endogenous molecule with multiple functions and its cellular signaling activity is mainly mediated by activation of the soluble isoform of guanylyl cyclase, a heterodimeric (alpha/beta) hemeprotein. The expression of the NO-sensitive soluble isoform of guanylyl cyclase was studied in various cultured melanocytic cells by measuring the accumulation of guanosine 3',5'-cyclic monophosphate in the presence and absence of NO donors. Here we report that 3-morpholino-sydnonimine, a donor of NO redox species, and (Z)-1-[2- (2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, a direct NO donor, induced a 20-fold increase in intracellular guanosine 3',5'-cyclic monophosphate in nonmetastatic melanoma cells and normal melanocytes in culture that could be related to cellular melanin content in a concentration-dependent manner. The increased intracellular guanosine 3',5'-cyclic monophosphate was due to stimulation of the activity of soluble guanylyl cyclase as such increase was completely abolished by using a specific inhibitor of soluble guanylyl cyclase. The involvement of functional soluble guanylyl cyclase was further confirmed by the presence of alpha1 and beta1 subunits in these cells at both mRNA and protein levels. In contrast, none of the NO donors induced guanosine 3',5'-cyclic monophosphate production in metastatic melanoma cells, which could be attributed to the absence of the beta1 subunit that is essential for catalytic activity of the soluble isoform of guanylyl cyclase. Metastatic melanoma cells produced higher levels of intracellular guanosine 3',5'-cyclic monophosphate in response to natriuretic peptides than other cell types, however, due to upregulation of membrane-bound guanylyl cyclase activities, but they are less pigmented or unpigmented. The present finding suggests that NO signaling in association with melanogenesis is dependent on the soluble isoform of guanylyl cyclase, whereas absence of soluble guanylyl cyclase but the presence of membrane-bound guanylyl cyclase correlates with the metastatic behavior of melanoma cells.

Methicillin resistant Staphylococcus aureus-strains, isolated from 1994 to 1997 from patients of the traumatic surgery hospital Tübingen, were compared using lysotyping and pulsed-field gel electrophoresis. Both typing methods detected two clones causing an outbreak 1994 in 6 patients and a third endemic clone of MRSA, which was isolated from 5 patients (1995), 4 patients (1996), and 6 patients (1997). Additionally other MRSA-types were found in 6 cases of which transmissions occurred in up to three patients. An epidemiological connection to MRSA isolated from patients of the university hospital of Tübingen was made. Possible consequences for patient management and antibiotic strategies in MRSA-infections were discussed.

A total of 457 Staphylococcus aureus strains from the culture collection of the National Reference Center for Staphylococci in Bonn, Germany, were screened for susceptibility to vancomycin because some Staphylococcus aureus strains are able to form subpopulations that show intermediate resistance to vancomycin. Two methicillin-resistant Staphylococcus aureus strains (isolated in 1993) exhibited intermediate resistance. One of these, Staphylococcus aureus 137-93, which displayed the genomic DNA fragment pattern of the northern German epidemic strain, appeared homogeneously resistant. Neither of these strains had been identified by routine susceptibility testing. The resistance of the German isolates was lower than that of the Japanese isolate Mu50. To determine whether a similar mechanism confers vancomycin resistance in Staphylococcus aureus Mu50 and 137-93, the intracellular cell wall precursor concentration was measured and was not found to be comparably increased in Staphylococcus aureus 137-93. In conclusion, strains showing intermediate resistance have been present in Germany for some time (at least since 1993), but the subpopulations with decreased sensitivity were overlooked during antibiotic susceptibility testing.

An 18-year-old Japanese boy and a 10-year-old Chinese boy both had nearly complete cutaneous syndactyly of the fingers and toes, six diphalangeal fingers on each hand, six toes on each foot (except the right foot of patient 2), and short, deformed, and on occasion partially fused metacarpals and metatarsals. Neither had other malformations and were of normal intelligence. The accessory toes in patient 1 were mesoaxial, each situated between the hallux and the third toe, whereas those in patient 2 were postaxial. In view of these findings, the disorder in 2 individuals is likely to represent a hitherto undescribed type of nonsyndromic synpolydactyly.

Background: To identify the molecular mechanisms underlying the release of a renal natriuretic peptide (NP) we selected a human kidney cell line (HEK 293) that displays several characteristics of distal tubular cells., Methods: Cells were exposed to different extracellular and intracellular stimuli, and the effect on NP release was measured with a specific urodilatin radioimmunoassay, as well as with an atrial NP (ANP) radioimmunoassay., Results: In the absence of stimuli, HEK 293 cells showed a basal release of urodilatin immunoreactivity and ANP immunoreactivity. Raising the osmolality of the secretion medium with sodium chloride and various other osmolytes rapidly increased cellular NP secretion. Elevation of intracellular cAMP levels by forskolin plus 3-isobutyl-1-methylxanthine and administration of phorbol-12-myristate-13-acetate together with the calcium-ionophore A23187 also resulted in respective increases in the amount of secreted peptide. HEK 293 cells exhibit the endogenous expression of both particulate and soluble guanylyl cyclases. In the presence of 8-Br-cGMP, cell cultures showed the enhanced secretion of an ANP immunoreactive peptide only, indicating that guanylyl cyclase activation provoked the secretion of ANP immunoreactivity but not of urodilatin immunoreactivity., Conclusions: The human embryonic kidney cell line HEK 293 represents a renal cellular model system in which we have identified a rapid and regulated release of NPs in response to the osmotic effect of increased extracellular sodium chloride and various intracellular stimuli.

Objective: The colorectal carcinoma is one of the most frequent malignomas in western countries. Therefore the gynecologist often will be confronted with the question whether a hormone replacement with sexual steroids is allowed after a curative operation., Material and Methods: Basing on the data of several international publications we have substituted in an own study from 1989 to 1997 42 women with colon and 10 with rectal cancer after successful operation with a combined preparation., Results: In the meantime it could be proved that in the cells of colorectal carcinomas estrogen and progesterone receptors are absent or only existing in a low concentration. Thus analogous to the receptor positive breast cancer the hormone replacement therapy also after curative treatment of a colorectal cancer should be justified. Therefore the benefit of the individual hormone replacement therapy shouldn't be withheld from these women without worsening the prognosis., Conclusions: After palliative therapy and in the case of a relapse a combined hormone replacement can be an act for diminishing the disease and should be recommended after a corresponding clearing-up and weighing the risk.

Background: The natriuretic peptide urodilatin was first isolated from human urine and may be one of the important mediators of natriuresis, while the atrial natriuretic peptide alpha-ANP, the circulating member of the family, rather seems to play a role in cardiovascular regulation. Although the renal expression of the common propeptide for urodilatin and alpha-ANP has been detected in rat and pig, it is not yet shown that urodilatin is synthesized in human kidney., Methods: Immunohistochemically we localized urodilatin with an urodilatin-antibody, which does not cross-react with alpha-ANP, the ANP propeptide, brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Radiolabelled urodilatin binding was examined autoradiographically., Results: We could demonstrate that urodilatin is present in human distal tubular cells, in which we could also localize propeptide immunoreactivity. The glomeruli, the cells of the proximal tubule, and the collecting duct did not show any urodilatin immunoreactivity. In human kidney homogenate the urodilatin content was 4600 + 520 fmol/g protein (n = 6). The renal concentration of BNP and CNP, mainly localized in the distal tubule, was much lower at 40 + 8 and 400+/-50 fmol/g protein (n=6) respectively. Furthermore the autoradiographic examinations showed that radiolabelled urodilatin binds to natriuretic peptide receptors in the glomeruli, blood vessels, and collecting ducts., Conclusions: Our data suggest that urodilatin may be the predominant representative of natriuretic peptides in human kidneys. Urodilatin being synthesized in the distal tubular region may be transported as a paracrine factor to the collecting duct, where it exerts its suppressing effect on the sodium reabsorption by stimulating the guanylyl cyclase A.

A commercial system for the rapid detection of methicillin-resistant Staphylococcus aureus, the BBL Crystal MRSA test (C-MRSA ID; Becton Dickinson, USA), was evaluated prospectively and compared with a polymerase chain reaction test for the presence of the mecA gene. Ten European centres tested a total of 676 isolates of Staphylococcus aureus from blood cultures. The system correctly identified 661 (97.8%) isolates within 4 h. All but three mecA gene-negative isolates (99.4% specificity) yielded a negative C-MRSA ID reaction, and 158 of 170 mecA gene-positive isolates were accurately detected (92.9% sensitivity). After repeated testing of discrepant results, sensitivity and specificity increased to 99% and 100%, respectively.

We analyzed the role of receptor internalization and recycling in muscarinic acetylcholine receptor (mAChR) desensitization and resensitization. Incubation of Chinese hamster ovary cells stably expressing the m4 mAChR with 1 mM carbachol for 1 hr reduced cell surface receptor number by 50-60% with no change in total receptor number. Pretreatment of the cells with 450 mM sucrose, which did not affect the ability of m4 receptors to inhibit forskolin-stimulated cAMP accumulation, completely blocked receptor internalization. On the other hand, the carbachol treatment reduced the ability of m4 receptors to inhibit cAMP accumulation in both sucrose-treated and untreated cells, with a similar onset and to a similar extent. The EC50 value for carbachol was increased approximately 10-fold, and maximal inhibition determined at 100 microM carbachol was reduced approximately 50%. In contrast, thrombin-induced inhibition of cAMP accumulation was not affected. Recycled receptors in cells not treated with sucrose remained refractory to carbachol stimulation for > or = 2 hr after agonist removal, even though cell surface receptor number had recovered completely within 1 hr. In contrast, resensitization of receptor function was very rapid in cells treated with sucrose. Ten minutes on removal of agonist, mAChRs in the plasma membrane of sucrose-treated cells were fully resensitized. Also, an internalization-defective m4 mAChR mutant, T399A, that was found to desensitize similar to the wild-type receptor, resensitized more rapidly than the wild-type receptor. We conclude that desensitization and resensitization of m4 mAChRs in Chinese hamster ovary cells can occur at the plasma membrane and that receptor internalization strongly delays the process of resensitization of desensitized receptors.

Staphylococcal scalded skin syndrome, a generalized exfoliative dermatitis complicating infections by exfoliative toxin-producing strains of Staphylococcus aureus, is rarely observed in adults. In contrast to mortality in infants, mortality in adults is usually high. A case of generalized staphylococcal scalded skin syndrome in an immunocompromised woman is reported. Culture of skin biopsy and pleural fluid yielded identical strains of staphylococcus aureus belonging to phage group II. Exfoliative toxins A and B were detected in both isolates. As far as can be determined, this is the first reported case of generalized staphylococcal scalded skin syndrome in an adult with detection of exfoliate toxins A and B in which the patient was treated successfully.

Over a period of three years, the frequency of the appearance of methicillin-resistant S. aureus strains (MRSA) was observed on a surgical intensive care unit. During this above-mentioned period of investigation it came to a heaped occurrence of nosocomial infections on this ICU with altogether 332 S. aureus-stems being isolated from different patient specimen. 204 (61.5%) of these were resistant against methicillin and could be divided into 48 first- and 156 follow-up-isolates. The thereupon accomplished differentiation of the 48 MRSA-first isolates by means of lysotyping and the pioneered GenePath Strain Typing System for a standardized pulsed-field-gel-electrophoresis (PFGE) gave the proof of 7 different MRSA-types. Around 7 different, in part parallel chains of infection on this ICU were observed, which could be led back to different strains. In reference to all analyzed S. aureus, an especially high rate (90%) of MRSA on this ICU could be isolated in taken wound-swabs, followed by 83.3% MRSA at catheter tips and 71,9% in tracheal and bronchial secretion. A consideration of the antibiotic susceptibility yielded, that also gentamicin and the quinolones showed an in-vitro resistance against MRSA, while fosfomycin, fusidic acid, chloramphenicol and trimethoprim/sulfamethoxazole reached positive responding rates between 80 and 100%. On the other hand, presently still 100% of the explored MRSA-strains are susceptible for glycopeptides such as vancomycin and teicoplanin. Because of intensive hospital hygienic measures the number of newly isolated MRSA could be reduced clearly on this ward.

Many guanine-nucleotide-binding-protein-coupled receptors contain consensus sequences for phosphorylation by cAMP-dependent protein kinase (PKA), often located in the membrane proximal regions critically important for receptor signalling. In the present study, we have evaluated by site-directed mutagenesis the role of the putative PKA phosphorylation sites in the m4 muscarinic acetylcholine receptor (mAChR), i.e. Thr145 in the second cytoplasmic loop and Thr399 in the third cytoplasmic loop, and the influence of PKA on m4 mAChR function and internalization. Antagonist binding was unaltered by any of the mutations studied, while the agonist-binding affinity was either not affected (Thr145 alanine), increased (Thr399 alanine) or decreased (Thr399 serine or aspartic acid). m4 mAChR-mediated inhibition of adenylyl cyclase was unaltered by the mutations, except for an approximately tenfold reduced agonist potency of the Thr399 aspartic acid mutated receptor. Agonist-induced receptor internalization was unaltered with Thr399 serine or aspartic acid mutations of the receptors, but was strongly decreased in its rate and extent upon replacement of Thr399, Thr145 or both of these residues with alanine. These mutational effects could not be reproduced by treatment of wild-type receptor-expressing cells with the PKA inhibitor H-8. Furthermore, maximal stimulation of cellular PKA neither affected receptor internalization nor signalling measured as receptor-mediated Ca2+ mobilization. We conclude that the membrane proximal threonine residues of the m4 mAChR are not required for receptor signalling, but replacement by alanine residues can significantly affect receptor internalization, independently of PKA phosphorylation. Sequence comparisons suggest that threonine residues at corresponding positions may be relevant to internalization of other guanine-nucleotide-binding-protein-coupled receptors.

An isolated occurrence of multifocal severe granulomatous dermatitis and mastitis accompanied by extensive calcifications is described in 2 female Sprague-Dawley, SPF breeding rats. Poorly growing Staphylococcus aureus of uncertain lysotype (probably lysotype II) was isolated from the lesions of both rats. The source of infection could not be determined. No further cases in the closed barrier maintained breeding colony occurred in the following 7 months. Difficulties in interpreting these findings and the practical consequences relating to the hygienic status of the barrier breeding colony are discussed.

The regulation of m4 muscarinic acetylcholine receptor mRNA expression by receptor activation was studied in N1E-115 neuroblastoma and AtT-20 pituitary cells that endogeneously express the m4 muscarinic receptor. Receptor concentration was measured by binding of the muscarinic receptor radioligand [3H]quinuclidinyl benzilate, and RNA-RNA solution hybridization/RNase protection assay with a m4 receptor-specific [32P]-cRNA probe was used to evaluate the levels of receptor mRNA. Treatment of both cell lines with a receptor-saturating concentration of the agonist carbachol decreased receptor number. However, there was no change in steady-state levels of m4 mAChR mRNA in both cell lines. Determination of mRNA stability in the presence of the transcription blocker actinomycin D revealed that carbachol treatment increased half-life of receptor mRNA in N1E-115 cells, but not in AtT-20 cells, suggesting that receptor activation can regulate m4 receptor mRNA stability dependently on cell type. Analysis of receptor degradation kinetics in the presence of the protein synthesis inhibitor cycloheximide showed that receptor down-regulation in N1E-115 and AtT-20 cells is sufficiently accounted for by increased receptor degradation. These results indicate than m4 muscarinic receptor down-regulation is substantially different from that of the muscarinic receptor subtypes m2 and m3 which is reported to be associated with agonist-induced reduction in receptor mRNA.

Objective: To examine genetic and environmental factors in the origin of isolated congenital limb deficiencies., Design: Case-control study with questionnaire at a family interview of cases of isolated congenital limb deficiencies (six types), negative controls (matched for age, sex, and place of residence), and positive controls (cases of sentinel anomalies)., Setting: The database of the Hungarian Congenital Abnormality Registry, 1975-84, complemented by three other sources of ascertainment (1,575,904 births)., Subjects: 537 case-control pairs; 392 positive controls., Main Outcome Measures: Smoking during pregnancy, congenital limb deficiencies., Results: The adjusted rate of smoking during pregnancy was significantly higher in the mothers of cases of terminal transverse defect (relative odds 1.48; 95% confidence interval 0.98 to 2.23; P = 0.017). This finding supports the hypothesis of vascular disruption as a cause of congenital limb deficiency., Conclusions: Maternal smoking during pregnancy raises the relative odds for terminal transverse limb deficiencies.

In order to investigate whether coupling to and/or activation of guanine-nucleotide-binding proteins (G proteins) is involved in agonist-induced internalization of m4 muscarinic acetylcholine receptors (mAChRs), a deletion mutant [des-(264-394)mAChR] was constructed that lacks a substantial portion of the putative third intracellular loop. The wild-type receptor and des-(264-394)mAChR stably expressed in Chinese hamster ovary cells in essentially comparable amounts, exhibited identical antagonist-binding affinities. Consistent with the reported importance of the third cytoplasmic loop for Gi protein activation, the des-(264-394)mAChR showed a drastically reduced potential to mediate agonist-induced inhibition of adenylyl cyclase. In contrast, the ability of the mutant receptor to couple to Gi proteins was not impaired, as demonstrated by a similar guanine-nucleotide-sensitive and pertussis-toxin-sensitive high-affinity agonist-receptor binding for both mAChRs. In contrast, des-(264-394)mAChR was hardly able to stimulate the GTPase activity of G proteins, suggesting impaired activation of Gi proteins rather than ineffective coupling to Gi proteins. Internalization of wild-type receptor and des-(264-394)mAChR was observed with similar agonist concentrations and showed similar maximal values. However, des-(264-394)mAChR displayed a significantly reduced rate of receptor internalization. A similar attenuation of wild-type mAChR internalization was obtained upon pertussis toxin treatment. In conclusion, our data provide evidence that the molecular determinants of the m4 mAChR involved in Gi-protein coupling and activation are not identical and that activation of, but not coupling to, Gi proteins regulates m4 mAChR internalization.

A population-based and validated data set of 195 cases with isolated terminal transverse-type congenital limb deficiency was evaluated in Hungary, 1975-1984. Terminal transverse types of congenital limb deficiency are not usually associated with non-limb defects, and typically only one limb is affected. Upper limb is more frequently affected than lower (9:1) in monomelic cases. The left side and females are affected more often in upper limbs while lower limb defects are evenly distributed between right and left sides and both sexes. Familial occurrence was not found.

A total of 50 oxacillin-resistant Staphylococcus aureus (ORSA) strains that were clumping factor negative (CFN) and protein A negative by latex agglutination were collected from patients in six different hospitals at different locations in Germany during 1991 and 1992. Antibiograms, bacteriophage typing, and plasmid analysis were performed. The antibiograms showed that, besides oxacillin, all CFN ORSA strains were resistant to gentamicin, clindamycin, erythromycin, ciprofloxacin, and fosfomycin. All these isolates were nontypeable with an international set of phages, and an additional experimental phage set indicated that the strains were phage type 16, 192. Moreover, all isolates possessed a single plasmid of 30 kb, and restriction analysis of those plasmids revealed identical patterns. For genotyping, these 50 isolates were also analyzed by pulsed-field gel electrophoresis (PFGE) and polymerase chain reaction (PCR) of the coagulase and protein A genes and then by restriction enzyme digestion and analysis of restriction fragment length polymorphisms (RFLPs). With 49 strains, electrophoresis of SmaI-digested chromosomal DNA revealed identical PFGE patterns regarding the number and size of the DNA fragments, which could be differentiated from those of clumping factor-positive ORSA strains. Typing for the coagulase gene by PCR revealed PCR products of identical sizes. The AluI restriction digestion patterns of the PCR products were identical. PCR with primers derived from the region of that part of the protein A gene that encodes the immunoglobulin G-binding domains showed a PCR product that was about 170 bp smaller than that of the protein A gene from strains that were positive in the protein A latex agglutination test. Since it is precisely this size that is required in order to encode one immunoglobulin G-binding region, we assume that this is not present in the CFN ORSA strains. The phenotypical and genotypical features identify these very unusual CFN ORSA stains as being of clonal origin.

Radial and tibial deficiencies are frequently (70%) associated with non-limb abnormalities. Isolated radial and tibial deficiencies may have a different etiology: in this study radial deficiencies were more frequent, there were milder subtypes and one-limb involvement was found in 70% of cases, tibial deficiencies were rare, mild subtypes did not occur and in general more limbs were involved. Among multimelic cases, one case had hypoplasia of the tibia with polydactyly and two cases had tibial aplasia with split hand +/- foot of autosomal dominant inheritance. Of 40 cases, four were familial. Findings of a case-control study on this population-based and validated 10-year cohort showed a lower mean birth weight and a higher rate of low birth weight in cases with isolated radial and tibial deficiency.

A population based and validated 10 year cohort of 94 cases with split hand/foot born in Hungary, 1975-1984 was evaluated. This type of congenital limb deficiency was relatively frequently (43%) associated with non-limb defects. Fifty-four cases with isolated split hand/foot are evaluated in this paper. A single limb was affected in 78% of cases. The upper limbs were 21 times more frequently affected in unimelic cases with a right sided predominance and male excess. Case-control analysis indicated intrauterine growth retardation and lower socioeconomic status of parents of cases. Family study showed six familial cases with autosomal dominant inheritance among 152 first and 452 second degree relatives. All familial cases were males.

Molecular cloning studies have demonstrated the existence in mammals of five genes encoding distinct muscarinic acetylcholine receptors which are heterogeneously expressed in the central nervous system and the target organs of the autonomic nervous system. In order to determine the factors responsible for regulation of receptor expression, we isolated a genomic clone encoding the mouse m4 muscarinic acetylcholine receptor. The gene contains no introns in the coding sequence, and encodes a polypeptide of 479 amino acids that is able to bind various muscarinic ligands with affinities typical for mAChRs and to couple efficiently to inhibition of adenylyl cyclase.

A population-based and validated data set of 114 cases with isolated ulnar-fibular deficiency was evaluated in Hungary, 1975-1984. Ulnar-fibular type had the third most common birth prevalence (0.07 per 1000) among isolated congenital limb deficiency types. This type is relatively rarely associated with nonlimb defects, a single limb is affected in two-thirds of cases, nearly all other cases had femur-fibula-ulna (FFU) dysostosis. Upper and lower limbs, right and left sides, are equally affected, however, there is an obvious male excess (71%). Case-control analysis indicated a lower birth weight due to intrauterine growth retardation, higher birth order, lower socioeconomic status of parents, and a more frequent reported subfertility. The family study identified one familial cluster (one siboccurrence) among 331 first-degree relatives.

A population-based and validated data set of 206 cases with apparent amniogenic limb deficiency was ascertained in Hungary between 1975 and 1984. Such limb defects frequently (36%) associated with nonlimb abnormalities. In 134 cases with isolated defects typically more limbs are affected, upper and lower limbs, right and left sides, and both sexes are equally affected. Case-control analysis of such isolated cases indicates a lower socioeconomic status of parents, a higher parity, more frequent unwanted pregnancies, preterm birth, and a higher rate of threatened abortion. Familial occurrence was not found in 415 first-degree relatives.

A study of 491 patients with femur-fibula-ulna (FFU) complex is presented. The term FFU complex has been proposed for cases in which the femur, fibula and/or ulna show defects, which tend to be associated. These cases are usually sporadic. Some rare anomalies of the arms which are present are particularly frequent in FFU complex. These are amelia, peromelia of humerus, humero-radial synostosis and defect of ulna. In our study, 491 patients were investigated for involvement of limb malformations. Our results, showing nearly equal proportions of the most common malformations in four analysed groups (with one, two, three and four limbs affected) supports the hypothesis that even if one arm or one leg only is affected, the cases may still be classifiable as FFU complex. There is a striking asymmetry in presence and in degree. All malformations are more often unilateral than bilateral. Upper limbs are affected more often than lower limbs. The right side and the male sex are preferentially affected. The limb malformations present in the FFU complex are different from those seen in most other types of limb defects, so there is virtually no overlap between FFU and other limb malformations. Some arguments in favour of early somatic mutation as a cause are discussed.

In a multicentre study, the methicillin-resistant Staphylococcus aureus (MRSA) isolates in 19 large clinics in Germany were recorded, and the resistance characteristics of these strains were studied. Oxacillin-mannitol-salt agar plates were distributed to all participants to ensure uniformity of screening, and each laboratory used these plates to investigate 200 consecutive Staphylococcus aureus isolates for oxacillin-methicillin resistance. Of the 3,794 evaluable Staphylococcus aureus isolates, 71.5% were penicillin and 3.7% (142) oxacillin resistant; four study centres reported methicillin-oxacillin resistance rates of more than 5%. Of the MRSA isolates, 75% were also resistant to ciprofloxacin, 61% to fosfomycin, 52% to imipenem, 50% to trimethoprim/sulfamethoxazole and 36% to clindamycin. All isolates were sensitive to vancomycin and teicoplanin. Of the Staphylococcus aureus strains isolated from patients in intensive therapy units, 10.4% were methicillin-oxacillin resistant. Drains and catheter tips (9.8% and 5.2% respectively) were the materials with the highest proportions of MRSA. Of the MRSA isolates in this study, 58.2% belonged to lysis group II.

The fourth case of primary melanoma of the bladder is presented together with a review of the previously reported cases and the relevant literature on malignant melanoma in urology. The criteria for classification of the bladder lesion as the primary site are discussed. The eighty-one-year-old female patient was felt not to be suitable for extensive surgery and was successfully treated with a combination of radiation and immunotherapy with recombinant alpha 2 interferon. After previous monthly recurrences of the tumor the patient is in complete remission fifteen months after initiation of therapy. It appears that this form of treatment might be a valuable alternative to radical surgery in elderly patients.

The sensitivity of Staphylococcus aureus strains isolated from Nigerian foods to phages in the international phage sets for typing human and bovine strains of staphylococci was determined. The enterotoxigenicity of the strains was also determined using the avidin-biotin enzyme-linked immunosorbent assay and the reversed passive latex agglutination test (for staphylococcal enterotoxin D only). One hundred and five (67.7%) of 155 strains tested were susceptible to phages in both typing sets. Phages for staphylococci of human origin lysed all 105 typeable strains while those for staphylococci of bovine origin were responsible for the lysis of 92 strains. Phages in the different phage groups (mixed) were most frequently responsible for lysis, 29 (27.6%), followed by group III phages with 26 (24.8%) strains susceptible. Of the 155 strains tested, 122 (78.7%) were enterotoxigenic producing staphylococcal enterotoxins A, B, C, D, or a combination. Dried beef isolates were most enterotoxigenic (100.0%) and those from fermented milk least (68.8%). Staphylococcal enterotoxins C, B, and A were elaborated either singly or in combination by 71 (58.2%), 69 (56.6%), and 62 (50.8%) strains, respectively. It was concluded that a majority of staphylococcal strains isolated from Nigerian foods originated from humans and their high enterotoxigenicity could be a health risk to consumers.

We report clinical, orofacial and radiological manifestations in a 4-year-old girl and a 33-year-old female with the Gorlin-Chaudhry-Moss (GCM) syndrome. Typical findings in the GCM syndrome are short stature, stocky body build, midface hypoplasia, small eyes, downslanting palpebral fissures, conductive hearing loss, highly arched and narrow palate, malocclusion, abnormally shaped teeth, oligodontia, microdontia, low scalp hairline, hypertrichosis of scalp, face, trunk and limbs and genital hypoplasia. Radiological features include premature synostosis of the coronal suture, brachycephaly, and maxillary under-development. Hypoplasia of the distal phalanges of fingers and toes (also present in the 2 original cases) represents a further manifestation of the GCM syndrome.

The avidin-biotin enzyme-linked immunosorbent assay (ELISA), reversed passive latex agglutination (RPLA) test, and the modified Ouchterlony precipitation test (MOPT) were compared in detecting enterotoxin production by Staphylococcus aureus strains. A total of 1015 strains isolated from human beings, animals, and foods were tested for staphylococcal enterotoxins A (SEA), B (SEB), and C (SEC). Of these, 495 (48.8%), 467 (46.0%), and 204 (20.1%) were classified as enterotoxigenic by the ELISA, RPLA test, and MOPT, respectively. The difference in the number of strains classified as enterotoxigenic by the ELISA and RPLA test was not significant (P > or = 0.05; chi 2), but both tests detected significantly (P < 0.001; chi 2) more enterotoxigenic strains than the MOPT. The combined use of the three assay systems classified 258 (25.4%), 278 (27.4%), and 263 (25.9%) of 1015 strains tested as positive for SEA, SEB, and SEC, respectively. However, the three systems were all positive in only 29.1% of SEA-producing strains, 32.0% of SEB-producing strains, and 25.1% of SEC-producing strains. The MOPT was negative when the corresponding ELISA and RPLA test were positive (46.9% for SEA, 43.5% for SEB, and 40% for SEC); the RPLA test was negative when the corresponding ELISA was positive (10.5% for SEA, 15.5% for SEB, and 25.5% for SEC); and the ELISA was negative when the RPLA test was positive (13.6% for SEA, 9.0% for SEB, and 9.5% for SEC). All factors considered, the RPLA test appears most suitable for quantitatively screening large numbers of strains for staphylococcal enterotoxins.

The phage types, enterotoxigenicity and antibiograms of Staphylococcus aureus strains isolated from human diarrhoea and skin wounds in Nigeria were determined. Of 194 strains tested, 140 (72.2%) were typable using a combination of phages in the International Phage Set (IPS) for human strains of S. aureus and the bovine phage set. IPS phages lysed 118 (60.8%) strains while 96 (49.5%) were susceptible to bovine phages. S. aureus strains from adult diarrhoea were significantly (P less than or equal to 0.01; x2) more sensitive to bovine phages (52.8%) than to IPS human phages (16.7%). Strains isolated from wounds were however significantly (P less than or equal to 0.001; x2) more susceptible to IPS human phages (72.9%) than to bovine phages (41.5%). Phage group III strains were predominant amongst diarrhoeal isolates while wound strains were most susceptible to group II phages. Phage 119, a bovine phage, lysed all 19 strains of diarrhoeal origin sensitive to group M phages but all wound strains were resistant. Overall, 132 (68.0%) strains were enterotoxigenic producing staphylococcal enterotoxins A (SEA), B (SEB), C (SEC) or a combination of these. A majority of diarrhoeal strains elaborated SEC while SEB production was predominant amongst wound strains. Of the eight antimicrobial agents used, S. aureus strains were most resistant to penicillin (71.6%) and least to sulfamethoxazole/trimethoprim (1.0%). Occurrence of resistance to one or more antibiotics was higher amongst wound strains (97.5%) than amongst strains isolated from diarrhoea (52.6%). It was concluded that bovine phage 119 may be a useful epidemiologic marker for S. aureus strains of bovine origin associated with human diarrhoea in Nigeria. It is however difficult to ascribe any aetiological significance to these strains because other enteropathogens not assayed for may have been present.

Staphylococcal skin colonization is a common feature of atopic dermatitis (AD) in adults. Little is known about prevalence and persistence of staphylococci in children. Forty-one AD children (mean age, 70 months) and 41 age-matched controls were studied. S. aureus was isolated from 38 AD patients (93%; 32% of controls, P less than .001) and 37% of AD patients (5% of controls, P less than .001) harbored toxigenic (enterotoxins, toxic shock syndrome toxin) S. aureus strains. No individual biotype prevailed. On follow-up (mean interval, 9 months), 70% of S. aureus strains were reisolated. Nasal and cutaneous S. aureus strains were identical in 73% of AD patients (7% of controls, P less than .001), reflecting increased self-contamination. Identical staphylococcal strains in AD children and their mothers were observed in 38% (S. aureus) and 16% (coagulase-negative strains; P less than .001). The prevalence of staphylococcal colonization in AD children is comparable to that in adults. High rates of self-contamination, transmission to contacts, and prevalence of toxigenic strains in AD children may have clinical and epidemiologic implications.

The production frequency of toxic shock syndrome toxin-1 (TSST-1) amongst Staphylococcus aureus strains isolated from humans, animals and foods in Nigeria was investigated. Of 1015 strains tested, 120 (11.8%) were positive for TSST-1. Thirty one (16.0%) of 194 strains from human diarrhoea and wounds were positive compared to 47 (7.1%) of 666 isolates from eight animal species. Goat strains were most often positive for this toxin (17.0%). A total of 42 (27.1%) of 155 strains from foods were positive for TSST-1. Regardless of source, phage non-typable strains (48.3%) were most common amongst TSST-1 producers followed by strains sensitive to phages in several groups (mixed), 18.3%, and phage group III strains (17.5%). Only 6 were phage group I strains (5.0%). TSST-1 producing strains were mostly resistant to penicillin. Eighty-four (70.0%) TSST-1 producers were also enterotoxigenic with staphylococcal enterotoxin C (SEC) most frequently elaborated as 46 (38.9%) strains were positive. However, 42 (35.5%) and 39 (32.5%) strains producing TSST-1 were also positive for SEA and SEB, respectively. It was concluded that TSST-1 producing strains of S. aureus are widespread in humans, animals and foods in Nigeria and such distribution may play some role in the epidemiology of toxic shock syndrome, the prevalence of which is currently unknown in the environment.

We have reviewed the follow-up of almost 3000 completed pregnancies in the Münster CVS Program and identified 4 children with distal limb deficiencies. Two cases involved only minor anomalies of distal digital phalanges. One child had a Hanhart anomaly (hypoglossia hypodactylia). We also reviewed 24 cases of limb defects following CVS reported previously. With the exception of a single series, neither the overall incidence of affected children nor cases reported from larger series provide unambiguous evidence of an increased risk of distal limb deficiency caused by CVS.

The lytic activity, protein profile and morphology of five newly isolated phages from canine Staphylococcus aureus strains and one from a human S. aureus strain were compared with those of selected phages in the international phage sets (IPS). Five canine phages lysed 57 (76.0%) of 75 canine isolates of Staphylococcus aureus from Nigeria at routine test dilution (RTD) while 34 (IPS) phages typed only 31 (41.3%) strains at RTD or/and 100-RTD. The new human phage lysed 11 (14.7%) of 75 strains isolated from human diarrhoea. The new phages were readily propagated, specific in activity and stable during storage at 4 degrees C. Prominent proteins detected by SDS-PAGE indicated similarities between some of the phages but one canine phage was distinctly different, as was its morphology which was an isometric head with a short tail compared to oval heads and long tails which characterized others. IPS phages in the same serologic group had similar protein profiles but no correlation was observed with lytic groups. The use of protein profile and electron micrographs allowed classification of the phages into serogroups. It is concluded that the newly isolated canine phages could be very useful in typing Nigerian canine strains of S. aureus.

A population-based and validated data set of 14 cases with isolated proximal intercalary type of congenital limb deficiency born in Hungary between 1975-84 was evaluated. Two cases had phocomelia of upper limbs, while 12 cases were affected with classical intercalary defects mainly in femurs. Of 14 cases, 13 had unimelic manifestation and both sexes were equally affected. The intrauterine growth retardation, the excess of second birth order, a higher rate of acute maternal disorder of the respiratory system and the lack of familial cluster are noteworthy. The vascular disruption hypothesis seems to be the most plausible explanation for the origin of isolated proximal intercalary defects.

Four cases of polysyndactyly from Japan, Taiwan and Turkey are described, which show similar short thumbs, metacarpals and middle phalanges as well as analogous malformations of the feet. A new type of polysyndactyly can be defined. The occurrence in brother and sister from a consanguineous marriage is consistent with autosomal recessive inheritance.

We report on a family with some features of the Pseudo-Ullrich-Turner-Syndrome, so-called Noonan-Syndrome. Besides low-set ears, microgenia, short neck, pterygium colli, low-anterior hair line and small stature as well as partial scoliosis, partial cubitus valgus and camptodactylia, retinal detachment, disturbances of the eye motility, keratoconus, unilateral ptosis and antimongoloid slant of the palpebral fissures in different expression are described. The caryotype was normal. Some of the features can be seen within at least 2 generations of the family. It seems to be an autosomal genetic mode of transmission. Differences and common characteristics in comparison to the literature are shown. Differential diagnostic aspects are described. A definite relation to a syndrome already described is not possible.

Strains of Staphylococcus aureus isolated from lesions and apparently healthy animals, human diarrhoea and wounds in Nigeria were phage typed and tested for exfoliative toxin (ET) production using the modified Ouchterlony double diffusion test. Thirty-four (4.0%) of 860 strains tested produced exfoliative toxins A (ETA), B (ETB) or a combination. ETA was produced singly by 91.1% of the toxigenic strains. Twenty-six (3.9%) of 666 animal strains were toxigenic compared to 8 (4.4%) of 194 strains from human beings. Overall, a majority of ET-producing strains were non-typable (58.8%), followed by phage group II strains (17.7%). The detection of a similar frequency of production of ET by strains of S. aureus from animals and non-scalded skin syndrome cases indicates that animals may serve as a reservoir for human infection.

998 cases affected with limb reduction deficiency were evaluated in Hungary, 1975-1984. Through the check-up of other sources of ascertainments, the Hungarian Congenital Abnormality Registry was found to be 98.4% complete. The proportion of misdiagnoses was 12.6%. In the period encompassed by the study, the birth prevalence of revised cases affected with congenital limb reduction deficiency was 0.55 per 1000 total births. Isolated and multiple cases were separated. The birth prevalence of revised isolated cases was 0.35 per 1000. Six types were separated based on their phenotypic manifestations. As the number of affected limbs, ratio of isolated and multiple cases and sex ratio showed obvious differences, etiological factors should be evaluated separately in these different types of congenital limb deficiencies.