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Biomedical subjects

W Hoffmann

Publications and source records attributed to W Hoffmann.

At least 19 recordsLinked to original sources

P-domains as shuffled cysteine-rich modules in integumentary mucin C.1 (FIM-C.1) from Xenopus laevis. Polydispersity and genetic polymorphism.

A new frog integumentary mucin (FIM-C.1) has been discovered by molecular cloning. This mucin contains at least six typical P-domains as cysteine-rich modules. Shuffled P-domains have previously been detected in FIM-A.1, and they also form the basis of various P-domain peptides, which presumably have growth-modulating activities. Furthermore, FIM-C.1 contains at least three threonine-rich clusters, which consist of semi-repetitive cassettes. Various polydisperse transcripts have been characterized. They originate from two genes only and differ by deletions/insertions that are congruent with the semi-repetitive cassettes. Thus, polydispersities are probably generated by alternative splicing. Southern analysis revealed genetic polymorphism between different individuals. Furthermore, a specific antiserum was generated against a synthetic peptide deduced from the COOH-terminal end of FIM-C.1 and used for Western analysis.

Amino Acid Sequence

Ependymins from the cerebrospinal fluid of salmonid fish: gene structure and molecular characterization.

So far, ependymins (Epds) have been sequenced only from cypriniform fish, and in the past all attempts have failed to characterize, on a molecular level, homologous Epd proteins in higher vertebrates. Therefore, rainbow trout (Oncorhynchus mykiss) Epds, which represent the predominant proteins of the cerebrospinal fluid, have been N-terminally sequenced and the encoding cDNA subsequently cloned using the polymerase chain reaction. Surprisingly, only 40-42% of the amino acids are identical with the corresponding sequences from goldfish (Carassius auratus), and no convincing immunological cross-reactivity is observed with an antiserum raised against purified Epds from C. auratus. O. mykiss possesses two highly homologous genes encoding Epds (Om-I, Om-II), a feature typical of a quasi-tetraploid species. Western analysis, using two specific antibodies against Epds from O. mykiss, revealed a variety of different glycosylation variants. In contrast to C. auratus, Epds from O. mykiss probably do not form disulfide-linked dimers. The structure of one Epd gene and its flanking regions have been determined for the Atlantic salmon (Salmo salar). Six exons were deduced by comparison with the corresponding cDNA sequence from O. mykiss (almost 98% homology with Om-II).

Amino Acid Sequence

xP2, a new member of the P-domain peptide family of potential growth factors, is synthesized in Xenopus laevis skin.

Similarly to epidermal growth factor (EGF) and EGF-like repeats, the "P-domain" represents a cysteine-rich module that has been detected in the past in a variety of polypeptides, as well as in high molecular weight proteins. Here, a precursor for a secretory polypeptide (xP2) is characterized that consists of two P-domains. xP2 has been discovered in Xenopus laevis with the help of the polymerase chain reaction. In contrast to all other P-domain peptides, it is synthesized in the skin but not in the stomach or the pancreas. By this and other criteria, it cannot be considered simply as the X. laevis homologue of recently described P-domain peptides, viz. the spasmolytic polypeptides (PSP/hSP/mSP). Furthermore, a polyclonal antiserum was generated against the deduced C-terminal end of xP2. Due to its immunoreactivity with granular glands, as well as with the epidermis, the possibility of a growth factor activity for xP2 in the germinal layer is discussed.

Amino Acid Sequence

The polymorphic integumentary mucin B.1 from Xenopus laevis contains the short consensus repeat.

The frog integumentary mucin B.1 (FIM-B.1), discovered by molecular cloning, contains a cysteine-rich C-terminal domain which is homologous with von Willebrand factor. With the help of the polymerase chain reaction, we now characterize a contiguous region 5' to the von Willebrand factor domain containing the short consensus repeat typical of many proteins from the complement system. Multiple transcripts have been cloned, which originate from a single animal and differ by a variable number of tandem repeats (rep-33 sequences). These different transcripts probably originate solely from two genes and are generated presumably by alternative splicing of an huge array of functional cassettes. This model is supported by analysis of genomic FIM-B.1 sequences from Xenopus laevis. Here, rep-33 sequences are arranged in an interrupted array of individual units. Additionally, results of Southern analysis revealed genetic polymorphism between different animals which is predicted to be within the tandem repeats. A first investigation of the predicted mucins with the help of a specific antibody against a synthetic peptide determined the molecular mass of FIM-B.1 to greater than 200 kDa. Here again, genetic polymorphism between different animals is detected.

Amino Acid Sequence

Goldfish ependymins: cerebrospinal fluid proteins of meningeal origin.

Ependymins are unique secretory proteins from the goldfish brain which have calcium binding capacity. They are synthesized in the leptomeninx and appear subsequently as the predominant protein constituents in the cerebrospinal fluid (CSF). In contrast, the serum is nearly devoid of ependymins. The perimeningeal fluid (PMF) between the meninx and the skull represents a mixture of CSF and serum. The different composition of PMF and CSF implies that there is no open communication between these two compartments. Separation is probably achieved by an arachnoid-like meningeal barrier as proposed from ultrastructural studies. This basic CSF system of fish is compared with that of higher vertebrates.

Animals

Laser lithotripsy of pancreatic and biliary stones via 3.4 mm and 3.7 mm miniscopes: first clinical results.

The pulsed dye laser is safe and effective in lithotripsy of biliary and pancreatic ductal stones, however delivery of the laser energy to the site of the calculi is technically difficult. A 3.4 mm miniscope inserted through a standard duodenoscope was used for transpapillary laser application under direct vision in one patient with an impacted pancreatic stone and in three patients with bile duct stones not amenable to treatment by routine endoscopy. Lithotripsy and ductal clearance was achieved in 3 of the 4 patients within a single treatment session. Percutaneous transhepatic laser lithotripsy via a 3.7 mm miniscope succeeded in the patient in whom the peroral approach had failed and in two further patients with bile duct stones not accessible by a retrograde approach. There were no major complications. The miniscopes provide an appropriate direct visual control for laser lithotripsy of pancreatobiliary calculi. This approach using miniscopes seems to be an effective, minimally invasive and time-saving alternative to conventional endoscopic laser lithotripsy.

Adult

Implantation of self-expanding esophageal metal stents for palliation of malignant dysphagia.

Eleven self-expanding metal stents were perorally implanted in ten patients with locally advanced malignant obstruction of the esophagus. After bougienage of the strictures, the stents were painlessly inserted and properly released by means of an 18 French gauge delivery catheter. In all cases, the endoprostheses expanded to a diameter of 14-20 mm and achieved immediate improvement of dysphagia. One perforation was seen after a single session of dilatation and subsequent stent insertion. No other early complication was observed. After a median follow-up of 74 days (Range, 33-252 days), one of eight patients is still alive and 7 died of non-procedural causes. The grade of dysphagia improved from a mean of 2.9 to a mean of 1.6 and 2.0, respectively, depending on the follow-up period (scale 0-4). Esophageal reobstruction occurred in four patients due to food impaction (two patients) or tumor ingrowth into the stent through the wire mesh (two patients). Recanalisation of the obstructed stent lumen was achieved by endoscopic irrigation (two patients), laser therapy only (one patient) or diathermia with subsequent insertion of a conventional plastic endoprosthesis into the metal stent (one patient). The initial results are promising. The delivery system, the wide-bore diameter, the macroporous configuration and the low mass of the self-expanding stents would seem to be associated with a less traumatic insertion procedure and a lower rate of stent migration as compared with conventional prostheses. Technical improvement may be required for prevention of tumor infiltration. Controlled trials are warranted to determine the future role of metallic stents for palliation of esophagocardial tumors.

Adult

Endoscopic laser lithotripsy with an automatic stone recognition system for basket impaction in the common bile duct.

In a patient with a common bile duct stone 28 mm in diameter, the traction wires of two basket catheters fractured during endoscopic mechanical lithotripsy. Disintegration of the concrement and removal of the impacted baskets failed even after extracorporeal application of 8,000 shockwaves. Pulsed dye laser lithotripsy was carried out via a 250 microns fiber which was advanced to the stone through a 6 French ERCP guiding catheter. Lithotripsy could be safely performed under fluoroscopic control since the laser used provides an automatic cut-out system upon tissue contact. 3,600 of 11,800 applied pulses were emitted with the total power setting and complete disintegration of the calculus was achieved. The baskets and the fragments could be removed endoscopically in the same session. Laser lithotripsy with a stone recognition system would seem to improve the applicability and safety of intracorporeal lithotripsy even when performed without direct visual guidance.

Aged

Prospective evaluation of the use of endoscopic retrograde cholangiography prior to laparoscopic cholecystectomy.

Preoperative cholangiography and subsequent removal of bile duct stones may increase the efficacy of laparoscopic cholecystectomy and reduce the rate of conversion to open cholecystectomy. Since there is little data on the incidence of choledocholithiasis in this group of patients, we undertook a prospective study on the routine performance of ERC in 288 patients selected for laparoscopic cholecystectomy. ERC succeeded in 264 of the 288 patients (91.7%) and showed a normal bile duct system in 227 (86.0%). Atypical bile duct anatomy was seen in eight patients. Open cholecystectomy was performed in seven of them but was judged to be absolutely necessary in only two cases (one patient each with Caroli syndrome and Mirizzi syndrome). ERC also revealed bile duct stones in 29 of 264 patients (11.0%) which had not been suspected on the basis of clinical, laboratory and ultrasonographic findings in nine cases (3.4%). EPT succeeded in all of the 29 patients with choledocholithiasis but open cholecystectomy was subsequently performed in four patients due to incomplete bile duct clearance (n = 3) or temporary bleeding after EPT (n = 1). The rate of ERC/EPT-related morbidity was 2.8%. It is concluded from a risk-benefit analysis in these patients that ERC should be restricted to patients with suspected bile duct stones. Following this strategy, small ductal concrements and bile duct abnormalities will be missed in 6.4% of cases but the clinical relevance of these findings is still unclear. In patients with combined gallbladder and common bile duct stones, preoperative EPT plus subsequent laparoscopic cholecystectomy appears to be an effective and time-saving therapeutic regimen which should be compared with open cholecystectomy plus common bile duct exploration in future studies.

Bile Duct Diseases

[Sequential parenteral and oral therapy with ofloxacin in urogenital infections].

125 hospitalized patients (56 men and 69 women) suffering from urinary tract infection (UTI) and 15 women with endometritis or pelvic inflammatory disease were treated with ofloxacin 6 mg/kg/d i.v. divided into 2 doses. Two thirds of the patients were switched to oral ofloxacin using the same dose regimen after 4 days. The median duration of treatment was 10 days. 98 patients were evaluable for efficacy: 45 had complicated lower UTI, 32 had upper UTI (75% of them with complications), 13 had endometritis and 8 an uncomplicated lower UTI. The most frequent complications of UTI were: obstruction (n = 27), indwelling catheters (n = 23), urinary concrements (n = 12), residual urine (n = 8) and a neurogenic bladder (n = 6). 22 patients had diabetes mellitus. A total of 103 pathogens was isolated from the urine of 85 patients, the most frequent being E. coli, Proteus spp. and Enterococcus faecalis. 98% of patients with UTI and 85% of patients with endometritis were clinically cured. Adverse drug events were observed in 6 patients.

Adolescent

[Role of cholangiography in laparoscopic cholecystectomy].

Cholangiography in laparoscopic cholecystectomy is indicated for the detection of bile duct stones and for visualization of the biliary anatomy in particular cases. For a selective approach patients with gallbladder stones can be split into groups with a low, an intermediate and a high probability of choledocholithiasis by use of ultrasonographic and laboratory parameters. In this respect, the choledochal diameter is the most accurate criterion for the prediction of duct stones. A narrow lumen, detectable in almost one-half of the patients, indicates a less than 4% incidence of duct stones. Cholangiography seems to be unnecessary in this low risk group. However, endoscopic retrograde cholangiography (ERC) or intraoperative cholangiography is indicated in patients with a 7-12 mm width of common bile duct and/or an elevated serum bilirubin level due to 10-50% risk of choledocholithiasis. There are several therapeutic options in case of detected duct calculi. To date, laparoscopic bile duct clearance can not be reliably performed. In about 15% of the patients an even larger choledochol diameter is associated with a high chance of bile duct stones. ERC and in case of detected stones endoscopic papillotomy (EPT) should be routinely performed in these patients to facilitate elective laparoscopic cholecystectomy.

Cholangiography

xP1 and xP4. P-domain peptides expressed in Xenopus laevis stomach mucosa.

Two different precursors for secretory polypeptides from the stomach of Xenopus laevis have been characterized by cDNA cloning. Both mature polypeptides are potential candidates for gastrointestinal growth factors. One, xP1, is the X. laevis homologue of the pS2 gene product consisting only of a single P-domain, whereas the second, xP4, is a novel polypeptide formed by four P-domains arranged in tandem. Northern analysis detected both transcripts in the stomach but not in the skin or the brain. In situ hybridizations localized the expression of both precursors in surface mucous cells of the gastric mucosa. With an antibody generated against the deduced C-terminal end of xP4, the mature polypeptide was investigated by Western analysis revealing N-glycosylation of xP4.

Amino Acid Sequence

Reevaluation of the Cottbus Reinfarction Study with 30 mg aspirin per day 4 years after the end of the study.

Four to 6 years after the end of the Cottbus Reinfarction Study with 30, 60 and 1000 mg/day aspirin, the survivors (72% of the patients) were reevaluated under standardized conditions at the district hospital. Nearly all patients (82%) of the former 30 mg group took further on 30 mg aspirin daily whereas of the former 1000 mg group only 20% continued to take doses higher than 500 mg aspirin. Forty-five percent changed to very low doses. Whereas the death rate was nearly the same in all three former dosage groups the total reinfarction rate was higher (22.5%) in the previous 1000 mg group in comparison to the 30 mg group (17.4%, p less than 0.05). The non-fatal reinfarction rate was by 50% lower in the former 30 mg group compared with the previous 1000 mg group. In the age group 50-59 a 8.6% non-fatal reinfarction rate is contrasted to 1.7% reinfarctions in patients of the former 30 mg group (p less than 0.01). The risk factors were not significantly different in the three groups.

Aspirin

Segmental renal hypoplasia of vascular origin causing renal hypertension in a 3-year-old girl.

A rare case of renal hypertension in a 3-year-old girl caused by segmental renal hypoplasia of vascular origin is presented. Resection of the hypoplastic segment of the kidney permitted successful treatment of the high blood pressure with preservation of renal function. Elevated plasma renin activity in the renal vein of the affected side and biochemical investigations demonstrated that the resected segment of the renal cortex was the source of the renin leading to hypertension by activation of the renin-angiotensin-aldosterone system.

Child, Preschool

An integumentary mucin (FIM-B.1) from Xenopus laevis homologous with von Willebrand factor.

We present a new protein from X. laevis skin termed "frog integumentary mucin B.1" (FIM-B.1) with a general structure similar to FIM-A.1 (formerly "spasmolysin"). The central region consisting of tandem repeats of 11 amino acid residues is probably a target for extensive O-glycosylation, whereas the C-terminal cysteine-rich domain shows pronounced homology with the C1-C2 domains and the C-terminal end of von Willebrand factor. Furthermore, we describe homology with antistasin, an anticoagulant peptide from a leech. We also discuss some implications concerning the evolutionary origin of von Willebrand factor. In situ hybridization studies revealed the expression of FIM-B.1 exclusively in mucous glands of the skin. This is comparable with FIM-A.1 but is in contrast to all other physiologically active peptides, which are synthesized in granular glands.

Amino Acid Sequence

Epirubicin and ifosfamide in patients with refractory breast cancer and other metastatic solid tumours.

The combination of ifosfamide (IFO) and epirubicin (EPI) has been found to be an effective regimen in the treatment of metastatic tumours and shows remarkable activity in heavily pretreated breast cancer patients. A combination of EPI (35 mg/m2 on days 1 and 2) and IFO (1.8-2.5 g/m2 on days 1-5) was given to 58 patients with refractory breast cancer (n = 23), metastatic sarcomas (n = 15) and other solid tumours (n = 20). Due to extensive prior therapy, the IFO dose had to be adapted to the individual haematological situation. In all, 55 patients were evaluable; we observed 5 complete (CRs) and 16 partial responses (PRs). In addition, 18 patients experienced a minor response (MR) or no change (NC). The median duration of all responses was 6.7 months. Toxicity was generally mild and closely related to previous therapy.

Antineoplastic Combined Chemotherapy Protocols

Expression of spasmolysin (FIM-A.1): an integumentary mucin from Xenopus laevis.

In the past, a unique type of precursor for a secretory protein was discovered. It contains a central repetitive domain rich in threonine residues and terminal cysteine-rich domains. Due to striking homologies of these terminal domains with pancreatic spasmolytic polypeptide, originally the name "prepro-spasmolysin" was proposed. Here we show that the mature protein has a MW of about 130 kDa, consisting of about 70% carbohydrate and 30% protein. Similar O-linked glycoproteins have been found in mucins from human intestine. For this and numerous other reasons we decided to rename this glycoprotein "frog integumentary mucin A.1" (FIM-A.1). Furthermore, analysis of the protein with specific antibodies against the predicted C-terminal end indicates that FIM-A.1 is probably not processed at pairs of basic residues. In situ hybridization as well as immunofluorescence studies revealed that FIM-A.1 is expressed and stored exclusively in mature mucous glands of Xenopus laevis skin. Only cone cells at the proximal part of these glands do not synthesize FIM-A.1. In contrast, all other physiologically active peptides from X. laevis skin investigated so far are synthesized in granular glands. A hypothetical function of FIMs for defense against microbial infections is discussed.

Amino Acid Sequence