DYX1C1 functions in neuronal migration in developing neocortex.

Rodent homologues of two candidate dyslexia susceptibility genes, Kiaa0319 and Dcdc2, have been shown to play roles in neuronal migration in developing cerebral neocortex. This functional role is consistent with the hypothesis that dyslexia susceptibility is increased by interference with normal neural development. In this study we report that in utero RNA interference against the rat homolog of another candidate dyslexia susceptibility gene, DYX1C1, disrupts neuronal migration in developing neocortex. The disruption of migration can be rescued by concurrent overexpression of DYX1C1, indicating that the impairment is not due to off-target effects. Transfection of C- and N-terminal truncations of DYX1C1 shows that the C-terminal TPR domains determine DYX1C1 intracellular localization to cytoplasm and nucleus. RNAi rescue experiments using truncated versions of DYX1C1 further indicate that the C-terminus of DYX1C1 is necessary and sufficient to DYX1C1's function in migration. In conclusion, DYX1C1, similar to two other candidate dyslexia susceptibility genes, functions in neuronal migration in rat neocortex.

Occurrence of esophageal granular cell tumors in The Netherlands between 1988 and 1994.

Granular cell tumors (GCT) of the esophagus are rare. The tumor is generally beleived to be of neurogenic origin and shows a malignant course in 2-4% of cases. No unanimity has been reached regarding the management of this tumor. A national survey was conducted on the incidence of GCT of the esophagus, related symptoms, management, and follow-up. A national survey was performed on all newly registered esophageal GCTs in the PALGA system (Dutch register of all pathology diagnoses) for seven consecutive years (1988-1994). Fifty-two new cases (17 men, 35 women; median age 46 years, range 22-77 years) were registered. In 44 cases clinical data could be obtained (survey response 85%). The majority of the GCTs were solitary (42/44) and localized in the distal esophagus (33/44). At endoscopy the size of the tumor was estimated at <5 mm in 50%, 5-10 mm in 25%, and 10-30 mm in 18%. Most patients (40/44) presented with nonspecific gastrointestinal symptoms, only four had dysphagia (tumor size >1 cm). No malignancies were reported. Management of the tumor included excisional biopsy (1/44), endoscopic polypectomy (3/44), and surgical excision (1/44). Endoscopic follow up (1-60 months) in 16 out of 17 patients left untreated showed either a stable tumor size or regression of the tumor. In one case with multiple GCT's a slight tumor growth was seen after a follow-up period of 48 months. Esophageal GCTs in the Netherlands are rare, and mostly diagnosed incidentally. Most patients suffer from nonspecific symptoms; dysphagia occurs only with tumors >1 cm. The usual clinical course of esophageal GCTs is benign. Patients without dysphagia probably do not require routine endoscopic follow-up, provided they are instructed to contact their physician, once dysphagia develops.

Gastroesophageal reflux disease in intellectually disabled individuals: leads for diagnosis and the effect of omeprazole therapy.

OBJECTIVES: The therapeutic approach to gastroesophageal reflux disease (GERD) in intellectually disabled individuals has not been studied extensively. So far, only low response rates to medical and surgical therapy of GERD have been reported. However, the efficacy of proton pump inhibitors, to date the most effective medical therapy for GERD, has never been evaluated in this population. Our purpose, therefore, was to study the effect of omeprazole on healing and symptom relief in the intellectually disabled. METHODS: The treatment scheme was as follows: omeprazole 40 mg was given once daily (o.d.) as a healing dose for 3 months, and omeprazole 20 mg o.d. was given as a maintenance dose for another 3 months, to intellectually disabled subjects with endoscopically proven esophagitis, grades I-IV, according to Savary-Miller classification. After 3 and 6 months, the result of this treatment was evaluated by symptom scoring and/or endoscopy. In case of relapse, the dose was increased. RESULTS: At the first endoscopy, 40 of 107 patients (37%) had grade I, 36 (34%) grade II, 18 (17%) grade III, and 13 (12%) grade IV esophagitis. In 92 of 104 patients (88%), the treatment scheme was effective in healing the esophagitis and keeping patients in remission, independent of the severity of esophagitis. In 11 of 104 (11%) patients, a symptomatic relapse was observed after the dose was decreased to 20 mg o.d. However, all of these patients became symptom free again after the dose was increased to 40 mg o.d., and all were healed endoscopically at the end of the study. One (1%) patient needed omeprazole 60 mg o.d. for healing, but in this patient, no relapse was seen while on a maintenance dose of omeprazole 40 mg o.d. Marked improvement of persistent vomiting, hematemesis, regurgitation, food refusal, iron deficiency anemia, and depressive symptoms was seen at the end of the study. CONCLUSIONS: This study indicates that omeprazole is highly effective for all grades of esophagitis in the intellectually disabled. The dose needed to maintain them in remission can be titrated according to the reflux symptoms.

Biodistribution of 123I-labeled 4-hydroxytamoxifen derivatives in rats with dimethylbenzanthracene-induced mammary carcinomas.

A 123I-labeled tamoxifen derivative with a high affinity for the antiestrogen-binding site (AEBS) has been prepared. Biodistribution studies in rats showed a good linear correlation between the AEBS contents of tissue in fmol/g and the accumulated amount of radioactivity in percent dose per gram at 24 h.

Prevalence of esophageal disorders in patients with chest pain newly referred to the cardiologist.

STUDY OBJECTIVE: The prevalence of esophageal disorders (dysmotility and/or gastroesophageal reflux) in patients with chest pain newly referred to a cardiologic clinic is unknown. The aims of our study were to investigate the prevalence of esophageal abnormalities in these patients and to assess the value of medical history in predicting the origin of the patient's chest pain. DESIGN: We evaluated 28 consecutive patients who were newly referred to the cardiologist because of angina-like chest pain. Patients with evidence of severe myocardial ischemia were excluded. Cardiologic evaluation included medical history, physical examination, ECG, and exercise testing; further cardiologic workup was carried out only when considered necessary. Gastroenterologic evaluation consisted of medical history, esophageal manometry, endoscopy, and 24-h ambulatory monitoring of esophageal pH and pressure. MEASUREMENTS AND RESULTS: In five patients a diagnosis of ischemic coronary artery disease was made. In only two of these five patients, the cardiologic history strongly suggested a cardiac origin of the pain. Twelve patients had a pathologic 24-h pH profile, four of whom also had reflux esophagitis. Ten patients had symptomatic reflux. In only three of these ten patients, the history was judged to be indicative of an esophageal origin of the chest pain. No motility disorders were found. CONCLUSIONS: Thirty-six percent of the patients with chest pain newly referred to a cardiologic out-patient clinic have symptomatic gastroesophageal reflux. Neither cardiologic nor gastroenterologic history data have a high predictive value with respect to the origin of the chest pain.

How does FtsZ find its location?

The conformational flexibility of FtsZ and the properties of its epitopes have been studied. Cellular fractions of Escherichia coli have been treated with Triton X-114. FtsZ distributed in the polar as well as in the non-polar phase. This has been interpreted to mean that FtsZ can change its conformation. For the nonpolar conformation it has been assumed that the putative hydrophobic pocket of FtsZ (cf. Voskuil et al., J. Bacteriol. 176:1886-1893) is being turned inside out upon interaction with the cytoplasmic membrane. In a tentative model we suggest that FtsA mediates this interaction. Immunoprecipitations of FtsZ with various monoclonal antibodies in the presence or absence of 1 M NaCl gave a clue concerning the hydrophobicity and hydrophilicity of FtsZ's epitopes. Immunogold-labeling also showed differences with respect to the accessibility of FtsZ.

The choriocarcinoma syndrome: an emergency.

A 36-year-old male patient is described who presented with gynaecomastia, pulmonary nodules and a retroperitoneal mass in combination with a markedly elevated HCG level. A diagnosis of "choriocarcinoma syndrome" was made. Despite a clear response from the tumour to chemotherapy the patient died, at least partially due to delay in treatment. Prompt treatment even without cytological or histological proof is therefore stressed.

Epitope mapping of Escherichia coli cell division protein FtsZ with monoclonal antibodies.

A fusion between lacZ and ftsZ of Escherichia coli was constructed to obtain a beta-galactosidase-FtsZ fusion protein. This fusion protein was used to raise antibodies against cell division protein FtsZ. Six monoclonal antibodies were obtained, and they reacted with FtsZ from cytoplasm and membrane fractions. The epitopes in FtsZ were localized by studying the reactions of the monoclonal antibodies with fusion proteins truncated at the carboxy terminus and with fragments that were obtained by CNBr cleavage of purified FtsZ. Five different epitopes were defined. Epitopes I and III reacted with the same monoclonal antibody, without showing apparent amino acid homology. Epitope II was defined by monoclonal antibodies that cross-reacted with an unknown cytoplasmic 50-kDa protein not related to FtsZ. Epitopes IV and V were recognized by different monoclonal antibodies. All monoclonal antibodies reacted strongly under native conditions, so it is likely that the five epitopes are situated on the surface of native FtsZ. By using these data and computer analysis, a provisional model of FtsZ is proposed. The FtsZ protein is considered to be globular, with a hydrophobic pocket containing GTP-binding elements. Epitopes I and II are situated on each side of the hydrophobic pocket. Because the carboxy terminus contains epitope V, the carboxy terminus of FtsZ is likely oriented toward the protein's surface.

Cefepime compared with ceftazidime as initial therapy for serious bacterial infections and sepsis syndrome.

In an open randomized multicenter comparative study, we evaluated the safety and efficacy of cefepime (CP; 2.0 g given intravenously every 12 h) and ceftazidime (CZ; 2.0 g given intravenously every 8 h) as initial treatment for adult patients with suspected serious bacterial infections. A total of 133 patients entered the study, of whom 114 were evaluable for clinical and microbiological response assessment: 56 received CP and 58 received CZ. About 50% (30 who received CP and 25 who received CZ) fulfilled the criteria of the sepsis syndrome. The treatment groups were comparable with respect to sex distribution, mean age, underlying diseases, treatment duration, APACHE II score, and type of infection. The most commonly cultured microorganisms were members of the family Enterobacteriaceae, Streptococcus pneumoniae, and Staphylococcus aureus. The causative microorganisms were eradicated from 92% (37 of 40) of patients with a microbiologically documented infection who underwent treatment with CP; they were eradicated from 86% (42 to 49) of patients who received CZ. The responses of only clinically documented infections in the CP group were 90% (27 of 30 patients); in the CZ group they were 87% (26 of 30 patients). When patients fulfilled the criteria of the sepsis syndrome (septic shock excluded), the causative microorganisms were eradicated from 89% (16 of 18) of CP-treated patients and 86% (12 of 14) of CZ-treated patients. None of these differences was statistically significant. Mortality was the same in both groups (four patients in each group) and was not attributable to the study medication. In conclusion, CP is at least as effective and as safe as CZ, as initial antimicrobial therapy for suspected serious bacterial infections in nonneutropenic patients with or without the sepsis syndrome. CP has the additional advantage in that it can be given twice daily, which may lead to a decrease in hospital costs.

Calcium in bacteria: a solution to which problem?

Calcium and calcium-binding proteins including those resembling calmodulin are implicated in numerous diverse processes in bacteria. These processes include chemotaxis, sporulation, virulence, the transport of sugars and proteins, phosphorylation, heat shock, the initiation of DNA replication, septation, nucleoid structure, nuclease activity and recombination, the stability of the envelope, and phospholipid synthesis and configuration. That such varied processes should have a common factor, calcium, suggests major underlying principles of calcium metabolism which have yet to be discovered.

Stimulation and inhibition of cell division in synchronized Escherichia coli.

Escherichia coli was synchronized by centrifugal elutriation. When grown in a Tris-based medium, addition of EDTA resulted in division about 20 min earlier (division of control at t = 75 min). EDTA addition caused a change in cell shape, with cells becoming narrower and longer, whereas the surface area to volume ratio increased. Irradiation with UV inhibited not only division and constriction, but also the increase in DAP incorporation found in dividing control cells. Possibly, division requires the construction of new polar caps, whereas premature division might involve remodeling of existing murein. In both cases, cell shape is presumed to be a relevant factor for division.