Accelerated Skeletal Maturation in Disorders of Retinoic Acid Metabolism: A Case Report and Focused Review of the Literature.

Nutritional excess of vitamin A, a precursor for retinoic acid (RA), causes premature epiphyseal fusion, craniosynostosis, and light-dependent retinopathy. Similarly, homozygous loss-of-function mutations in CYP26B1, one of the major RA-metabolizing enzymes, cause advanced bone age, premature epiphyseal fusion, and craniosynostosis. In this paper, a patient with markedly accelerated skeletal and dental development, retinal scarring, and autism-spectrum disease is presented and the role of retinoic acid in longitudinal bone growth and skeletal maturation is reviewed. Genetic studies were carried out using SNP array and exome sequencing. RA isomers were measured in the patient, family members, and in 18 age-matched healthy children using high-performance liquid chromatography coupled to tandem mass spectrometry. A genomic SNP array identified a novel 8.3 megabase microdeletion on chromosome 10q23.2-23.33. The 79 deleted genes included CYP26A1 and C1, both major RA-metabolizing enzymes. Exome sequencing did not detect any variants that were predicted to be deleterious in the remaining alleles of these genes or other known retinoic acid-metabolizing enzymes. The patient exhibited elevated plasma total RA (16.5 vs. 12.6±1.5 nM, mean±SD, subject vs. controls) and 13-cisRA (10.7 nM vs. 6.1±1.1). The findings support the hypothesis that elevated RA concentrations accelerate bone and dental maturation in humans. CYP26A1 and C1 haploinsufficiency may contribute to the elevated retinoic acid concentrations and clinical findings of the patient, although this phenotype has not been reported in other patients with similar deletions, suggesting that other unknown genetic or environmental factors may also contribute.

Whole exome sequencing in a patient with uniparental disomy of chromosome 2 and a complex phenotype.

Whole exome sequencing and chromosomal microarrays are two powerful technologies that have transformed the ability of researchers to search for potentially causal variants in human disease. This study combines these tools to search for causal variants in a patient found to have maternal uniparental isodisomy of chromosome 2. This subject has a complex phenotype including skeletal and renal dysplasia, immune deficiencies, growth failure, retinal degeneration and ovarian insufficiency. Eighteen non-synonymous, rare homozygous variants were identified on chromosome 2. Additionally, five genes with compound heterozygous mutations were detected on other chromosomes that could lead to a disease phenotype independent of the uniparental disomy found in this case. Several candidate genes with potential connection to the phenotype are described but none are definitively proven to be causal. This study highlights the potential for detection of a large number of candidate genes using whole exome sequencing complicating interpretation in both the research and clinical settings. Forums must be created for publication and sharing of detailed phenotypic and genotypic reports to facilitate further biological discoveries and clinical counseling.

Decrease in nosocomial pneumonia in ventilated patients by selective oropharyngeal decontamination (SOD).

OBJECTIVE: To determine the influence of selective oropharyngeal decontamination (SOD) on the rate of colonization and infection of the respiratory tract in intensive care patients requiring mechanical ventilation for more than 4 days. A financial assessment was also performed. DESIGN: Randomized, prospective, controlled study using amphotericin B, colistin sulfate (polymyxin E), and tobramycin applied to the oropharynx and systemic cefotaxime prophylaxis. SETTING: Anesthesiology intensive care unit (ICU) of a 1500-bed hospital. PATIENTS: A total of 88 patients admitted as emergencies and intubated within less than 24 h were enrolled. Fifty-eight patients received SOD and 30 patients served as controls. Randomization was in the proportion of 2 : 1 study patients to controls. INTERVENTIONS: Microbiological samples from the oropharynx and other infected sites were taken at the time of admission, then twice a week and after extubation. MEASUREMENTS AND RESULTS: With the use of SOD, colonization was significantly reduced. Furthermore, the infection rate decreased from 77% in the controls to 22% in the study patients. Staphylococcus aureus was the main potential pathogen causing colonization and pneumonia. Number of days in the ICU, duration of ventilation, and mortality were not significantly decreased. The total cost of antibiotics was reduced. Development of resistance was not observed. CONCLUSIONS: The use of SOD significantly reduced the colonization and pneumonia and the total charge for antibiotics. The length of stay in the ICU, duration of ventilation, and mortality were similar. No resistance was observed. Staphylococcus aureus was selected by SOD in some patients and the clinical relevance needs further observation.

A randomized study comparing fluconazole with amphotericin B/5-flucytosine for the treatment of systemic Candida infections in intensive care patients.

In this prospective, randomized study fluconazole and amphotericin B/5-flucytosine were compared in the treatment of systemic candidiasis. Seventy-two non-neutropenic intensive care patients with systemic Candida infections were enrolled. Thirty-six patients were randomly assigned to receive fluconazole (400 mg on the first day then 200 mg) and 36 were randomized to amphotericin B/5-flucytosine (1.0-1.5 mg/kg body weight every other day and 3 x 2.5 g flucytosine/day) for 14 days following the diagnosis. There was no statistically significant difference in clinical outcome in regard to the treatment of pneumonia and sepsis: 18/28 of the patients were treated successfully with fluconazole and 17/27 with amphotericin B/5-flucytosine. For the treatment of peritonitis, however, amphotericin B/5-flucytosine was more effective than fluconazole (55% vs. 25%). Furthermore, amphotericin B/5-flucytosine was found to be superior to fluconazole with regard to pathogen eradication (86% vs. 50%). Fluconazole was associated with less toxicity than amphotericin B/5-flucytosine.

Evolution of rescue systems: a comparison between Cologne and Cleveland.

INTRODUCTION: Comparisons of different emergency medical services (EMS) systems often are reduced to simple comparisons between distinct facilities or strategies (e.g., prehospital physician versus paramedic, "scoop and run" versus "stay and play"). METHODS: The EMS systems of similar cities (Cologne and Cleveland) in two different countries (Germany and the United States) are compared. The comparison is seen from the perspective of an evolutionary standpoint that reflects the development of the EMS system in connection with the special environments. Data on rescue times, facilities, and (trauma) outcomes are compared. RESULTS: No statistically significant differences in outcome between the systems were detected. CONCLUSION: Both systems are developed in special environments and are optimized over decades, which explains the similarities in outcome.

Stress-induced regulation of a human proenkephalin-beta-galactosidase fusion gene in the hypothalamus of transgenic mice.

Transgenic mice expressing an Escherichia coli beta-galactosidase reporter gene under the control of 3 kilobases of human proenkephalin gene 5'-flanking sequence and 1.2 kilobases of 3'-flanking sequence exhibited an anatomically correct pattern of basal and stress-regulated transgene expression within the hypothalamus. Acute osmotic stress and hypovolemia induced transgene expression in neurons within both the paraventricular and supraoptic nuclei. Chronic osmotic stress resulted in dramatic induction of transgene expression in both nuclei. These results demonstrate that the information required for correct hypothalamic expression and stress regulation of the proenkephalin gene is contained within our fusion construct.

[The incidence of postoperative pain on general surgical wards. Results of different evaluation procedures]. / Zur Inzidenz postoperativer Schmerzen auf chirurgischen Normalstationen. Ergebnisse unterschiedlicher Evaluierungsverfahren.

Knowledge of the incidence and significance of postoperative pain is essential for the establishment of effective pain treatment programmes. Detailed investigations on the incidence, severity and quality of postoperative pain from the surgeon's perspective are scarce in German hospitals. It was the aim of our study to investigate postoperative pain in general surgery under routine conditions. PATIENTS AND METHODS. A total of 168 patients scheduled for abdominal, vascular and orthopaedic surgery were investigated in a prospective trial. Pain was assessed by means of a 100-point visual analogue scale (VAS), a 5-point verbal rating scale (VRS), the original version of the McGill Pain Questionnaire (MPQ) and the short form of the McGill Pain Questionnaire (SFMPQ). These were applied preoperatively and daily thereafter up to the 7th postoperative day. Patients were randomly assigned into two groups with different sequences of application of the instruments. The pain treatment programme included intravenous analgesia with tramadol/metamizol (max. tramadol 400 mg+metamizol 5 g in any 24 h) after major surgery and additional administration of piritramide as needed (max. 60 mg/24 h.i.v.). After minor surgery ibuprofen was routinely given for analgesia (3 x 500 mg). RESULTS. All patients had pain on the days 1 and 2 postoperatively. The mean intensity of pain was 44 VAS points on day 1 and 6.8 points on day 7. The mean intensity of pain measured by the VRS on the 1st postoperative day was between "mild" and "moderate". The quality of pain showed a constant pattern concerning the mean scale values of descriptors of each subgroup (sensory, evaluative, affective, mixed) for both the original and the short form of the McGill Pain Questionnaire up to the 7th postoperative day. Sensory descriptors were reported more frequently than affective descriptors. Typical pain patterns were identified for different operations. After subtotal thyroidectomy, for example, patients perceived a high intensity of pain of short duration. In contrast, patients still have a high intensity of pain up to 7 days after abdominal and rectal operations. CONCLUSIONS. We conclude from our results that patients perceive significant postoperative pain under current standardized pain treatment in our department. Effective programmes for pain relief should take account of the different patterns of pain after different operations, as identified in this study.

[Surgical or conservative therapy of rupture of the lateral ligament of the ankle joint?]. / Operative oder konservative Therapie der Aussenbandruptur am oberen Sprunggelenk?

To determine whether operative treatment is superior to conservative therapy, 60 patients were randomized to surgical suture and cast immobilisation for six weeks (n = 30) or cast immobilisation alone for the same time (n = 30) for acute rupture of the ligaments of the ankle. Variables of well being (ability to work, to do sports, dysesthesia, pain during exercise, swelling, tendency for recurrent distorsion), stability (dislocation and tilting of the talus on X-ray examination) and the radiological evidence of arthrosis were chosen as endpoints. Complete follow-up was obtained one year after the accident. In both groups we did not find any evidence of arthrosis one year after the accident. No significant differences were found between the study groups neither for the parameters of well being nor for objective criteria of stability. No correlation was found between well being and stability of the ankle joint. These results suggest that for the chosen endpoints no treatment modality can be recommended after one year follow-up. Only long-term studies using incidence of arthrosis as the most important endpoint will be able to answer the question whether conservative or operative treatment of rupture of the ankle ligaments is superior.

[Pain in ambulatory surgery. A prospective follow-up study]. / Schmerz in der chirurgischen Ambulanz. Eine prospektive Beobachtungsstudie.

Although acute pain is most often the dominant symptom that causes a patient to visit the out-patient clinic there is a lack of data concerning duration, intensity and quality of pain. Therefore, the physician's treatment is most often insufficient and the patient has to fix the dose of drugs himself. To get reliable and objective data a prospective trial on 161 patients in our out-patient clinic was performed using clinical instruments for measurement. 84% of the patients reported significant pain in the out-patient clinic compared to 96% during the prehospital period. Pain intensity is highly depended on the type of injury (bone injuries hurt more than soft tissue injuries). To get more reliable data on the acute pain situation and to improve therapeutic interventions it is suggested to use the methods presented routinely.