Human cytomegalovirus seropositivity is associated with reduced patient survival during sepsis.

BACKGROUND: Sepsis is one of the leading causes of death. Treatment attempts targeting the immune response regularly fail in clinical trials. As HCMV latency can modulate the immune response and changes the immune cell composition, we hypothesized that HCMV serostatus affects mortality in sepsis patients. METHODS: We determined the HCMV serostatus (i.e., latency) of 410 prospectively enrolled patients of the multicenter SepsisDataNet.NRW study. Patients were recruited according to the SEPSIS-3 criteria and clinical data were recorded in an observational approach. We quantified 13 cytokines at Days 1, 4, and 8 after enrollment. Proteomics data were analyzed from the plasma samples of 171 patients. RESULTS: The 30-day mortality was higher in HCMV-seropositive patients than in seronegative sepsis patients (38% vs. 25%, respectively; p = 0.008; HR, 1.656; 95% CI 1.135-2.417). This effect was observed independent of age (p = 0.010; HR, 1.673; 95% CI 1.131-2.477). The predictive value on the outcome of the increased concentrations of IL-6 was present only in the seropositive cohort (30-day mortality, 63% vs. 24%; HR 3.250; 95% CI 2.075-5.090; p < 0.001) with no significant differences in serum concentrations of IL-6 between the two groups. Procalcitonin and IL-10 exhibited the same behavior and were predictive of the outcome only in HCMV-seropositive patients. CONCLUSION: We suggest that the predictive value of inflammation-associated biomarkers should be re-evaluated with regard to the HCMV serostatus. Targeting HCMV latency might open a new approach to selecting suitable patients for individualized treatment in sepsis.

Measurements of burr-hole localization for endoscopic procedures in the third ventricle in children.

OBJECTIVE: In a retrospective study, we measured the localization for the burr hole for neuroendoscopic procedures in the third ventricle, which are determined by anatomical landmarks like the foramen of Monro (FM) and the respective targets. PATIENTS AND METHODS: In 48 children, thin-sliced T2-weighted magnetic resonance images were analyzed within an imaging software tool to determine the trajectory between the FM to the floor of the third ventricle (F3V) or the entrance of the sylvian aqueduct (SA). The crossing point at the skull convexity defined the entry points. Coordinates are given relative to nasion and midline. A mean virtual entry point to reach both targets was compared to the burr-hole localization used in the respective surgeries. The tissue shift at the FM was quantified for the trajectories. RESULTS: The entry point to reach the F3V or the SA measured 119.7+/-26.4 mm (to nasion)-20.5+/-11.5 mm (to midline) and 57.4+/-26.5-18.8+/-8.3 mm, respectively. The virtual mean entry point to reach both targets was located at 86.5+/-25.3-20.9+/-9.8 mm. There was a statistical difference in the entry point localization relative to nasion of the virtual mean trajectory compared with the burr-hole localization used in these patients. The tissue shift at the level of the FM using the mean virtual trajectory was significantly lower than by using the actual burr hole to the SA. CONCLUSIONS: Planning an optimal burr-hole localization is important in neuroendoscopic procedures in children, especially where the target is located around the sylvian aqueduct.

Local chemotherapy in the rat brainstem with multiple catheters: a feasibility study.

OBJECTS: Technical aspects of local chemotherapy in inoperable brainstem gliomas by convection-enhanced delivery (CED) are still under experimental considerations. In this study, we characterize the feasibility of multiple cannula placements in the rat brainstem. MATERIALS AND METHODS: In 38 male Fisher rats, up to three guided screws were positioned in burr holes paramedian at 2.5 mm anterior and posterior to as well as at the lambdoid suture. Using Alzettrade mark pumps (1 microl/h flow rate over 7 days) either vehicle (5% dextrose) or 0.1 mg carboplatin was delivered via one, two, or three cannulas, respectively. During cannula insertion, electrocardiogram and respiratory rate was monitored. All rats were subsequently evaluated neurologically for 8 days. For drug distribution in coronal sections, the brain tissue concentration of platinum was measured. HE staining was used to evaluate the local site of drug delivery. Heart and respiratory rate remained within normal range during surgical procedure. Neurological scoring showed only mild neurological impairment in the groups receiving two or three cannulas, which resolved after vehicle delivery. However, after carboplatin delivery, this deficit remained unchanged. Drug distribution was more homogeneous in the three cannula group. Histological slices visualized edematous changes at the sight of cannula placement. CONCLUSION: The unilateral application of up to three cannulas in the brainstem of rats for local drug delivery studies is feasible. The remaining neurological deficit in carboplatin-treated animals underlines the need of low toxicity drugs for CED in the brainstem.

A clinical pilot study of fresh frozen plasma versus human albumin in paediatric craniofacial repair.

Paediatric craniofacial surgery (pCFS) regularly requires transfusion of packed red blood cells (pRBC). In this clinical pilot study two different transfusion regimens were prospectively compared concerning pRBC transfusions, postoperative bleeding and other clinical parameters. Thirty infants (aged < 12 months) scheduled for pCFS were assigned to receive fresh frozen plasma (FFP-group, n = 15) or 5% human albumin (HA-group, n = 15) during the entire surgical procedure. Perioperative amounts of pRBC, postoperative bleeding, major complications, duration of stay in the intensive care unit and overall hospital stay were compared. Differences in pRBC transfusions, postoperative bleeding, and duration of intensive care unit stay were not significant and no major complications occurred in either group. A significantly shorter overall hospital stay was observed in favour of the FFP-group. Volume replacement during pCFS can be safely performed with both applied protocols. Our data do not demonstrate a major advantage for FFP use, but further evaluation is necessary.

Surgical aspects and outcome of delayed tethered cord release.

Out of a total of 550 children followed up at our spina bifida center, we report on 81 patients who were reoperated upon for secondary tethered cord syndrome between 1993 and 2000. In four cases with preceding severe progressive scoliosis, untethering was followed by surgical correction and stabilization of curvatures. In 77 patients, the indication for surgery was based on late progressive neurological deterioration. The current clinical relevance of competing etiologic factors such as symptomatic Chiari malformation, hydromyelia, and shunt dysfunction, requiring different clinical management, had been previously carefully excluded. The children underwent magnetic resonance imaging (MRI) or myelo-computed tomography (m-CT) to identify the morphologic extent of tethering and any associated spinal malformations such as dermoid tumors (19 cases) or diastematomyelia (9 cases). Surgery became faster and safer through bilateral dural incision, undercutting arachnoid adhesions along the tethered area, although this procedure increased the need for dural grafting. Complete release of the conus medullaris and cauda equina was achieved in a total of 75 cases (93 %) including those who had undergone prophylactic surgery. A mean follow-up of 4.8 years in 77 patients operated upon for late progressive neurological deterioration confirmed stabilization of presenting symptoms in 65 cases (84 %) with 20 of them (26 %) even showing significant improvement. In 12 patients (16 %), including all cases of incomplete untethering (n = 4), there was further deterioration.

[Virtual MR endoscopy of the ventricles prior to neurosurgical interventional endoscopy -- evaluation of different presentation techniques]. / Virtuelle MR-Ventrikelendoskopie vor neurochirurgischer interventioneller Endoskopie -- Evaluierung verschiedener Darstellungstechniken.

PURPOSE: In the past, virtual endoscopies have been performed for planning of endoscopic interventions or for diagnostic purposes in various organ systems with increasing frequency. This study evaluates the ability of virtual ventricular endoscopy to depict anatomical structures and the use for planning of real endoscopy. MATERIALS AND METHODS: In a prospective study, 4 volunteers and 8 patients were examined with MRI. In 3 of the patients endoscopy was performed by our neurosurgeons thereafter. The calculation of the virtual endoscopy was based on 1 mm sagittal T2-weighted images. Comparison of surface rendering and volume rendering was made by means of video sequencing of individual views, and these were compared with the intraoperative endoscopic videos concerning the depictability of anatomical landmarks. RESULTS: The reconstructions using volume rendering were more significant and easier to calculate than those based on surface rendering. Virtual endoscopy in the transparent mode allowed visualization of hazardous structures outside the ventricular system such as the basilar artery tip. Transparent 3D images of the ventricles gave a good overview on the depicted structures and enabled a better orientation during the virtual camera flight than surface rendered views. CONCLUSION: MR-based virtual endoscopy of the ventricular system can be obtained on the basis of surface- and volume-rendered views of sagittal T2-weighted thin sections. Preoperative utilization of this method simplifies the planning of endoscopy by visualization of anatomical structures.

Technical aspects and results of surgery for craniosynostosis.

BACKGROUND: The timing and extent of surgery continue to be a matter of discussion in current craniosynostosis management. PATIENTS AND METHODS: We retrospectively reviewed the first 159 children seen from 1996 to 2000 of a total of 243 patients presenting with suspected craniosynostosis. We did not establish a surgical indication in 74 children (47%), either because their malformations were of different origin without associated craniosynostosis (11/7%) or they presented with only mild clinical manifestations of sutural synostosis (63/40%). In 85 cases (53%), we established a surgical indication. Parents did not follow our recommendation in two cases (1%). In 83 cases, we performed diagnosis-related remodeling at the age of 4-12 months. Demographic data, clinical follow-up findings, and regular photo documentation were analyzed. RESULTS: After a mean follow-up of 3 years and 8 months, the results were satisfactory in 68 cases (82%). Of 15 cases (18%) with only limited improvement, two children were submitted to a second intervention. Another two children had to be reoperated on immediately for insufficient hemostasis. In the largest subgroup of children (47) with sagittal synostosis, there was no difference in outcome between surgery performed before and after 6 months of age. DISCUSSION: Surgical indication and assessment of results are based on subjective criteria which limit the comparison with the literature. Our results correspond to those of similar published series. Most of the unfavorable results could be attributed either to inadequate adaptation of the surgical technique to the individual form of the malformation or to a significant secondary loss of correction in multi-sutural synostosis. CONCLUSIONS: The overall results of surgery within the first year of life were satisfactory in 82%. Standard procedures need to be adapted carefully to the individual form of craniosynostosis to avoid unfavorable results. We therefore propose a new surgical technique based on a statistically averaged modular system of skull models to replace freehand remodeling.

Spontaneous intracerebral hemorrhage and multiple infarction in Williams-Beuren syndrome.

A 7-year-old boy diagnosed with Williams-Beuren syndrome was admitted for spontaneous right hemispheric intracerebral hemorrhage. Cerebral angiography did not reveal any source of bleeding. After a short period of clinical improvement under conservative treatment, the boy deteriorated rapidly. CT showed the beginning of a complete infarction of both hemispheres. Operative evacuation of the bleeding and bilateral osteoclastic decompression had no perceptible influence on the clinical course. To the present day, the boy has remained in a vegetative state. Reports in the literature suggest that Williams syndrome with cerebral infarction is associated with a markedly poorer prognosis when there is additional intracerebral bleeding.

[3-dimensional post-myelographic CT reconstruction in diagnosis and therapy planning of spinal dysraphism]. / Dreidimensionale postmyelographische CT-Rekonstruktion in der Diagnostik und Therapieplanung spinaler Entwicklungsstörungen.

Dysrhaphia is often associated with severe osseous aberrations of the spine such as, for example scoliosis, hemivertebra, and synostosis. With the advanced possibilities of the post-processing of CT-data (segmentation, three-dimensional reconstruction), post-myelo-CT is an excellent method for the evaluation of osseous structures and the myelon in preoperative planning.

Nail incorporation kinetics of terbinafine in onychomycosis patients.

Patients with toe-nail onychomycosis were treated with terbinafine (250 mg daily, n = 20) for either 6 or 12 weeks in a randomized double-blind study. Plasma and distal nail clippings were taken before initiation of therapy and 1, 6, 12, 18, 24, 36 and 48 weeks thereafter. Analytical data of terbinafine extracted from nail clippings or plasma were obtained by high-performance liquid chromatography (HPLC). Nail extracts and isolated HPLC terbinafine peaks were analysed using a combined gas chromatography-mass spectroscopy system (GC-MS) for unequivocal identification of the drug. Terbinafine could be detected in the distal nail in the majority of the patients within 1 week of starting therapy. Maximum terbinafine levels of 0.52 and 1.01 micrograms/g were measured after 18 weeks in the 6- and 12-week treatment groups, respectively. While plasma levels decreased rapidly after termination of therapy terbinafine was detected in the nails as long as 30 weeks (6 weeks treatment) and 36 weeks (12 weeks treatment) after termination of therapy at a range of 0.28-0.19 microgram/g. The drug concentrations measured at all time points are well above the minimum inhibitory concentration (MIC) for dermatophytes and other fungi. These data suggest that the drug reaches the nail plate rapidly and persists there for several months after cessation of active treatment.

Surgical observations in extremely lateral lumbar disc herniation.

About 10% of lumbar disc herniations are localized in an extreme lateral position referred to as "extracanalicular". The clinical syndrome is a typical one with compression signs of the lateral, extra-foraminal nerve root and minimal lumbar pain. A reliable diagnosis can be made only since high resolution spinal computed tomography has become available. Surgical treatment will be rendered difficult by the "hidden" localisation of the disc fragments. A total number of 15 patients has been operated on in our department during the last year. In 10 patients, we used the lateral microsurgical approach proposed by REULEN, in five cases a combined procedure with lateral sequestrotomy and medial nucleotomy. In the first group, re-sequestration occurred in three cases and further surgery including medial nucleotomy was performed then. A good result with remission could be achieved in 13 cases, whereas in two cases with additional spondylolisthesis, lumbar back pain continued, but the radicular symptoms were reduced.

Analytical methods for the determination of terbinafine and its metabolites in human plasma, milk and urine.

Analytical procedures have been developed for the determination of the allylamine antimycotic terbinafine (1) and its demethylderivate (2) in plasma, milk and urine, and the metabolite carboxy-terbinafine (3) in plasma and urine, as well as the further metabolites demethyl-carboxy-terbinafine (4) and naphthoic acid (5) in urine. HPLC-methods for plasma analysis employed either electrochemical detection (for 1 and 2) or UV-detection (for 3) following a protein precipitation step with methanol or sample extraction with hexane as appropriate. For quantitative urine analysis of substances 1-4 native urine samples were deconjugated, mixed with internal standard and injected by an autosampler into a microprocessor controlled HPLC-system. The substances were monitored by UV-absorption. The metabolite 5 was determined in urine after deconjugation, sample preparation with commercially available cartridges and silylation by automatized GC with fused silica capillary column and FID-detection. The standard calibration curves for the parent compound (1) and metabolites (2-5) are linear within the required analytical ranges. The detection limit for 1 and 2 is 50 ng/ml in plasma and 150 ng/ml in milk and for 3 in plasma 100 ng/ml. The detection limit in urine is 300 ng/ml for all substances (1-4) analyzed by HPLC and 50 ng/ml for 5 analyzed by GC.

[Diagnosis and surgical treatment of cervical intervertebral disk displacement and cervical myelopathy]. / Zur Diagnostik und operativen Behandlung des cervicalen Bandscheibenvorfalles und der cervicalen Myelopathie.

Despite the availability of excellent neuroradiological examination techniques, a decision to operate is usually still reached largely on the basis of a diagnosis of radical and/or medullary cervical compression syndrome made by clinical neurological examination. Computer tomography has allowed a decisive improvement in the diagnosis of these processes, since the position of parts of discs that have prolapsed or sequestrated dorsally or dorsolaterally relative to the spinal cord and the nerve roots can be visualized directly. Since core spin tomography does not yield information that is any more helpful in the diagnosis, despite the considerably higher level of technical sophistication and higher costs, we are of the opinion that there is no call to apply this procedure routinely for the diagnosis of medial and lateral cervical disc rupture. Since the neurological symptoms do not always allow localization of the radicular or medullary damage to the segment or segments affected, it is sometimes necessary to perform myelography with water-soluble contrast media for this purpose. The microsurgical procedures available are restricted foraminotomy for the relief of cervical nerve root compression and ventral diskectomy for the relief of spinal cord compression.

Comparative pharmacokinetic analysis of latamoxef and CPW 86-363, a novel carboxy-pyrazol-cephalosporin and formation of N-methyl-thiotetrazole.

The pharmacokinetics of latamoxef and CPW 86-363, a novel carboxy-pyrazol-cephalosporin, were evaluated in healthy volunteers after intravenous bolus injection of 1 g. Based on concentration-time courses in serum both cephalosporins showed similar distribution properties, although CPW 86-363 was eliminated significantly faster. The route of elimination of latamoxef was mainly via the urine, whereas CPW 86-363 was also excreted into the bile. N-methylthiotetrazole, which is the common side chain in position 3 of both cephalosporins, was found in the serum as well as in the urine. Its rate and extent of formation was higher for latamoxef than for CPW 86-363 and depends rather on the instability of the parent compound than on metabolic transformation. This is supported by studies on the in vitro degradation of both derivatives. The relevance of these findings are discussed in view of secondary coagulopathies, which are associated with cephalosporins having a N-methylthiotetrazole side chain.

Analytical methods for the determination of naftifine and its metabolites in human plasma and urine.

Analytical procedures have been worked out for the determination both of naftifine, the antifungal constituent of Exoderil, and its demethyl derivative in plasma, and of the metabolites p-hydroxyphenyl-, 3,4-dihydrodiol- and 7,8-dihydrodiol-naftifine and naphthoic acid in urine. For plasma a HPLC-method with UV-detection after extraction of the samples with hexane is used. In urine samples the metabolites are deconjugated, extracted with chloroform, silylated and measured by GC with flame ionization detection. The standard calibration curves for the parent compound and metabolites are linear. The detection limit for naftifine and its demethyl derivative is ca. 5 ng/ml, for naphthoic acid 1 microgram/ml and for the other metabolites 2 micrograms/ml.

Major routes of naftifine biotransformation in laboratory animals and man.

Following dermal or oral administration to laboratory animals and man (E)-N-methyl-N-(1-naphthylmethyl)-3-phenyl-2-propen-1-amine- hydrochloride (naftifine), the antifungal constituent of Exoderil, is quantitatively biotransformed into, and excreted as metabolites devoid of antifungal activity. The structures of 15 metabolites were elucidated. In rat urine and bile these metabolites represent 70% of the orally absorbed dose. The biotransformation routes are: N-dealkylation, oxidation or reduction of the aldehyde intermediates from a) to the corresponding carboxylic acid- or alcohol-type metabolites, arene oxide formation in the phenyl- and naphthalene moieties of Naftifine, and conjugation, mainly with glucuronic acid and glycine. Similar metabolite patterns were obtained after oral and parenteral administration. The same pathways of naftifine biotransformation were observed in all species investigated, i.e. in man, rat, dog, rabbit and guinea pig, the last two species most closely resembling to man with respect to overall kinetics and urinary metabolite pattern.