Gastrointestinal and eating problems in SCN1A-related seizure disorders.

OBJECTIVE: Our study aimed to describe the prevalence and characteristics of gastrointestinal and eating problems in Dravet syndrome (DS) and other SCN1A-related seizure disorders and to determine the association between the occurrence of gastrointestinal and eating problems and core features of DS. METHODS: Gastrointestinal and eating problems were assessed with a questionnaire in a Dutch cohort of participants with an SCN1A-related seizure disorder. Associations between the number of gastrointestinal and eating problems and core features of DS, seizure severity, level of intellectual disability, impaired mobility, behavioral problems, and use of anti-seizure medication, were explored by multivariate ordinal regression analyses. Symptoms were divided into the categories dysphagia-related, behavioral, and gastrointestinal, and were assessed separately. RESULTS: One hundred sixty-nine participants with an SCN1A-related seizure disorder, of whom 118 (69.8%) with DS and 51 (30.2%) with Generalized Epilepsy with Febrile Seizures Plus / Febrile Seizures (GEFS+/FS), the non-DS phenotype, were evaluated. Gastrointestinal and eating problems were highly prevalent in DS participants, 50.8% had more than three symptoms compared to 3.9% of non-DS participants. Of participants with DS, 17.8% were fully or partly fed by a gastric tube. Within the three different symptom categories, the most prevalent dysphagia-related symptom was drooling (60.7%), distraction during mealtimes (61.4%) the most prevalent behavioral symptom, and constipation and loss of appetite (both 50.4%) the most prevalent gastrointestinal symptoms. DS participants who use a wheelchair (odds ratio (OR) 4.9 95%CI (1.9-12.8) compared to walking without aid), who use ≥3 anti-seizure medications (ASM) (OR 5.9 95%CI (1.9-18.2) compared to <3 ASM) and who have behavioral problems (OR 3.0 95%CI (1.1-8.1) compared to no behavioral problems) had more gastrointestinal and eating problems. CONCLUSION: Gastrointestinal and eating problems are frequently reported symptoms in DS. Distinguishing between symptom categories will lead to tailored management of patients at risk, will improve early detection, and enable a timely referral to a dietitian, behavioral expert, and/or speech therapist, ultimately aiming to improve the quality of life of both patients and caregivers.

Refractory juvenile myoclonic epilepsy: a meta-analysis of prevalence and risk factors.

BACKGROUND AND PURPOSE: Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome for which treatment response is generally assumed to be good. We aimed to determine the prevalence and prognostic risk factors for refractoriness of JME. METHODS: We systematically searched PubMed and EMBASE and included 43 eligible studies, reporting seizure outcome after antiepileptic drug (AED) treatment in JME cohorts. We defined refractory JME as persistence of any seizure despite AED treatment and performed a random-effects meta-analysis to assess the prevalence of refractory JME and of seizure recurrence after AED withdrawal in individuals with well-controlled seizures. Studies reporting potential prognostic risk factors in relation to seizure outcome were included for subsequent meta-analysis of risk factors for refractoriness. RESULTS: Overall, 35% (95% confidence interval, 29-41%) of individuals (n = 3311) were refractory. There was marked heterogeneity between studies. Seizures recurred in 78% (95% confidence interval, 52-94%) of individuals who attempted to withdraw from treatment after a period of seizure freedom (n = 246). Seizure outcome by publication year suggested that prognosis did not improve over time. Meta-analysis suggested six variables as prognostic factors for refractoriness, i.e. having three seizure types, absence seizures, psychiatric comorbidities, earlier age at seizure onset, history of childhood absence epilepsy and praxis-induced seizures. CONCLUSION: One-third of people with JME were refractory, which is a higher prevalence than expected. Risk factors were identified and can be used to guide treatment and counselling of people with JME.

Measuring outcome after arterial ischemic stroke in childhood with two different instruments.

BACKGROUND: Assessment of outcome after childhood stroke is important both for clinical practice and for research purposes. The objective of this study was to compare two frequently used outcome measures. METHODS: In 40 children with arterial ischemic stroke (AIS), dichotomized outcome obtained from the Pediatric Stroke Outcome Measure (PSOM) was compared with a dichotomized modified Rankin Scale (mRS) combined with information on type of school attendance. In addition, we compared dichotomized outcome, obtained from the PSOM and the mRS combined with school attendance, with the results of pediatric quality of life (PedsQL) questionnaires and the impressions of the child's general functioning on a visual analogue scale (VAS) that was filled out by parents and investigators. RESULTS: In 35 children (88%), outcome classification was concordant between the two outcome measures. Five children had a poor outcome according to the PSOM and good outcome with the mRS including school performance. In these patients, mRS outcome classification agreed better with the impression of the investigators, as reflected by VAS scores ≥7.5. For both the PSOM and mRS in combination with school performance, patients with a good outcome had significantly higher PedsQL and VAS scores than those with a poor outcome (p values <0.01 for all comparisons). VAS scores of investigators and parents correlated significantly with PedsQL. CONCLUSIONS: In children with AIS, both PSOM and mRS combined with school type correlated significantly with quality of life and VAS scores of general functioning. The mRS combined with school type is easier to obtain than the PSOM, reflects function rather than deficits, includes an important measure of cognitive outcome, and corresponds better with the doctor's impression of outcome.

[The association of job satisfaction with self-reported burnout among urologists with migration background working at German hospitals : Results of the EUTAKD study]. / Die Assoziation von beruflicher Zufriedenheit mit selbstberichtetem Burnout bei Urologen und Urologinnen mit Migrationshintergrund tätig an deutschen Kliniken : Ergebnisse der EUTAKD-Studie.

INTRODUCTION: Urologists with a migration background currently provide patient care in German hospitals. Study results on job satisfaction and burnout of this important professional group have not been available so far. MATERIALS AND METHODS: Between August and October 2020, a questionnaire (SurveyMonkey® with 101 items) was conducted among urologists with migration background working in German hospitals regarding professional satisfaction and a validated survey of burnout (Maslach Burnout Inventory), among others. The subject of this work was the association of job satisfaction with the critical thresholds of burnout in the domains of emotional exhaustion (EE), depersonalization (DP), and low personal accomplishment (PA). RESULTS: For this work, 68 questionnaires could be completely analyzed. Study participants were dominantly male (90%), between 30 and 39 years of age (69%), married (72%), and working full-time (94%). Above critical thresholds of high burnout in the EE, DP, and PA domains were 27.9% (n = 19), 35.3% (n = 24), and 73.5% (n = 50) of study participants. A sum score was formed from five of a total of 39 satisfaction items, which independently predicted the EE and DP endpoints and a combined EE and DP endpoint in well-adjusted regression models. For each individual score of the sum score (range 5-25 points), the probability of a critical burnout is reduced by a relative 57% (EE), 25% (DP), and 34% (combined endpoint). In contrast, permanent employment contract, the clinic position as senior physician or chief physician, working full-time, and a married marital status significantly reduced the critical PA domain. CONCLUSION: Several dimensions of professional satisfaction were identified, the improvement of which could contribute to a decrease in burnout among urologists with a migrant background. Future intervention studies aimed at improving job satisfaction must follow.

The course and outcome of unilateral intracranial arteriopathy in 79 children with ischaemic stroke.

Arteriopathies are the commonest cause of arterial ischaemic stroke (AIS) in children. Repeated vascular imaging in children with AIS demonstrated the existence of a 'transient cerebral arteriopathy' (TCA), characterized by lenticulostriate infarction due to non-progressive unilateral arterial disease affecting the supraclinoid internal carotid artery and its proximal branches. To further characterize the course of childhood arteriopathies, and to differentiate TCA from progressive arterial disease, we studied the long-term evolution of unilateral anterior circulation arteriopathy, and explored predictors of stroke outcome and recurrence. From three consecutive cohorts in London, Paris and Utrecht, we reviewed radiological studies and clinical charts of 79 previously healthy children with anterior circulation AIS and unilateral intracranial arteriopathy of the internal carotid bifurcation, who underwent repeated vascular imaging. The long-term evolution of arteriopathy was classified as progressive or TCA. Clinical and imaging characteristics were compared between both groups. Logistic regression modelling was used to determine possible predictors of the course of arteriopathy, functional outcome and recurrence. After a median follow-up of 1.4 years, 5 of 79 children (6%) had progressive arteriopathy, with increasing unilateral disease or bilateral involvement. In the others (94%), the course of arteriopathy was classified as TCA. In 23% of TCA patients, follow-up vascular imaging showed complete normalization, the remaining 77% had residual arterial abnormalities, with improvement in 45% and stabilization in 32%. Stroke was preceded by chickenpox in 44% of TCA patients, and in none of the patients with progressive arteriopathies. Most infarcts were localized in the basal ganglia. In 14 (19%) of TCA patients, transient worsening of the arterial lesion was demonstrated before the arteriopathy stabilized or improved. Thirteen TCA patients (18%) had a recurrent stroke or TIA. Thirty TCA patients (41%) had a good neurological outcome, compared with none of the five patients with progressive arteriopathy. Arterial occlusion, moyamoya vessels and ACA involvement were more frequent in progressive arteriopathies. Cortical infarct localization was significantly associated with poor neurological outcome (OR 6.14, 95% CI 1.29-29.22, P = 0.02), while there was a trend for occlusive arterial disease to predict poor outcome (OR 3.00, 95% CI 0.98-9.23, P = 0.06). Progressive arteriopathy was associated with recurrence (OR 18.77, 95%CI 1.94-181.97, P = 0.01). The majority of childhood unilateral intracranial anterior circulation arteriopathies (94%) have a course that is consistent with TCA, in which transient worsening is common. Although the arterial inflammation probably causing TCA is 'transient', most children are left with permanent arterial abnormalities and residual neurological deficits.

[Rare tumor of the epididymis]. / Seltene Raumforderung des Nebenhodens.

A 51-year-old man with known ethyl toxic chronic pancreatitis presented with a tumor of the left epididymis. Immunohistological examination disclosed it as a metastasis of a pancreatic carcinoma. Paratesticular metastases of a pancreatic carcinoma are very rare. Nevertheless a metastasis of a primary pancreatic carcinoma should be included in the differential diagnosis of a tumor of the paratesticular tissue. The epididymis should be integrated in the diagnostic procedures of pancreatic carcinoma.

[Detection of papillomavirus DNA in the prostate: a virus with underestimated clinical relevance?]. / Die Detektion von Papillomavirus-DNA in der Prostata : Ein Virus mit unterschätzter klinischer Relevanz?

BACKGROUND: Human papillomaviruses (HPV) are the most frequent pathogens of sexually transmitted diseases. They have been associated with an increased incidence of several anogenital tumors. Whether oncogenic HPV are involved in the pathogenesis of prostate cancer has been a subject of great controversy. This study's purpose was to investigate the association between HPV infection and prostate cancer (PCA). MATERIAL AND METHODS: The study included 213 consecutive patients with an average age of 65.7 (+/-8.4) years. Within the framework of transrectal, ultrasonic-guided multibiopsy of the prostate, one additional core was examined by means of polymerase chain reaction (PCR) in relation to bacterial, fungal, and viral (including HPV) DNA, with subsequent DNA sequencing. The collected data were correlated with the histological results and with diverse clinical variables. The influence of several predictors for the existence of PCA was verified with a logistic regression model. RESULTS: No general bacterial DNA (16S rDNA) was detected. Of the 213 patients, 145 (68.1%) showed HPV DNA. In 64% (n=137), high-risk HPV DNA were depicted; these were 18% of the total in each case of HPV genotypes 16 and 18. From our examinations, no significant positive correlation existed between the HPV evidence and the histologically verified PCA that was found in 23.5% of the patients (n=50; odds ratio 1.45; 95% confidence interval 0.71-2.91). The BK virus was not found in any of the cores confirmed through PCR. CONCLUSION: Although no positive correlation between HPV infection and PCA existed in our study, data from the literature suggest an influence of the papillomavirus on PCA oncogenesis. Future studies should highlight to what extent HPV DNA is inserted in the genome of prostate cells and is able to cause subsequent malignant transformation of particular genes.

[The general practitioner's part in the initiation of diagnostic procedures in prostate cancer]. / Die Rolle des Hausarztes bei der Initiierung der Diagnostik des Prostatakarzinoms.

AIM: The aim of the study is the analysis of diagnostic procedures performed by general practitioners (GPs) leading to the detection of prostate cancer (PCA). PATIENTS AND METHODS: A retrospective evaluation was performed on all 406 patients who underwent ultrasound-supported transrectal multibiopsy of the prostate in our department between January 2004 and August 2005. The GPs were interviewed by use of standardised questionnaires concerning the indication for specific examinations, referrals to the specialist, the clinical findings and results, and the GPs own urological qualification. The rate of returned questionnaires was 72.9 % (105 of 144 GPs), therefore a study group (SG) of 295 patients (72.7 %) was formed. The mean age was 67.2 (40 - 90) years. RESULTS: In 190 patients (64.4 %) primary diagnostic measures were performed by the GP herself/himself. All the other patients had already been in urological specialist treatment (n = 43), were either referred directly to an urologist for primary diagnostics (n = 42) or were diagnosed during a hospital stay (n = 3). The reasons for the performed diagnostic measures were not to be found in 17 cases. In 50.8 % of all cases the initiation of preventive medical check-ups or determination of PSA levels was done at the patient's own request. 91 of 176 digital rectal examinations (DRE) performed by GPs showed suspect findings, leading to referral to the urologist in 62 cases. PSA levels of 105 patients measured by the GPs ranged between 0.0 and 1662 ng/mL with a mean level of 29.81 and a median of 6.20 ng/mL. In 75 cases the PSA level led to a referral to the urologist. In the case of 27 patients the referral was decided because of clinical symptoms. In 39.0 % (n = 115) of the SG a PCA was detected by biopsy. In 43.0 % (n = 64) of the patients originally examined by the GPs the suspected diagnosis of a PCA based on a pathological PSA level and/or DRE proved to be correct. The GPs stated in 35.2 % (n = 37) that they had spent a certain period of time in a urological department during their medical training. Concerning referrals and the positive predictive value of DRE, there was no statistically significant different to be found in GPs without urological training. CONCLUSION: Every fifth patient in the study group showed a histologically proven PCA that had initially been suspected by a GP based on a pathological PSA level and/or DRE. This underlines the value of preventive exams in the hands of GPs. In addition, the correct and sensible use of PSA levels controls by GPs as well as a pronounced desire for preventive medical check-ups on the patient's side was shown.

[Paediatric epilepsy surgery; the earlier, the better]. / Kinderepilepsiechirurgie: liever vroeg dan laat.

The first randomised trial of paediatric epilepsy surgery demonstrated what was already known for decades among physicians of children with refractory epilepsy: surgical treatment is a highly successful treatment option with superior efficacy compared to ongoing drug treatment in well-selected surgical candidates. The lack of equipoise and the design of the trial - in which half of the children had to wait for one year before being offered surgery - raises questions about its ethical justification. A shorter duration of epilepsy predicts better cognitive and seizure outcomes after surgery. Surgical risks are low, seizure-freedom rates are high for specific pathologies, and the chance of spontaneous permanent remission is low in children with focal lesional epilepsy. These children should be referred for presurgical evaluation early after diagnosis. Benefits of surgery may outweigh the limited surgical risks when the lesion is located outside eloquent brain areas, even when seizures are well controlled with antiepileptic drugs.

Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study.

INTRODUCTION: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. METHODS: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. RESULTS: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28-84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). CONCLUSION: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.

[Multicystic renal tumor in a patient with WAGR syndrome]. / Multizystischer Nierentumor bei einem Patienten mit WAGR-Syndrom.

The WAGR syndrome is a combination of Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation. We report on a 2-year-old boy, who had a deletion of the aniridia gene PAX6 and the Wilms' tumor gene 1 (WT1 gene). At the age of 23 months, a 1.7 x 1.9 cm-sized intrarenal tumor was detected by ultrasound examination. According to the protocol of the SIOP study, a cycle of neoadjuvant chemotherapy was prescribed followed by a left-sided nephrectomy. However, postsurgical histomorphology failed to confirm the suspected diagnosis of Wilms' tumor and instead revealed dysgenetic cysts of the kidney. Based on the image morphology in connection with the deletion of the WT1 gene, the tentative diagnosis of a nephroblastoma had to be made. The study protocol of the SIOP does not permit another therapy algorithm.

[Radical cystectomy in the treatment of bladder cancer always in due time?]. / Stellen wir die Indikation zur radikalen Zystektomie immer zeitgerecht?

INTRODUCTION: The aim of this study was to examine how the survival rates for patients with muscle-invasive bladder carcinoma are influenced by the tumor stage at initial presentation. PATIENTS AND METHODS: This study examined the clinical course of 452 patients who underwent radical cystectomy for bladder carcinoma from 1992 to 2004. The patients were divided into three groups according to the histological results of the initial and final transurethral tumor resection (TURB). In group 1 (n=114) patients who presented with a superficial bladder carcinoma which had a high likelihood of progressing underwent radical cystectomy. Group 2 included (n=92) patients who displayed a superficial tumor stage when they first presented and developed progressive muscle-invasive bladder carcinoma under conservative treatment. Group 3 (n=246) comprised patients who were already at the muscle-invasive tumor stage in the course of primary TURB. The histopathological characteristics of all transurethral tumor resections and radical cystectomy were recorded. Progression-free survival rates and overall survival rates in the three groups were then compared. RESULTS: The average patient age at cystectomy was 64.3 (35-80) years, and the average follow-up period was 49 months. Progression-free survival and overall survival of all 452 patients were 56.1 and 53.6%, respectively, after 5 years. The best outcome was a progression-free 5-year survival rate of 78.4% with organ-confined, lymph node-negative tumors (n=213). This result was statistically significant (p<0.01) compared with the progression-free 5-year survival rate of 42.3% for non-organ-confined, lymph node-negative tumors (n=112). Lymph node-positive patients (n=127) achieved a progression-free 5-year survival rate of 29.0% regardless of the tumor infiltration. Group 1 patients achieved a progression-free survival rate of 71.3% and an overall survival rate of 69.1% after 5 years. Group 2 patients achieved a progression-free survival rate of 52.9% and an overall survival rate of 51.4% after 5 years. Group 3 patients achieved a progression-free survival and overall survival of 50.2% and 47.1%, respectively, after 5 years. There was no significant difference between groups 2 and 3 with regard to their progression-free or overall survival rates (p>0.45). However, both groups displayed significantly poorer progression-free and overall survival rates compared with group 1 (p<0.01). CONCLUSION: Our results show that patients with superficial bladder carcinoma with tumor progression to muscle invasion do not have a better prognosis after radical cystectomy than patients presenting initially with muscle-invasive bladder carcinoma. Survival rates in this group can only be improved by singling out patients on the basis of risk factors at an earlier stage and carrying out cystectomy. Due to these results we must expect that waiting for a muscle invasion in patients with superficial bladder carcinoma with a high risk profile results in a significant impairment of prognosis.

Evoked versus spontaneous high frequency oscillations in the chronic electrocorticogram in focal epilepsy.

OBJECTIVE: Spontaneous high frequency oscillations (HFOs; ripples 80-250Hz, fast ripples (FRs) 250-500Hz) are biomarkers for epileptogenic tissue in focal epilepsy. Single pulse electrical stimulation (SPES) can evoke HFOs. We hypothesized that stimulation distinguishes pathological from physiological ripples and compared the occurrence of evoked and spontaneous HFOs within the seizure onset zone (SOZ) and eloquent functional areas. METHODS: Ten patients underwent SPES during 2048Hz electrocorticography (ECoG). Evoked HFOs in time-frequency plots and spontaneous HFOs were visually analyzed. We compared electrodes with evoked and spontaneous HFOs for: percentages in the SOZ, sensitivity and specificity for the SOZ, percentages in functional areas outside the SOZ. RESULTS: Two patients without spontaneous FRs showed evoked FRs in the SOZ. Percentages of evoked and spontaneous HFOs in the SOZ were similar (ripples 32:33%, p=0.77; FRs 43:48%, p=0.63), but evoked HFOs had generally a lower specificity (ripples 45:69%, p=0.02; FRs 83:92%, p=0.04) and higher sensitivity (ripples 85:70%, p=0.27; FRs 52:37%, p=0.05). More electrodes with evoked than spontaneous ripples were found in functional (54:30%, p=0.03) and 'silent' areas (57:27%, p=0.01) outside the SOZ. CONCLUSIONS: SPES can elicit SOZ-specific FRs in patients without spontaneous FRs, but activates ripples in all areas. SIGNIFICANCE: SPES is an alternative for waiting for spontaneous HFOs, but does not warrant exclusively pathological ripples.

High frequency oscillations and high frequency functional network characteristics in the intraoperative electrocorticogram in epilepsy.

OBJECTIVE: High frequency oscillations (HFOs; > 80 Hz), especially fast ripples (FRs, 250-500 Hz), are novel biomarkers for epileptogenic tissue. The pathophysiology suggests enhanced functional connectivity within FR generating tissue. Our aim was to determine the relation between brain areas showing FRs and 'baseline' functional connectivity within EEG networks, especially in the high frequency bands. METHODS: We marked FRs, ripples (80-250 Hz) and spikes in the electrocorticogram of 14 patients with refractory temporal lobe epilepsy. We assessed 'baseline' functional connectivity in epochs free of epileptiform events within these recordings, using the phase lag index. We computed the Eigenvector Centrality (EC) per channel in the FR and gamma band network. We compared EC between channels that did or did not show events at other moments in time. RESULTS: FR-band EC was higher in channels with than without spikes. Gamma-band EC was lower in channels with ripples and FRs. CONCLUSIONS: We confirmed previous findings of functional isolation in the gamma-band and found a first proof of functional integration in the FR-band network of channels covering presumed epileptogenic tissue. SIGNIFICANCE: 'Baseline' high-frequency network parameters might help intra-operative recognition of epileptogenic tissue without the need for waiting for events. These findings can increase our understanding of the 'architecture' of epileptogenic networks and help unravel the pathophysiology of HFOs.

Is it possible to provide a prognosis after radical prostatectomy for prostate cancer by means of a PSA regression model?

BACKGROUND: For over 15 years, studies have been done to evaluate the elimination kinetics of the prostate-specific antigen (PSA) after radical prostatectomy. Even though evaluation of PSA regression in the two-compartment model has become established, no clear data are currently available as to whether a statement can be made with regard to tumor prognosis from a computation of the PSA half-life (PSA-HL). This study focuses on the determination of the PSA-HL in the two-compartment model and on its correlation with the biochemical recurrence-free survival. In addition, a computer program is being developed to simplify the determination of PSA-HL. MATERIAL AND METHODS: Seventy-seven prospective patients were examined who subsequently had a radical prostatectomy at our facility without neoadjuvant or adjuvant hormone deprivation. In addition to preoperative measurement of the PSA value (dO), PSA determinations were carried out postoperatively on days 5, 10 and 60, and at four-monthly intervals thereafter (mean follow-up: 16 months). By means of the computer program developed for this purpose, CTK.TumW, the PSA half-lives for the first (d0-d5, PSA-HL1) and second (d5-d10, PSA-HL2) compartments were subsequently determined and their effect on biochemical recurrence-free survival was assessed. RESULTS: PSA-HL1 and PSA-HL2 were 1.89 (+/- 0.03) and 3.39 (+/- 0.14) days, respectively. Whilst PSA-HL1 did not permit any prognostic statement, the median PSA-HL in the second compartment between patients with and without disease progression differed significantly (4.44 versus 3.12 days; p < 0.001). Discrimination analysis produced a cutoff of 3.8 days for the second compartment; patients with a PSA-HL2 > or = 3.8 days had a significantly worse biochemical recurrence-free survival after 18 months than the other patients (27% versus 93%; p < 0.001). CONCLUSION: The PSA regression kinetics after radical prostatectomy follows a two-compartment model in which the prognostic value of the PSA-HL1 is limited. When a cutoff of 3.8 days is used, evaluation of the PSA-HL in compartment 2 (d5-10) appears to permit a prognostic statement. Due to the limited postsurgical follow-up, the disease process was only assessed as biochemical recurrence-free survival, and a longer follow-up will be necessary to generate data on progression-free survival.

Cerebral ischemia and white matter edema in experimental hydrocephalus: a combined in vivo MRI and MRS study.

T2 and diffusion weighted MRI, as well as 31P and 1H MRS were performed in kaolin-induced hydrocephalic rats. Extracellular white matter edema was detected in the early stages of progressive hydrocephalus. Phosphocreatine (PCr)/inorganic phosphate (Pi) ratios in hydrocephalic animals were decreased compared to controls, and lactate was detected during the acute and chronic stages of hydrocephalus. These MR spectroscopic results are indicative of a compromised energy metabolism and suggest the occurrence of cerebral ischemia in experimental hydrocephalus.

Non-radioactive determination of inosine 5'-monophosphate dehydro-genase (IMPDH) in peripheral mononuclear cells.

BACKGROUND: The immunosuppressive activity of mycophenolate mofetil (MMF) is based on the reversible inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). It was the aim of this study to develop a nonradioactive method for specific measurement of IMPDH activity in isolated peripheral mononuclear cells (MNC). METHODS: The procedure is based on the incubation of lysed MNC with inosine 5'-monophosphate (IMP) followed by direct chromatographic determination of produced xanthosine 5'-monophosphate (XMP). IMPDH activity was measured in MNC of MMF-treated patients and nontreated volunteers. RESULTS: The within-run (n = 10) and between-run (n = 20) coefficients of variation (CV) for IMPDH activity were < 8% and < 10%, respectively. IMPDH activity in 60 healthy volunteers (19-63 yr) ranged from 4.72 to 32.92 nmol/h/mg protein (mean = 18.39 +/- 6.24). The IC(50) for in vitro inhibition of IMPDH activity was about 2 to 3 microg/L. Application of a single dose of 1 g MMF in dialysis patients resulted in a significant inhibition (by 47-95%; p < 0.05) of IMPDH activity in lysed MNC. CONCLUSIONS: The proposed assay specifically and reliably measures IMPDH activity in MNC. The procedure is applicable to evaluate pharmacodynamic activity in MMF-treated patients. The observed interindividual variability of IMPDH activity may reflect pharmacodynamic differences in MMF-treated patients.

Cerebral metabolism in experimental hydrocephalus: an in vivo 1H and 31P magnetic resonance spectroscopy study.

OBJECT: Brain damage in patients with hydrocephalus is caused by mechanical forces and cerebral ischemia. The severity and localization of impaired cerebral blood flow and metabolism are still largely unknown. Magnetic resonance (MR) spectroscopy offers the opportunity to investigate cerebral energy metabolism and neuronal damage noninvasively and longitudinally. Previous 1H MR spectroscopy studies have shown an increased lactate resonance that is suggestive of anaerobic glycolysis. The aim of this study was to assess cerebral damage and energy metabolism in kaolin-induced hydrocephalus in adult rats by using in vivo 1H and 31P MR spectroscopy. The presence of lactate was correlated with high-energy phosphate metabolism and intracellular pH. The measurement of relative concentrations of N-acetyl aspartate (NAA), choline (Cho), and total creatine (tCr) served to assess neuronal damage. METHODS: Hydrocephalus was induced in adult rats by surgical injection of kaolin into the cisterna magna. Magnetic resonance studies, using a 4.7-tesla magnet, were performed longitudinally in hydrocephalic animals at 1 (10 rats), 8 (six rats), and 16 weeks (six rats) thereafter, as well as in eight control animals. To evaluate ventricular size and white matter edema T2-weighted MR imaging was performed. The 1H MR spectra were acquired from a 240-microl voxel, positioned centrally in the brain, followed by localized 31P MR spectroscopy on a two-dimensional column that contained the entire brain but virtually no extracranial muscles. The 1H and 31P MR spectroscopy peak ratios were calculated after fitting the spectra in the time domain, intracellular pH was estimated from the inorganic phosphate (Pi) chemical shift, and T2 relaxation times of 1H metabolites were determined from the signal decay at increasing echo times. CONCLUSIONS: In hydrocephalic rats, ventricular expansion stabilized after 8 weeks. White matter edema was most pronounced during acute hydrocephalus. Lactate peaks were increased at all time points, without a decrease in phosphocreatine (PCr)/Pi and PCr/adenosine triphosphate (ATP) peak ratios, or pH. Possibly lactate production is restricted to periventricular brain tissue, followed by its accumulation in cerebrospinal fluid, which is supported by the long lactate T2 relaxation time. Alternatively, lactate production may precede impairment of ATP homeostasis. The NAA/Cho and tCr/Cho ratios significantly decreased during the acute and chronic stages of hydrocephalus. These changes were not caused by alterations in metabolite T2 relaxation time. The decreases in the NAA/Cho and tCr/Cho ratios implicate neuronal loss/dysfunction or changes in membrane phospholipid metabolism, as in myelin damage or gliosis. It is suggested that 1H MR spectroscopy can be of additional value in the assessment of energy metabolism and cerebral damage in clinical hydrocephalus.

The utility of 2-hydroxypropyl-beta-cyclodextrin as a vehicle for the intracerebral and intrathecal administration of drugs.

The substituted glucopyranose ring structure 2-hydroxypropyl-beta-cyclodextrin (CDEX) increases the solubility of molecules by inclusion of the agent in the lipophilic interior of the ring. This property is of particular use for the administration of molecules by the intracerebral (ICV) or intrathecal (IT) routes. In concentrations up to 40% w/v (isotonic), this agent (10 microliters) effect upon nociceptive or motor function after IT injection or on EEG and general behavior after ICV injection in rats. Using 20% CDEX, there is no change in the ED50 as compared to saline on the hot plate (HP) after IT injection of morphine, D-Ala2-D-Leu5 enkephalin or Tyr-Aib-Gly-gPhe-mAib-NH2, (Aib: alpha-aminoisobutyric acid) although there is an increase in their respective durations of effect. Cyclic peptide opioids: Tyr-c[D-A2bu-Gly-D-beta Nal(1)-D-Leu] (A2bu: alpha, gamma-diaminobutyric acid; beta-Nal(1): beta-naphthylalanine(1)) or Tyr-c[DA2bu-Gly-beta Nal(1)-D-Leu] are insoluble in saline but are readily dissolved in CDEX, and display a naloxone-sensitive antinociception following spinal administration. In other studies, saline insoluble capsaicin is administered in 25% dimethylsulfoxide (DMSO) or 20% CDEX (15 microliters; 5 mg/ml) which result in a significant reduction in the spinal levels of substance P and calcitonin gene related peptide and an increase in the HP latency. DMSO alone, but not CDEX alone, reduces the levels of the two peptides. These data emphasize the utility of complexation with CDEX for intracerebral drug delivery and compatibility with brain and spinal tissue.

NMR spectroscopic evaluation of cerebral metabolism in hydrocephalus: a review.

Cerebral ischemia contributes to cerebral damage in hydrocephalus. Many studies have reported changes in cerebral blood flow and metabolism, supporting this hypothesis. Magnetic resonance spectroscopy (MRS) enables us to investigate cerebral metabolism in a non-invasive and longitudinal manner, thereby providing a promising way of evaluating pathophysiological changes in experimental and clinical hydrocephalus. In this review, the potential of 1H (proton) and 31P (phosphorus) MRS in the assessment of cerebral metabolism will be summarized, and a synopsis of in vitro and in vivo MRS studies in experimental and human hydrocephalus will be presented. Changes in high-energy phosphate metabolism, intracellular pH and lactate production in several MRS studies are presumed to reflect cerebral ischemia. In vivo information on neuronal damage, maturational delay and membrane phospholipid metabolism may also be derived from 1H and 31P MRS data. Technical, methodological and pathophysiological considerations, which are important for a correct interpretation and comparison of different MRS studies, will be discussed. Finally, we will draw some conclusions on the significance of these MRS findings and the applicability of MRS in the diagnosis and evaluation of clinical hydrocephalus.