Pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) to patients with peritoneal carcinomatosis

The pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) was characterized in patients with peritoneal carcinomatosis. Cisplatin was added into the perfusate with escalating doses from 100 mg/m2 to 400 mg/m2. The hyperthermic perfusion was maintained for 90 minutes with a flow rate of 1.5 L/min and a target peritoneal temperature of 42.5 degrees C after a tumor debulking procedure. Samples of both the perfusate and blood were obtained during the perfusion and 30 minutes after the perfusion. Cisplatin plasma and perfusate concentrations were determined by flameless atomic absorption spectrometry with a lower limit of detection of 2 ng/ml and a coefficient of variation (CV) < 10%. Fifty-six patients were enrolled in the study. The mean (+/- SD) percentage of cisplatin present in the perfusate at the completion of perfusion was 27.8% +/- 20% of the total dose. The maximum cisplatin concentrations in the perfusate were 10 times higher than those in plasma. The area under the concentration-time curve (AUC) of the perfusate was 13 times higher than the AUC of plasma. A two-compartment model with an additional peritoneal cavity compartment fits to the data best based on the Akaike information criterion. However, the interpatient variability was considerably high (CV < 100%). In conclusion, cisplatin administered by hyperthermic peritoneal perfusion resulted in a pharmacological advantage by obtaining higher and direct drug exposure to the tumor in the peritoneal cavity while limiting systemic absorption and toxicity. Using a complex two-compartment model, the authors were able to characterize the pharmacokinetics of cisplatin given intraperitoneally via this technique.     

Inflammatory mechanisms in Alzheimer's disease

In recent years many studies have indicated an involvement of inflammatory mechanisms in Alzheimer's disease (AD). Acute-phase proteins such as 1-antichymotrypsin and c-reactive protein, elements of the complement system, and activated microglial and astroglial cells are consistently found in brains of AD patients. Most importantly, also cytokines such as interleukin-6 (IL-6) have been detected in the cortices of AD patients, indicating a local activation of components of the unspecific inflammatory system. Up to now it has remained unclear whether inflammatory mechanisms represent a primary event or only an unspecific reaction to brain tissue damage. Therefore, we investigated whether IL-6 immunoreactivity could be found in plaques prior to the onset of neuritic changes, or whether the presence of this cytokine is restricted to later stages of plaque pathology. we confirmed our previous observation that IL-6 is detectable in a significant proportion of plaques in the brains of demented patients. In AD patients IL-6 was found in diffuse plaques in a significant higher ratio as would have been expected from a random distribution of IL-6 among all plaque types. This observation suggests that IL-6 may precede neuritic changes, and that immunological mechanism may be involved both in the transformation from diffuse to neuritic plaques in AD and in the development of dementia.     

Transformed cells trigger induction of their own apoptosis in coculture with normal cells

In vitro, transforming growth factor type betal triggers normal cells to induce apoptosis in transformed cells. We show that in the absence of exogenous transforming growth factor type betal, induction of apoptosis of transformed cells in coculture with normal cells is dependent on the number of transformed cells per assay and is abrogated by antibodies against TGF-beta 1. Therefore, transforming growth factor type betal produced by transformed cells seems to be responsible for triggering a mechanism that leads to the induction of their apoptosis. This mechanism may be crucial for the control of carcinogenesis in vivo.     

Serological response of multiple sclerosis patients and controls to 6/94-parainfluenza virus

Summary The serological responses of 195 multiple sclerosis (MS) patients and 251 controls were tested against 6/94-parainfluenza virus, which was previously isolated from brain tissue of two patients with MS. The hemagglutination-inhibition titers of 1:128 were found more frequently in MS patients (21.5%) than in controls (14.0%). However, the geometric mean titers did not differ between these two groups. The present study concludes that a causal relationship of 6/94-virus to MS, based on a specific immune response, is improbable, although it does not exclude the possibility of a pathogenetic significance of the agent in the cases from which the autopsy material was derived.Supported by Deutsche Forschungsgemeinschaft (Schwerpunkt Ätiologie und Pathogenese der Multiplen Sklerose und verwandter Erkrankungen)     

Isolation and detection of phorbolesters in crotonoil with HPLC.

A HPLC method using reversed-phase columns is described for the determination and isolation of phorbolesters in crotonoil. The identification of the compounds is based on an off-line combination of HPLC-MS, as well as on fatty acid analysis by GC. With this method several new phorbolesters of crotonoil could be detected. This method is also suitable for the determination of phorbol- or similar diterpenesters in other Euphorbiaceae.     

Transformation of rodent fibroblasts by herpes simplex virus: presence of morphological transforming region 1 (MTR 1) is not required for the maintenance of the transformed state.

Studies on the mechanisms of transformation of mammalian cells by herpes simplex virus (HSV) in vitro have been prevented so far by the extremely low transformation frequencies obtained in monolayer culture. Here we present a transformation system that relies on the direct seeding in soft agar of infected single cells, thus avoiding negative interactions between normal and transformed cells. We took advantage of HSV-I temperature-sensitive mutants at the UL9 locus, which codes for a DNA-binding protein necessary for viral DNA replication. At the non-permissive temperature, viral DNA synthesis and late gene expression are prevented. Viral gene expression is restricted to immediate early and early genes. Induction of transformation was highly efficient in our one-step transformation system. It depended on intact viral particles and viral DNA. Immediate early and/or early viral gene expression was sufficient to induce transformation. Colonies were stably transformed and did not show any rescue of viable virus after temperature downshift and co-cultivation with susceptible cells. Transformed cells maintained the transformed state in the absence of viral DNA. Our data therefore support the "hit-and-run" hypothesis for the transforming effect of HSV.     

The prophylactic value of clean intermittent catheterization and anticholinergic medication in newborns and infants with myelodysplasia at risk of developing urinary tract deterioration.

OBJECTIVE--To determine if prophylactic use of clean intermittent catheterization and oxybutynin chloride is effective in preventing urinary tract deterioration in myelodysplastic children with high bladder pressure and detrusor-sphincter dyssynergia. DESIGN--Sequential, nonrandomized trial. SETTING--Referral-based urodynamics facility and myelodysplasia program at a major city pediatric hospital. PARTICIPANTS--Twenty-six of 71 consecutive newborns with myelodysplasia who exhibited these urodynamic findings were treated prophylactically over 5 years, whereas 56 of 105 consecutive newborns with the same findings treated during the previous 7 years were treated expectantly. INTERVENTION--Clean intermittent catheterization and oxybutynin therapy were begun when these specific urodynamic findings were detected. MEASUREMENTS AND RESULTS--Follow-up urodynamic studies and roentgenographic assessment of the urinary tract were performed periodically over 5 years. Oxybutynin eliminated uninhibited contractions in two of 14 newborns and lowered peak contractile pressure in the remaining 12. Oxybutynin also lowered bladder-filling pressure at capacity in all 12 additional neonates with only hypertonicity. Twenty-four (92%) of 26 children had normal kidney function and drainage during the observation period, two (8%) developed hydroureteronephrosis, and one of these two had vesicoureteral reflux. In a prior study of children similarly at risk who were treated expectantly, the roentgenographic appearance of the upper urinary tract had changed in 48%. Minimal side effects were noted with oxybutynin, and no adverse effects of clean intermittent catheterization were detected. CONCLUSIONS--Oxybutynin effectively reduces uninhibited contractions and lowers detrusor filling pressure, while clean intermittent catheterization allows bladder emptying at low pressures with no measurable side effects in these neonates. The overall effect maintains the integrity of the upper urinary tract in almost all myelodysplastic children at risk of urinary tract deterioration. Expectant therapy can no longer be advocated when these "at risk" children are identified because prophylactic treatment is so effective.     

Anaesthetic anagement of Miller’s syndrome

Miller's syndrome is a rare congenital disorder with facial features similar to that of Treacher-Collins syndrome. This report details the anaesthetic management of an infant during multiple surgical procedures, beginning with pylormyotomy at one month of age. Airway management was difficult because of severe micrognathia and was accomplished using an awake intubation with a conventional straight blade modified for continuous administration of oxygen ("oxyscope"). Due to recurrent upper airway obstruction and the anticipated need for multiple surgical procedures in the first years of life, a tracheostomy was placed. Because of the multiple airway, orthopaedic, and nutritional difficulties, it is important that a prospective, multidisciplinary approach be used in these patients' care. Consideration should be given to early tracheostomy for airway maintenance.     

Digitizing the moving face during dynamic displays of emotion

Humans typically decode facial signals during dynamic interactions in which the face moves. In this study, we digitized real time video signals in order to examine movement asymmetries across the face during emotional and nonemotional expressions. Forty dextral males were tested. For each expression, a 400 ms video segment was analyzed for changes in signal value (pixel intensity) over consecutive frames. The upper and lower face regions were examined separately due to differences in the cortical enervation of facial muscles in the upper (bilateral) vs lower face (contralateral). Results revealed distinctly different movement asymmetries over the lower and upper hemiface. In the upper face, more movement occurred over the right side for most facial expressions, regardless of emotionality. The latter finding questions the assumption that muscles of the upper face are symmetrical and/or bilaterally enervated in a symmetrical manner. In the lower face, negative expressions linked to fight-flight emotions (i.e. fear, anger) were associated with greater left sided movement, whereas happiness tended to be associated with more right sided movement. No consistent pattern of movement asymmetry occurred for nonemotional expressions. Although the valence-related movement asymmetries in the lower face are consistent with neuropsychological models of emotional expressivity, it remains unclear whether they reflect activation or inhibitory hemispheric mechanisms. Taken together, these data suggest that multiple factors may contribute to expressive movement asymmetries of the face.