Age dependency of DNA repair in rats after DNA damage by carcinogens

Damage to DNA seems to be an important cause of cancer and to play a role in aging. Much of this damage results from the action of chemical agents in the environment. These chemicals provide a chance to study DNA repair mechanisms and to construct a model for the investigation of changes in repair with aging. To damage the DNA of male Sprague-Dawley rats aged 6, 22–24 and 24–26 months, three carcinogens were used: N-methyl-N-nitrosourea (MNU), methyl methane sulfonate (MMS) and N,N-dimethylnitrosamine (DMN). DNA repair was measured as unscheduled DNA synthesis (UDS) in ten (MNU and DMN) and five (MMS) different organs. MNU and MMS react with DNA without being first metabolized and show a higher UDS in lower concentration than DMN which is metabolized enzymatically prior to the reaction. This result suggests that MNU and MMS produce more damage in the DNA. There are distinct differences in the spleen, lung, liver, kidney and heart in young animals as well as in the tissues of the kidney and the duodenum in old rats. Clearly we can see a reduction of UDS in the old as compared to the young animals after damage by MNU in the skin, lung, brain and heart, by MMS in the heart and liver, and by DMN in the kidney, duodenum, lung and liver, and by all three mutagens in the spleen and testes. These results confirm those obtained after damaging DNA by means of γ- and UV-irradiation.     

Analysis of the ST-segment in terms of principal components: application on multichannel magnetocardiographic recordings

Parameterization of the ST-segment is used as a tool for risk stratification for patients to suffer from ventricular tachycardia. This parameterization is performed in terms of Principal Component Analysis (PCA) applied on multichannel magnetocardiographic (MCG) recordings. 55-channel MCG was recorded from 14 normal persons, 10 patients with CHD, 14 patients with MI, and six patients with VT. We found a significantly (p < 0.05) lower PCA-score in patients with MI compared to normals. The lowest PCA-score was found in VT patients. Significant differences can be found between VT patients and normals and also between VT patients and CHD patients.     

Prognostic values of galectin-3 and the macrophage migration inhibitory factor (MIF) in human colorectal cancers.

This study aims to investigate whether the immunohistochemical levels of expression of galectin-3 and the macrophage migration inhibitory factor (MIF) are associated with prognostic values in human colorectal tumors. This was performed on 99 specimens including 69 colorectal tumors (17 Dukes A, 19 Dukes B, 15 Dukes C and 18 metastatic tumors that we labeled as D), 10 hepatic metastases from colorectal cancers and 20 normal specimens (biopsies). The immunohistochemical levels of expression of MIF and galectin-3 were quantified on routine histological slides by means of computer-assisted microscopy. Separate analyses were performed on epithelial and connective tissue. The levels of expression of both MIF and galectin-3 were very significantly higher in epithelial tumor tissue when compared with normal epithelial specimens. A positive and significant correlation between MIF and galectin-3 expression was evidenced in connective tumor tissue, and in particular in the cases associated with short survival periods (less than 5 years). In the case of the Dukes A or B tumors, we established two new prognostic groups (labeled I and II) on the basis of the levels of galectin-3 expression measured in the tumor epithelium. In the case of the Dukes C or D tumors, we established two other prognostic groups (labeled III and IV) on the basis of the levels of MIF expression measured in the connective tissue. Kaplan-Meyer analyses confirmed the additional prognostic values (as compared with conventional clinical staging) given by this new classification (groups I to IV). They show that the Dukes A or B tumors characterized by low levels of galectin-3 expression in the tumor epithelium are associated with significantly better prognoses than those characterized by high levels. In addition, the Dukes C or D tumors characterized by high levels of MIF expression in the connective tumor tissue are associated with significantly better prognoses than those characterized by low levels. In conclusions, MIF and galectin-3 expression levels in colorectal tumors are related to their levels of biological aggressiveness. These markers could be used to identify patients at risk, for whom more aggressive adjuvant therapy seems to be indicated.     

Ultrastructural Changes Suggestive of Focal Segmental Glomerulosclerosis in Atypical Minimal Change Nephrotic Syndrome

In an attempt to recognize early stages of focal segmental glomerulosclerosis (FSGS) in patients with a clinical course suggesting a diagnosis other than minimal change disease (MCD) and normal histology, or minor, nondiagnostic changes on light microscopy (LM), we used a protocol for systematic and extensive electron microscopy (EM) examination of kidney biopsies obtained from such patients. By this method ultrastructural pathology was found in 8 patients. These changes were localized, involving only portions of single glomerular segments. The findings included mild to moderate increase of the mesangial matrix, focal wrinkling of the capillary basement membrane, and early obliteration of the normal architecture of individual capillary loops, as well as electron-dense deposits in a mesangial and subendothelial distribution. Of these 8 patients, 2 are at present in remission without therapy (in 1, following therapy with cyclophosphamide); 3 are in remission on steroid therapy; 1 developed massive proteinuria during pregnancy, after a spontaneous remission lasting almost 2 years; 1 patient advanced to terminal renal failure 3 1/2 years after biopsy; and 1 died of sepsis 1 month after biopsy. We believe that the ultrastructural changes found may represent early or mild FSGS and that the protocol described can add valuable information in clinically worrisome patients in whom renal histology appears normal.     

The response of heat shock proteins 25 and 72 to ischaemia in different kidney zones

 Induction of heat shock proteins (HSPs) following cell injury contributes to the protection of vital cell functions. It was, therefore, of interest to study the effects of transient renal ischaemia on the abundance and distribution of two HSPs, HSP25 and HSP72, in renal tissue using Western-blot techniques. Analyses were performed on the supernatant (HSP25, HSP72) and pellet (HSP25) of homogenates obtained from cortex (CX) and outer (OM) and inner (IM) medulla of the rat kidney immediately after 60 min of ischaemia followed by varying periods of reperfusion. Ischaemia of the left kidney caused HSP25 contents to decrease in CX, OM and IM by 73, 89 and 54% respectively, compared with the corresponding zones of the contralateral control kidney. This initial decrease in supernatant HSP25 was accompanied by an increased abundance of HSP25 in the pellet. Following reperfusion, HSP25 contents in the supernatant gradually increased in CX and OM, reaching, after 24 h, values that were 5.4- and 2.5-fold higher, respectively, than those in the control kidneys. After 7 or 14 days of reperfusion, HSP25 contents had not completely normalised in CX, but had reached control levels in OM. In IM, the HSP25 content remained below control throughout the entire reperfusion period. HSP72 (supernatant) was below the detection limit in the CX of the control kidney. Similar to the level of HSP25, that of HSP72 was also markedly lower in OM and IM immediately after ischaemia. The intrarenal distribution of HSP72 and the sequence of zonal changes in HSP72 contents were similar to those observed for HSP25. These results are compatible with the view that, during ischaemia and the initial reperfusion period, HSP25 migrates from the cytoplasmic compartment (supernatant) into the nucleus and/or associates with cytoskeletal structures. The observation that both HSP25 and HSP72 are transiently induced in CX and OM, but not in IM, may be explained by the fact that, while all kidney cells are exposed to ischaemic stress, only inner medullary cells experience a major postischaemic attenuation of osmotic stress. Received: 11 February 1997 / Received after revision and accepted: 26 March 1997     

Untersuchungen zum Einfluß der Urämie auf die Metabolisierung von Phenylbutazon und Aminophenazon beim Menschen

Zusammenfassung Je 10 urämische Patienten und nierengesunde Probanden mit normaler Leberfunktion erhielten entweder 6 mg Phenylbutazon/kg oder 12 mg Aminophenazon/kg KG per os. Beide Pharmaka werden durch mischfunktionelle Oxygenierung im endoplasmatischen Reticulum der Leber abgebaut.Anschließend wurden zu bestimmten Zeiten die Plasmakonzentrationen gemessen und die Plasmahalbwertszeiten beider Substanzen ermittelt.24 h nach Phenylbutazongabe wurde bei Nierengesunden eine mittlere Plasmakonzentration von 4,3±0,85 mg/100 ml gemessen, bei Urämikern dagegen nur 1,75±0,91 mg/100 ml.Die mittlere Plasmahalbwertszeit betrug bei Nierengesunden für Phenylbutazon 50.9±13.5 h, bei Urämikern war sie um 48% auf 75.4±12.8 h verlängert.4 h nach oraler Gabe von Aminophenazon betrug die Plasmakonzentration von Aminophenazon bei Nierengesunden 0,99±0,31 mg/100 ml, bei Urämikern 1,03±0,45 mg/100 ml. Bei urämischen Patienten wurde eine mittlere Aminophenazonhalbwertszeit von 4.1 ± 1.6 h, bei Urämikern von 4.0±1.7 h gemessen.Es bestand keine signifikante Korrelation zwischen den Serumkonzentrationen von Harnstoff oder Kreatinin einerseits und der Plasmahalbwertszeit von Phenylbutazon oder Aminophenazon andererseits.Aus diesen Ergebnissen und den in der Literatur mitgeteilten Befunden wird geschlossen, daß beim Menschen unter den Bedingungen der Urämie eine Beeinflussung des oxydativen Abbaus einzelner lipophiler Pharmaka eintritt. Allgemein gütige Regeln bezüglich der Dosierung von Arzneimitteln, die durch mischfunktionelle Oxygenierung metabolisiert werden, können bei urämischen Patienten aber bis jetzt nicht gegeben werden, da offensichtlich der Abbau verschiedener Substanzen durch die Urämie unterschiedlich beeinflußt wird.Mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Airway obstruction due to massive lingual oedema following cleft palate surgery

The Pierre Robin syndrome consists of micrognathia, pseudo-macroglossia, glossoptosis and a high arched or cleft palate. Difficult intubation of the trachea and associated abnormalities such as congenital heart disease are well known complications of this syndrome. Intraoral surgery (such as cleft palate repair and palatoplasty) can also be technically difficult for the surgeon resulting in prolonged retraction on the tongue with a mouth gag to provide adequate surgical exposure. We report a case where massive lingual oedema following a cleft palate repair resulted in life-threatening airway obstruction.     

Mechanical Activation of Pharmaceutical Systems

Mechanical activation has become a phenomenon of general significance in pharmaceutics. This report describes the extent of activation induced by relevant processes. With the use of the Eyring equation the transformation of structurally stored energy into chemical energy and the implied free enthalpy as well as the excess free enthalpy (activity) were evaluated from the rate of an indicator reaction. A comparison was made between different kinds of milling and tabletting with respect to pharmaceutical conditions. An optimization of these processes was derived.     

Opioid dependence prevents the action of pertussis toxin in the guinea-pig myenteric plexus

Summary The longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum has been employed for the study of the effect of pertussis toxin (IAP) on opioid dependence. Guinea-pigs were treated with IAP (120 g/kg, i.p.) either prior to chronic administration of an opioid or after opioid dependence had been established. The isolated preparations were tested in vitro for dependence; that is, the naloxone-precipitated withdrawal contracture. Naloxone almost failed to evoke a sign of dependence in preparations treated with IAP prior to chronic exposure to an opioid. In contrast, IAP failed to affect the withdrawal contracture when applied to an animal after dependence has been established. It is concluded that theN _i-unit, the substrate for IAP, plays a critical function in the development of dependence. The continuous activation of the opioid receptor associated with the development of dependence may induce changes inN _i which in turn prevent the interaction of IAP with its substrate.