The influence of gemcitabine on the CD4/CD8 ratio in patients with solid tumours

Gemcitabine (dFdC) is a novel pyrimidine antimetabolite with documented antineoplastic activity against metastatic non-small cell lung cancer (NSCL), pancreatic carcinoma, ovarian and breast cancer. The side effects of gemcitabine are generally mild; severe infections are reported in less than Ilo of patients. In contrast, other new nucleoside analogues such as the purine antimetabolite fludarabine lead to a significant alteration of the CD4/CD8 lymphocyte ratio associated with an increased risk for opportunistic infections. This study investigates the effect of gemcitabine on different lymphocyte subsets during consecutive applications. 16 patients with solid rumours (3 non-small cell lung cancer, 3 pancreas, 3 testicular, 2 breast, ovarian germ-cell, 1 ovarian, 1 small cell lung, 1 gastric cancer, 1 carcinoma of unknown primary); 15 patients were previously treated, received at least 3 applications of gemcitabine (1,000 mg/m(2) as a 30 min infusion, at days 1, 8, 15; q 4 weeks). Lymphocytes surface antigens were analysed by standard technique flow cytometry prior to every infusion. The median number of leukocytes before therapy was 7823/mu l, with lymphocytes 875/mu l, including 68% T-cells (CD3(+)), 9% B-cells (CD19(+); CD20(+)) and 15% NK-cells (CD56(+); CD16(+); CD3(-)), the CD4/CD8 ratio was 1.7. After gemcitabine therapy the median number of leukocytes was 5136/mu l, with lymphocytes 1012/mu l, including 77% T-cells, 8% B-cells and 10% NK-cells and a CD4/CD8 ratio of 2.2. Severe complications or opportunistic infections were not seen in these 16 patients. No significant change of CD4/CD8 ratios and NK-ccll numbers was seen in our patients with solid tumours during weekly treatment with gemcitabine. A severely increased risk for opportunistic infections following treatment with the new antimetabolite gemcitabine appears unlikely.     

The function of presenilin-1 in amyloid β-peptide generation and brain development

Several mutations in genes that cause the familial form of Alzheimer’s Disease (FAD) have been identified. All mutations in the three FAD genes, i.e., amyloid precursor protein (APP), presenilin 1 (PS-1), and presenilin 2 (PS-2) cause an increased production of a longer, more amyloidogenic form of the amyloid peptide corroborating strongly the idea that abnormal processing of APP is central to the pathogenesis. In PS-1 deficient mice, 80% less amyloid peptide was produced. Instead, membrane associated carboxyterminal fragments generated by α- and β-secretase accumulated suggesting that PS-1 is involved in the gamma-secretase activity cleaving the transmembrane domain of APP after α- and β-secretase cleavage has occured. The clinical mutations in PS-1 which increase the production of βA4_1-42 therefore seem to cause a “selective” gain of its normal function. During cortical plate development in PS-1-deficient mice, neurons do not terminate their movement at the outer margin of the cortical plate, but enter the marginal zone and subarachnoid space. These focal heterotopias closely resemble those occuring, e.g., in human lissencephaly type II. The extracellular matrix of the cortical plate and marginal zone was altered as a consequence of a loss of Cajal-Retzius (CR) neurons from the marginal zone. The pathogenesis of this neuronal migration disorder is associated with a reduction and redistribution of notch-1 immunoreactivity in CR- and cortical plate neurons, a cell surface receptor operative in cell fate selection, which similar to APP is cleaved in its transmembrane domain during activation by a γ-secretase like protease.     

In Process Citation

Pure word deafness (auditory verbal agnosia) is characterized by an impairment of auditory comprehension, repetition of verbal material and writing to dictation whereas spontaneous speech production and reading largely remain unaffected. Sometimes, this syndrome is preceded by complete deafness (cortical deafness) of varying duration. Perception of vowels and suprasegmental features of verbal utterances (e.g., intonation contours) seems to be less disrupted than the processing of consonants and, therefore, might mediate residual auditory functions. Often, lip reading and/or slowing of speaking rate allow within some limits to compensate for speech comprehension deficits. Apart from a few exceptions, the available reports of pure word deafness documented a bilateral temporal lesion. In these instances, as a rule, identification of nonverbal (environmental) sounds, perception of music, temporal resolution of sequential auditory cues and/or spatial localization of acoustic events were compromised as well. The observed variable constellation of auditory signs and symptoms in central hearing disorders following bilateral temporal disorders, most probably, reflects the multitude of functional maps at the level of the auditory cortices subserving, as documented in a variety of non-human species, the encoding of specific stimulus parameters each. Thus, verbal/nonverbal auditory agnosia may be considered a paradigm of distorted "auditory scene analysis" (Bregman 1990) affecting both primitive and schema-based perceptual processes. It cannot be excluded, however, that disconnection of the Wernicke-area from auditory input (Geschwind 1965) and/or an impairment of suggested "phonetic module" (Liberman 1996) contribute to the observed deficits as well. Conceivably, these latter mechanisms underly the rare cases of pure word deafness following a lesion restricted to the dominant hemisphere. Only few instances of a rather isolated disruption of the discrimination/identification of nonverbal sound sources, in the presence of uncompromised speech comprehension, have been reported so far (nonverbal auditory agnosia). As a rule, unilateral right-sided damage has been found to be the relevant lesion.     

Prognostic factors in seminomas with special respect to HCG: results of a prospective multicenter study. Seminoma Study Group

OBJECTIVE: In a prospective multicenter trial, it was our intention to elucidate clinical prognostic factors of seminomas with special reference to the importance of human chorionic gonadotropin (HCG) elevations in histologically pure seminomas. METHODS: Together with 96 participating urological departments in Germany, Austria, and Switzerland, we recruited 803 seminoma patients between 1986 and 1991. Out of 726 evaluable cases, 378 had elevated, while 348 had normal HCG values in the cubital vein. Histology was reviewed by two reference pathologists. HCG levels were determined in local laboratories and in a study laboratory. Standard therapy was defined as radiotherapy in stages I (30 Gy) and IIA/B (36 Gy) to the paraaortal and the ispilateral (stage I) and bilateral (stage IIA/B) iliac lymph nodes; higher stages received polychemotherapy and surgery in case of residual tumor masses. Statistics included chi-square tests, linear Cox regression, and log-rank test. RESULTS: The HCG elevation is associated with a larger tumor mass (primary tumor and/or metastases). HCG-positive and HCG-negative seminomas had no different prognostic outcome after standard therapy. The overall relapse rate of 6% and the survival rate of 98% after 36 months (median) indicate an excellent prognosis. The calculation of the relative risk of developing a relapse discovered only stage of the disease and elevation of the lactate dehydrogenase concentration and its prolonged marker decay as independent prognostic factors for seminomas. A more detailed analysis of the prognostic significance of the stage revealed that the high relapse rate in stage IIB seminomas after radiotherapy (24%) is responsible for this result. CONCLUSIONS: We conclude that HCG-positive seminomas do not represent a special entity. Provided standard therapy is applied, HCG has no influence on the prognosis. Patients with stage IIB disease should be treated with chemotherapy because of the demonstrated higher relapse rate outside the retroperitoneum.     

The efficacy of a risk factor-based cognitive behavioral intervention and electromyographic biofeedback in patients with acute sciatic pain. An attempt to prevent chronicity

STUDY DESIGN: An investigation of the efficacy of an individually scheduled, risk factor-based cognitive behavioral therapy and a standardized electromyographic biofeedback intervention in the prevention of chronicity in patients with acute sciatica and psychosocial risk factors for chronicity. OBJECTIVES: To investigate the possibility of enhancing pain relief and preventing chronicity in patients with acute sciatica, based on a screening for psychosocial high-risk factors of chronification. SUMMARY OF BACKGROUND DATA: Psychological interventions were evaluated mainly in patients with chronic low back pain. Numerous randomized trials have demonstrated their efficacy, whereas the amount of pain relief was found to be marginal. METHODS: Subjective and behavioral outcome parameters were compared with the respective parameters in age-, gender-, and diagnosis-matched high- and low-risk patients. No additional behavioral treatment for in-patient medical therapy was offered to the patients. Outcome of these patients also was compared with that of a group of refusers of behavioral therapy. Psychological, functional, and behavioral variables were measured before and after treatment and at 3-, 6-, 12- and 18-month follow-up visits. Changes over time, group differences, and possible group x time interactions were analyzed by analysis of variance and nonparameteric comparisons. RESULTS: Data analysis showed a statistically and clinically significant, beneficial effect of both behavioral interventions. However, risk factor-based cognitive behavioral therapy was superior to electromyographic biofeedback intervention with respect to pain relief and application for early retirement. The cognitive behavioral therapy showed a similar good outcome (e.g., 90% showed a clinical significant pain reduction) as the low-risk patients (83% pain reduction). High risk patients and refusers of therapy showed a poor outcome in pain (33% and 20% pain reduction, respectively), disability, and work performance. CONCLUSIONS: Individually scheduled, risk factor-based cognitive behavior therapy could be a beneficial treatment modality, which can be offered, in addition to a medical treatment, to patients with acute sciatica and psychosocial high risk factors for chronicity. It may be an effective way to prevent chronification in these patients.     

Qualitative and Quantitative Analysis of the Phenolic Constituents from Orthosiphon aristatus

ORTHOSIPHON ARISTATUS (Orthosiphonis folium DAB 9) was studied with regard to its phenolic constituents. Twenty compounds were isolated and identified on the basis of their spectral characteristics. The compounds included nine lipophilic flavones, two flavonol glycosides, and nine caffeic acid derivatives. The presence of the recently reported methylripariochromene A could not be confirmed. All compounds identified were quantified by HPLC. The caffeic acid derivatives including the major compounds rosmarinic acid and 2,3-dicaffeoyltartaric acid (67% of total identified phenolics) predominated over the flavones (33%) in an aqueous MeOH extract. The predominance of the caffeic acid derivatives was even more pronounced in a hot water extract (94.5% of total identified phenolics) that was comparable to a herbal tea.     

Extracorporeal membrane oxygenation as a bridge to lung transplantation

The occurrence of severe graft failure after lung transplantation which appears refractory to conventional treatment represents a difficult situation with regard to the therapeutic strategies available. Of 17 patients undergoing single lung transplantation at our center, 2 developed early graft failure. In both, temporary artificial cardiopulmonary support by means of extracorporeal membrane oxygenation became necessary as a bridge to retransplantation. Both patients were successfully retransplanted after 8 h and 232 h, respectively, of extra-corporeal support. Postoperatively, there was a variety of complications. The first patient completely recovered from temporary severe cerebral dysfunction diagnosed as "locked-in syndrome". She was discharged from hospital on the 93rd postoperative day and remains alive and well 10 months after her operation. The other patient recovered well early after retransplantation. Later, however, airway problems developed, requiring the implantation of endotracheal stents. Cachexia and several episodes of viral pneumonia contributed to the progressive deterioration of her clinical status. She finally died after being hospitalized for 5 months after the original operation. These two cases illustrate the feasibility of using extracorporeal membrane oxygenation as a bridge to pulmonary transplantation.     

Studies on the development of extra-endothelial and intra-endothelial pigment deposits by means of direct and indirect contact specular microscopy of the cornea

Retro-corneal pigmentation as a result of primary (degenerative) or secondary (inflammatory, traumatic) pigment dispersion represents one of the most frequent findings in specular microscopy. The analysis of the pigment distribution patterns of dense deposits like those inKrukenberg spindle (KS) permits the postulation of ahypothesis concerning the development of such typical corneal pigmentations and the pigmentation of the posterior surface of the cornea in general, such as diffuse pigment dispersion (Vogt 1930), which is seen frequently.In a particular case of double KS with extreme myopia and cataract, endothelial morphological findings were documented over a period of 1 year, both before and after cataract extraction. This was done by means of contact and non-contact specular microscopy in various spindle areas.Themorpho-metric studies (cell density/mm²; cell perimeter; largest, smallest and average cell diameter; specific surface; horizontal and vertical cell orientation) were carried out automatically using a computerised video image analyser. The changes in the area of densest pigmentation in the KS centre confirm the histologically proven capacity of pigment phagocytosis by human corneal endothelium. These findings indicate that in specular microscopy, both endothelial cellular surface modifications andintra-cellular changes are documentable. The extracellular pigment deposits can also be shown by means ofindirect specular microscopy, the optical principle of which is described.

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Zusammenfassung Feinste Pigmentablagerungen an der Hornhautrückfläche als Folge einer primären (degenerativen) oder sekundären (entzündlichen, traumatischen) Pigmentdispersion stellen einen der häufigsten Befunde bei der endothelmikroskopischen Untersuchung dar.Die Analyse des Pigmentverteilungsmusters bei dichten Ablagerungen, wie z.B. bei derKrukenbergspindel, erlauben die Aufstellung einerHypothese bezüglich der Entwicklung dieser typischen primären Hornhautpigmentierung und von degenerativen Pigmentierungen der Hornhautrückfläche im allgemeinen, wie der klinisch sehr häufigen senilen, diffusen Pigmentbestäubung.Bei einem ausgewählten Fall von beidseitiger Krukenbergspindel bei hoher Myopie und Katarakt, wurden vor und nach Katarakt-Extraktion in einem Zeitraum von über einem Jahr endothelmorphologische Befunde in verschiedenen Zonen der Pigmentspindel mittels Contact-/Noncontact-Endothelmikroskopie dokumentiert. Diemorphometrischen Untersuchungen (Zelldichte/mm², Zellumfang; größter, kleinster und mittlerer Zelldurchmesser; spezifische Oberfläche; Zell-Horizontal- und Vertikal-Orientierung) wurden mittelsautomatisierter Endothelanalyse über ein Video-Computer-Bildanalysesystem durchgeführt.Die Veränderungen im Bereich der dichtesten Pigmentablagerungen im Spindelzentrum bestätigen die histologisch gesicherte Fähigkeit des Hornhaut-Endothels zur Pigment-Phagocytose.Die erhobenen Befunde sprechen dafür, daß bei der Endothelmikroskopie nicht nur die Endothelzelloberfläche, sondern auchintrazelluläre Endothelzellveränderungen dokumentiert werden können. Extrazelluläre Pigmentauflagerungen konnen auch mittels indirekter Endothelmikroskopie dargestellt werden, deren optisches Prinzip erklärt wird.

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Professor Dr. H. Neubauer for his 60th birthday