Molecular Determinants of Carbocation Cyclisation in Bacterial Monoterpene Synthases.

Monoterpene synthases are often promiscuous enzymes, yielding product mixtures rather than pure compounds due to the nature of the branched reaction mechanism involving reactive carbocations. Two previously identified bacterial monoterpene synthases, a linalool synthase (bLinS) and a cineole synthase (bCinS), produce nearly pure linalool and cineole from geranyl diphosphate, respectively. We used a combined experimental and computational approach to identify critical residues involved in bacterial monoterpenoid synthesis. Phe77 is essential for bCinS activity, guiding the linear carbocation intermediate towards the formation of the cyclic α-terpinyl intermediate; removal of the aromatic ring results in variants that produce acyclic products only. Computational chemistry confirmed the importance of Phe77 in carbocation stabilisation. Phe74, Phe78 and Phe179 are involved in maintaining the active site shape in bCinS without a specific role for the aromatic ring. Phe295 in bLinS, and the equivalent Ala301 in bCinS, are essential for linalool and cineole formation, respectively. Where Phe295 places steric constraints on the carbocation intermediates, Ala301 is essential for bCinS initial cyclisation and activity. Our multidisciplinary approach gives unique insights into how carefully placed amino acid residues in the active site can direct carbocations down specific paths, by placing steric constraints or offering stabilisation via cation-π interactions.

Las trombosis venosas profundas distales de los miembros inferiores: un problema controvertido / Distal deep vein thrombosis of the lower limbs: A controversial problem

La frecuencia de la trombosis venosa profunda distal oscila entre un 20 y un 50% de todas las trombosis profundas de los miembros inferiores y presenta los mismos factores de riesgo que las proximales y que el embolismo pulmonar, con un 50% menos de riesgo de recurrencia. Su historia natural, deficientemente conocida, explica el debate sobre su importancia. La complicación más frecuente es el síndrome postrombótico. El ecodoppler es el método diagnóstico más empleado. El dímero D solo no excluye la trombosis, no es útil como factor pronóstico de recurrencia ni se asocia con el síndrome postrombótico. La selectina P soluble combinada con el índice de Wells es una prueba diagnóstica excelente. La anticoagulación varía entre 3 meses e indefinidamente según la trombosis sea provocada o idiopática. En caso de cáncer se recomienda continuar el tratamiento hasta pasados 6 meses después de su curación o de su remisión completa

The frequency of the distal deep vein thrombosis is between 20 and 50% of all deep lower limb thrombosis, and has the same risk factors as proximal and pulmonary embolism, and with 50% lower risk of recurrence. Its natural history is not well-known, and may explain the debate about its importance. The most common complication is post-thrombotic syndrome. The echo-Doppler is the most used diagnostic method. D-dimer alone does not exclude thrombosis, is not useful predictors of recurrence, and is associated with post-thrombotic syndrome. Soluble P-selectin, combined with the Wells index is an excellent diagnostic test. Anticoagulation varies between 3 months and indefinitely depending on whether the thrombosis is provoked or idiopathic. If cancer, it is recommended to continue treatment until 6 months after cure or complete remission

Cisplatin and vinorelbine followed by radiotherapy in the treatment of stage III-B non-small-cell lung cancer patients.

Combined chemotherapy/radiotherapy treatments appear to yield better results in locally advanced non-small-cell lung cancer (NSCLC) than radiotherapy alone. The optimal induction chemotherapy regimen remains to be established. In the present study, chemotherapy with cisplatin and vinorelbine was used prior to radical radiotherapy in Stage III-B NSCLC. Thirty-three patients were entered prospectively into a Phase II study. Treatment consisted of three cycles of chemotherapy with cisplatin 100 mg/m2 on day 1 and vinorelbine 30 mg/m2 on days 1 and 8, followed by thoracic radiotherapy (60 Gy). Twenty-two percent of the 33 patients had grade 3-4 leukopenia, and there were six episodes (in 4 patients) of neutropenia-associated fever. Gastrointestinal toxicity was generally moderate. Peripheral neuropathy was present in 42% of the patients, although in most of them it was slight. The main radiotherapy toxicity was esophagitis grade I-II. Evaluation of response after the third chemotherapy course showed an objective response in 16 patients (48%), whereas in three patients (9%) the disease progressed during therapy. The median survival of the entire group was 13 months. Cisplatin plus vinorelbine followed by radiotherapy is an effective schedule for patients with locally advanced non-small-cell lung cancer.

Frequent dose delays and growth factor requirements with the sequential doxorubicin-CMF schedule.

Doxorubicin for four cycles plus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) for eight cycles is an effective adjuvant regimen for breast cancer patients with more than three involved axillary lymph nodes. We reviewed the incidence of dose delays and growth factor requirements when this regimen is administered to patients receiving concurrent irradiation. Thirty-six patients with more than three involved axillary lymph nodes were treated with the sequential regimen doxorubicin-CMF and irradiation. Patients with two or more dose delays received G-CSF treatment. Seventy-five percent of the patients required dose delays for day-22 neutropenia, and growth factors were needed for half of the patients in order to maintain a received dose intensity of 0.940. The first delayed cycle occurred in 74% of the patients while receiving concomitant chemoradiotherapy. Frequent dose delays were required when the sequential regimen doxorubicin-CMF was administered along with radiotherapy. Growth factors are needed to maintain dose intensity similar to that achieved in the original trial.

Fast algorithms for computing and displaying dose-distributions in tomogram-oriented brachy-radiotherapy.

This paper describes in detail a dose calculation algorithm tailored to the needs of tomogram-oriented brachy-radiotherapy and a general-purpose dose visualization for displaying the dose distribution as isolines (or rather interval planes). The verbal description of the algorithms is accompanied by structograms. However, the intention of the authors is to present very fast algorithms that are easy to implement and to give a ready-to-use example formulated in 68020 assembler code. Execution times are estimated theoretically by counting clock cycles and practically by measuring the execution time of sample calculations. It turns out that both the dose calculation as well as the visualization algorithm need less than 1 s when applied to a radioactive point source lying on an arbitrary 320 x 256 grid of three-dimensional space.

Endobronchial metastases in colorectal adenocarcinoma.

Between 1982 and 1990, 2388 bronchoscopic examinations were carried out in patients with cancer in our hospital. A diagnosis of endobronchial metastasis was established in 30 patients (2.09%), with the following primary tumors in descending order of frequency: breast, large bowel, melanoma, neuroblastoma, leiomyosarcoma and endometrial. Despite the rarity of endobronchial metastases secondary to colon adenocarcinoma, we were able to study 3 cases from our Center. In one case the diagnosis of endobronchial metastasis was simultaneous with that of the primary tumor, and in the other 2 this metastatic complication occurred 16 and 42 months, after the original diagnosis. When this complication occurred, the stage of the disease was advanced in all 3 cases: 2 were Dukes' stage C and one stage D. Although this metastatic location usually implies a very negative prognosis as regards life expectancy, it did not seem to significantly reduce the latter in our patients.

Intuitive user interfaces (IUI): a CASE starting point for design and programming.

The acceptance of a software product depends to a considerable extent on the user interface. The class of graphic-oriented user interfaces that are called Intuitive User Interfaces (IUI) is described. These interfaces allow the user to learn to operate software programs quickly. In the following the graphical layout put to use in an IUI is elaborated. All images the layout consists of are created with the aid of a paint program. Using these images, a procedure for creating, programming and linking an IUI to software applications is discussed and recommendations are made concerning software and hardware demands for easily creating IUIs. Practical experience of the authors with this procedure, mainly in the medical area, is described.

A Rexx-controlled developing environment for implementing intuitive user interfaces (IUI).

In [our companion paper] intuitive user interfaces as well as a method for developing and programming such interfaces have been described. The present article will improve and simplify this mode of action. The main tool for this undertaking is the programming and script language Rexx. Using Rexx, all software components described in [the companion paper] are linked to form a developing environment, which acts like an integrated software package. Moreover, with the aid of Rexx, source-code and data structure generation is greatly extended, further decreasing the expenditure of programming intuitive user interfaces. This paper first gives a brief introduction to Rexx. A description of the Rexx-controlled developing environment then follows. Finally, there are elucidated the details of the question of how each single software component is linked to the environment using Rexx.

Meningeal fibrosarcoma: a case report and review of the literature.

Meningeal Fibrosarcoma (MF) accounts only for 0.5% of the brain tumors. Since the clinical manifestations and radiologic findings are non-specific, the diagnosis can only be achieved by pathological examination of surgically removed specimens. MF are tumors that behave locally very aggressively and respond poorly to treatment, with reported median survivals ranging from 6 to 15 months. We report a new case of MF describing the peculiar onset as a slow growing mass in scalp with bone destruction and without neurological clinical findings.

[Alternating chemotherapeutic treatment in patients with localized undifferentiated small-cell carcinoma of the lung]. / Tratamiento quimioterápico alternante en pacientes con carcinoma indiferenciado de célula pequeña de pulmón localizado.

The results obtained from 23 patients suffering small cell lung carcinoma limited to the thorax, treated with 4 cycles of cyclophosphamide, adriamycin, vincristine alternating with cisplatin and VP/16, followed by mediastinal and holocranial prophylactic radiotherapy in patients with a complete response (CR) are here presented. An 87% of global responses were obtained with a 64% rate of RC. The average survival rate was 12 months with an 18% of patients alive two years after treatment. The main toxicity was hematologic and neurologic. Even if this alternating regime produces a high response rate, the results are not superior to those obtained with conventional chemotherapy.

[Cerebral metastases in adenocarcinoma of the colon]. / Metástasis cerebrales en el adenocarcinoma de colon.

Between 25% and 35% of all patients with cancer, will develop metastases to the brain. Gastrointestinal neoplasms are responsible for 8% of all cases of metastatic brain involvement. The frequency of brain metastases in carcinoma of the colon ranges from 0.3 to 6%, and this location is usually accompanied by metastatic involvement of the lung and liver. Cerebral metastatic lesions are uncommon in colon cancer, and are usually a late manifestation of the disease. Because of the rarity of this complication, we report a case of metastatic colon adenocarcinoma to the brain, and we review the literature on this subject.

[2 years' experience with a monitoring and recording system for gynecological afterloading irradiation]. / Zwei Jahre Erfahrung mit einem Uberwachungs- und Protokollierungssystem für gynäkologische Afterloading-Bestrahlungen.

A computer program running on a simple desk calculator has been developed for monitoring and recording gynecological high-dose afterloading therapy. For treatment monitoring the multiple-probe AM6-system (PTW-Freiburg) is used which allows for dose measurements in the urinary bladder and the rectum. The probe signals are processed on line in order to indicate the actual dose at the measuring points. After completing the irradiation the treatment is documented. Performing fractionated treatment the measuring data are stored in the computer memory for calculating total accumulated dose. The above-described monitoring and recording [correction of protocolling] system has proven its usefulness during two years of clinical work.

Circulating CA 15-3 levels in the postsurgical follow-up of breast cancer patients and in non-malignant diseases.

Circulating CA 15-3 antigen levels were evaluated in patients with benign diseases and breast cancer patients with no clinical evidence of disease after surgery (NED). Patients with breast cancer NED were followed for tumor recurrence or death during a median of 12.9 months (range 1 to 25 months). CA 15-3 and carcinoembryonic antigen (CEA) were compared in the same breast cancer NED patient population. Elevated CA 15-3 levels (greater than 40 U/ml) were observed in 38 of 1220 patients with benign diseases (3.1%) and in 25 of 350 breast cancer NED patients (7.1%). Elevations of CEA (greater than 5 ng/ml) were observed in 23 patients with breast cancer NED (6.5%). Benign diseases that produced significant elevations of CA 15-3 were chronic hepatitis (42.9%), liver cirrhosis (13.3%), sarcoidosis (16.7%), tuberculosis (9.7%), and systemic lupus erythematosus (6.7%). In breast cancer NED, initial elevations of CA 15-3 were observed in 12 of the 297 patients that remained free of disease during the follow-up, and in 13 of the 40 patients that relapsed (4.0% vs. 32.5%, p less than 0.001). Initial CEA levels were elevated in 16 patients that remained NED and in 7 patients that relapsed (5.3% vs. 17.5%, p less than 0.001). Serial determinations of CA 15-3 in patients continuously NED showed persistent elevations in 4 cases. Three of these exhibited concomitant benign diseases. In relapsing patients, serial tumor marker determinations showed that elevations of CA 15-3 before any other clinical evidence of recurrence occurred significantly more frequently than elevations of CEA (45% vs. 25%, p less than 0.001). Overall, two or more serial elevated values of CA 15-3 were observed in 7 cases, and 6 of them (85%) eventually relapsed. Median survival from study entry was 18.3 months in patients with breast cancer NED that had initial elevated CA 15-3, compared to 25+ months in those with negative CA 15-3 (p less than 0.0001). We conclude that circulating levels of CA 15-3 antigen can be elevated in some patients with non-malignant diseases, and that serial determinations of CA 15-3 may be useful in the postsurgical follow-up of patients with breast cancer when specific types of benign diseases that may cause elevations of the antigen are excluded. Additionally, CA 15-3 is more sensitive than CEA in the early diagnosis of breast cancer recurrences, and the simultaneous assay of CEA does not add information to that of CA 15-3 alone.

[Importance of the tissue polypeptide antigen level in neoplastic patients. Its correlation with other tumor markers]. / Interés de la dosificación del "TPA" en pacientes neoplásicos. Su correlación con otros marcadores tumorales.

In order to know the behavior of the tissue polypeptide antigen (TPA) as a tumor marker, the authors determine its amount in serum by means of radioimmunoassay (TPA Prolifigen RIA) in 441 patients having respiratory, digestive, urogenital, hematopoietic, mammary and other malignant tumors. The obtained results indicate that: TPA has no tumor specificity; however it increases in tumors without any other known tumor marker. TPA has no diagnostic value, but it is useful for the following up of digestive, mammary, respiratory, ovarian and testicular cancer; amounts of TPA comprised between 90 and 120 U/l are not specific and have no clinical significance; and it is very useful the simultaneous determination of CEA and TPA in the respiratory, digestive and mammary malignant neoplasms to help the clinical data in the evaluation of tumor mass (CEA) and tumor activity (TPA) without indication of tumor localization.

[Creatine phosphotransferase, B subunit, as a tumor marker. Preliminary results]. / La creatinfosfotransferasa, subunidad B, como marcador tumoral. Resultados preliminares.

Creatine kinase B (CK-B) was evaluated as a tumor marker by radioimmunoassay determination of the isoenzyme in 518 persons (control group, malignant tumors, and several other diseases). Amounts higher than 8 ng/ml (upper normal limit) was observed in 12.6 per 100 of the digestive tumors, 6.1 per 100 of the mammary tumors, 37.7 per 100 of the respiratory tumors, and 22.2 per 100 of the prostatic tumors. A relation exists between CK-B and sigmoid flexure, liver, pancreas and esophagus tumors, between CK-B and acid phosphatase in prostate tumors, and between CK-B and evolution of digestive tumor. The determination of CK-B is useful in the case of tumors lacking known tumor markers, and also as a complementary sign in the diagnosis and evolution of sigmoid flexure and prostate neoplasms.