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Biomedical subjects

J Frankel

Publications and source records attributed to J Frankel.

At least 19 recordsLinked to original sources
PubMed1992

Genes and structural patterns in ciliates: Vance Tartar and the "cellular architects".

The one form of cytoplasmic inheritance that has not been assimilated into the Central Dogma is the inheritance of surface structural patterns, a phenomenon most clearly expressed in ciliates. Vance Tartar, although he worked with a genetically undomesticated organism (Stentor coeruleus), provided early evidence for the crucial role of clonally propagated features of the cell cortex. He showed that the capacity for development of cortical organelle systems is associated with a particular relational feature, the "locus of stripe contrast" (LSC), and that clonally inherited cortical variants (homopolar doublets) could be created at will by microsurgical operations that duplicated the LSC. Tartar also hoped to demonstrate the existence of what David Nanney called "cellular architects" by provoking stentors to carry out entirely novel types of morphogenetic performances. He eventually acknowledged failure, although the bizarre juxtapositions by which he attempted to elicit such novel performances did bring about specific and illuminating defects in cortical development. Subsequent analyses of similar defects in other ciliates revealed not the unitary "pattern factor" postulated by Tartar, but rather a hierarchy of distinct patterning mechanisms. Nonetheless, by pursuing an embryological approach toward morphogenesis in a highly regulative ciliate, Tartar uncovered relational aspects of pattern-determination; this, in my view, delineates the major problem that we must solve to gain understanding of intracellular patterning.

Animals↗
PubMed1992

Phase I trial of postoperative 5-FU, radiation therapy, and high dose leucovorin for resectable rectal cancer.

Following surgery for Stages T3-4N0-2M0 primary and recurrent resectable rectal cancer limited to the pelvis, 25 patients have been entered on a Phase I trial of pelvic radiation therapy (RT) [5040 cGy] and 12 cycles of postoperative 5-FU and high dose Leucovorin (LV) chemotherapy. 5-FU was escalated 50 mg/m2 while the LV remained constant at 200 mg/m2. The initial doses of 5-FU were: combined-RT/chemotherapy = 200 mg/m2 and post-RT chemotherapy = 325 mg/m2. The median F/U was 25 months (range: 13-36). Two maximum tolerated doses (MTD's) have been determined, one for combined-RT/chemotherapy and one for post-RT chemotherapy. The MTD for combined-RT/chemotherapy was 250 mg/m2; therefore, the recommended dose of 5-FU is 200 mg/m2. The MTD for post-RT chemotherapy was 375 mg/m2; therefore, the recommended dose of 5-FU is 325 mg/m2. The dose limiting toxicities were diarrhea, tenesmus, frequent bowel movements, dysuria, and myelosuppression. For the nine patients who received 5-FU at the recommended dose level the median low counts were WBC 3.5 (2.2-4.0), HGB 10.3 (9.0-12.3), and PLT (x 1000) 167 (133-280), and the incidence of any grade greater than or equal to 3 toxicity was 22% diarrhea, 17% tenesmus, and 22% frequent bowel movements. The recommended dose of combined-RT/chemotherapy as used in this protocol was relatively well tolerated. However, optimal doses of 5-FU cannot be delivered until the fourth postoperative month. Therefore, despite the encouraging results reported with high dose LV in patients with advanced disease, we do not recommend that high dose LV be used with combined RT and 5-FU in the treatment regimen as presently designed.

Adenocarcinoma↗
PubMed1992

Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy.

PURPOSE: To determine if fluorouracil (5-FU) plus high-dose leucovorin (LV) enhances local response in patients receiving preoperative radiation therapy (RT) for adenocarcinoma of the rectum, we compared the degree of downstaging in patients receiving preoperative RT with or without chemotherapy. PATIENTS AND METHODS: For this comparison, three groups of patients who were treated with identical doses and techniques of preoperative pelvic RT (total dose of 5,040 cGy) were examined. Group 1 included 20 patients with unresectable disease who received combined RT and LV/5-FU. Group 2 included 11 patients with unresectable disease who received preoperative RT. Group 3 included 21 patients with invasive, resectable, primary disease who received preoperative RT. RESULTS: Patients with unresectable disease who received LV/5-FU had a higher rate of pathologic complete response (20% v 0%) and a lower incidence of positive nodes (30% v 64%) compared with those who did not receive chemotherapy. Even when the most favorable group of patients was included (group 3), patients who received LV/5-FU still had a higher complete response rate (20% v 6%) and a lower incidence of positive nodes (30% v 53%) compared with those who received RT without LV/5-FU. Of those patients with initially unresectable disease, the resectability rate was higher in those who received LV/5-FU compared with those who did not receive LV/5-FU (90% v 64%). Patients who received LV/5-FU experienced slightly more grade 1 to 2 fatigue, stomatitis, nausea, and grade 3 diarrhea, tenesmus, and dysuria. CONCLUSIONS: Despite the fact that patients who received chemotherapy (group 1) had more advanced disease compared with those with resectable disease (group 3), the addition of LV/5-FU increased the resectability and downstaging rates. The ultimate impact of a complete response as well as a decrease in the incidence of pelvic nodes on local control and survival remains to be determined. However, given the enhancement of down-staging in patients with unresectable rectal cancer, we are encouraged by the combined modality approach.

Adenocarcinoma↗
PubMed1992

Combined modality therapy of rectal cancer: decreased acute toxicity with the preoperative approach.

PURPOSE: We compared the combined radiation therapy (RT) plus chemotherapy segments of two separate parallel phase I trials to determine if combined pelvic RT, fluorouracil (5-FU), and high-dose leucovorin (LV) had less acute toxicity when delivered preoperatively versus postoperatively in patients with rectal cancer. PATIENTS AND METHODS: Patients with unresectable disease received preoperative RT plus LV and 5-FU followed by surgery and postoperative LV and 5-FU. Patients with resectable disease received identical doses, techniques, and schedules of RT and LV and 5-FU except all therapy was delivered postoperatively. On day 1, patients received LV and 5-FU times one cycle. RT began on day 8. A second cycle of LV and 5-FU was given concurrently with the fourth week of RT. RESULTS: Although more patients (75% v 32%; P = .02) received the higher dose level of 5-FU (250 mg/m2), significantly fewer experienced acute grade 3 to 4 toxicity with preoperative versus postoperative therapy (13% v 48%; P = .045). There was no grade 3 to 4 myelosuppression in either group. The two grade 3 toxicities in the preoperative group were gastrointestinal. The grade 3 toxicities in the postoperative group included seven gastrointestinal and two genitourinary; four patients had a grade 4 toxicity. CONCLUSION: Given the high incidence of grade 3 to 4 toxicity also reported in the postoperative combined modality adjuvant randomized trials, future adjuvant trials should explore the preoperative approach.

Adult↗
PubMed1991

Preoperative high-dose leucovorin/5-fluorouracil and radiation therapy for unresectable rectal cancer.

Twenty patients with primary or recurrent unresectable rectal cancer limited to the pelvis were entered on a Phase I trial of preoperative pelvic radiation therapy (RT) (5040 cGy) and two cycles of combined high-dose leucovorin (LV) and 5-fluorouracil (5-FU), followed by surgery and ten cycles of postoperative LV/5-FU (sequential). Maximum tolerated doses (MTD) were determined for preoperative combined LV/5-FU and RT and for postoperative sequential LV/5-FU. 5-FU was escalated 50 mg/m2 while the LV remained constant at 200 mg/m2. The initial doses of 5-FU were combined LV/5-FU and RT (200 mg/m2) and sequential LV/5-FU (325 mg/m2). The median follow-up time was 14 months. The resectability rate was 89%, and the pathologic complete response rate was 21%. The MTD for combined LV/5-FU and RT was 300 mg/m2; therefore, the recommended dose of 5-FU is 250 mg/m2. The recommended dose of 5-FU for sequential LV/5-FU is 375 mg/m2. The dose-limiting toxicities in this trial were diarrhea, tenesmus, increased bowel movements, dysuria, and myelosuppression. For the six patients who received 5-FU at the recommended dose level, the median low counts were leukocyte count, 3.7/microliters (range, 2.4 to 4.9/microliters); hemoglobin, 9.0 g/dl (range, 8.2 to 11.9 g/dl); and platelet count (X1000), 146/microliters (range, 89 to 182/microliters). The incidence rate of any Grade 3 toxicity was 17% (diarrhea and frequent bowel movements). The recommended doses of 5-FU used in this protocol were well tolerated. Because there was a long delay before optimal doses of 5-FU could be delivered, the authors do not recommend that high-dose LV be used in conjunction with combined 5-FU and RT with the treatment regimen as currently designed. However, because the resectability and complete response rates were higher than those previously reported for preoperative RT alone, the authors are encouraged by the combined technique approach. New trials are currently being undertaken to determine if the use of a low-dose LV regimen is more tolerable.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Intracellular handedness in ciliates.

Ciliated protozoa have intrinsically asymmetrical ciliary structures that are asymmetrically arranged over the cell surface. These structures can be arranged in two enantiomorphic configurations, 'right-handed' (RH) and 'left-handed' (LH). Whereas one of these configurations (arbitrarily, RH) is apparently universal in Nature and predominant in the laboratory, mirror-image (RH-LH) doublets and reverse (LH) singlets have been generated and studied in eight different ciliate genera. In all these, the internal asymmetry of individual ciliary structures remains normal even when the asymmetry of arrangement of these structures is reversed. The individual structures may sometimes become inverted (rotationally permuted). LH forms reproduce themselves if they are able to feed, or reorganize periodically before starving to death if they are not. Changes of cellular handedness depend upon unusual geometric configurations and in most cases are unrelated to genic changes. In hypotrich ciliates changes of handedness can be provoked by artificially generated juxtapositions of anterior and posterior cell regions or of right and left cell margins. Reversal of handedness in ciliates can be visualized as a consequence of (re-)establishment of a normal sequence of normally spaced positional values following geometric disturbances created by the experimenter or by the regulating cell.

Animals↗
PubMed1991

Conjugal blocks in Tetrahymena pattern mutants and their cytoplasmic rescue. II. janus A.

A conjugal block phenotype is described for the Tetrahymena pattern mutant, janA. janA exhibits a characteristic "janus" phenotype in which cells develop with a global mirror-image duplication of the ventral pattern of cortical organelles. janA cells are competent to form mating pairs, but later become irreversibly fused as heteropolar doublets. The few pairs that successfully dissociate fail to undergo postconjugal oral replacement and perish. The janA conjugal block is 100% penetrant, is under prezygotic macronuclear control, and is lethal. Here we characterize this conjugal block genetically and cytologically and demonstrate that it can be rescued by a transferable, wild-type product. New insights into late conjugal events, especially the replacement of the oral apparatus, are reported for wild-type cells as well.

Animals↗
PubMed1991

Microsurgically generated discontinuities provoke heritable changes in cellular handedness of a ciliate, Stylonychia mytilus.

Stylonychia mytilus is a dorsoventrally flattened ciliate with compound ciliary structures arranged in a specific manner on the cell surface. In mirror-image (MI) doublets of this ciliate, two nearly complete sets of ciliary structures are arrayed side-by-side, one in a normal or 'right-handed' (RH) arrangement, the other in a reversed or 'left-handed' (LH) arrangement. MI-doublets exist in two forms, one with the RH component on the right, the LH component on the left, and feeding structures near the center ('buccal-adjoining MI-doublet'); the other with the RH component on the left, the LH component on the right, and feeding structures on the lateral edges ('buccal-opposing MI-doublet'). We describe an operation that can generate either type of MI-doublet. This operation interchanges large anterior and posterior regions of the cell, transposing the original posterior region anteriorly (P----A) and the original anterior region posteriorly (A----P), while retaining the original anteroposterior polarity of each region. Two sets of new ciliary structures then are formed in mirror-image arrangement, with the set in the P----A region oriented normally and the set in the A----P region undergoing a reversal of polarity along its anteroposterior axis. This sometimes creates end-to-end MI forms, but more commonly produces side-by-side MI-doublets through a folding together of the P----A and A----P regions. This folding occurs because one lateral edge of the cell had been removed during the operation; if the left edge was removed, the complex folds to the left and forms a buccal-adjoining MI-doublet, whereas if the right edge was removed, the complex folds to the right and forms a buccal-opposing MI-doublet. Both types can reorganize and later divide true-to-type, although the 'buccal-opposing' type is by far the more stable of the two. The generation of mirror-image forms is dependent on the prior abnormal juxtaposition of regions from opposite ends of the cell, and involves a coordinated respecification of large-scale organization. We interpret this response to be a consequence of intercalation of missing intervening positional values in the zone of posterior-anterior abutment.

Animals↗
PubMed1991

Learning style preferences: a comparison of younger and older adult females.

This study explored the learning styles of older adult females (65 + years) as compared to younger adult females (35-55 years) in the areas of immediate environment, emotionality, sociological needs and physical needs. At recreation community centers, 80 subjects were selected on a non-random basis, with one-half falling in each age category. Each subject was individually questioned using the Productivity Environmental Preference Survey, which analyzes a personal preference for each of 20 elements and identifies how adults prefer to function, learn, concentrate and perform in their educational or occupational activities. An analysis by t test showed a significant difference between the two groups in the elements of light, learning alone--peer oriented, authority figures present, and evening--morning. When the elements were combined and treated by discriminant analysis, most of these findings were confirmed, showing a significant difference in five elements: light, motivation, responsibility, learning alone--peer oriented, evening--morning. These findings might be useful to nutrition educators when developing nutrition programs for the elderly.

Adult↗
PubMed1991

Complications of calcaneal osteotomies.

This article describes the associated complications encountered with calcaneal osteotomies. The paper stresses the importance of preoperative evaluation, surgical technique, and postoperative care. We also emphasize the triplanar nature of calcaneal deformities that calcaneal osteotomies correct.

Calcaneus↗
PubMed1989

New approaches in the use of selegiline for the treatment of Parkinson's disease.

Selegiline hydrochloride (deprenyl) is a safe, useful adjuvant therapy in patients with Parkinson's disease treated with L-dopa. The optimum time for its introduction into the treatment regimen of a patient remains controversial. A multicentre long-term study being conducted by the Parkinson's Disease Research Group of the United Kingdom to attempt to answer whether selegiline improves the natural history of Parkinson's disease is discussed. In a separate study we have been unable to demonstrate that higher doses of selegiline (up to 40 mg a day) produce additional therapeutic benefit above the conventional dose of 10 mg a day in levodopa-treated patients with motor fluctuations. Preliminary data from a neuropsychological study is also presented which suggests that selegiline may have beneficial effects on the speed of psychomotor responses supporting the anecdotal clinical observations of increased mental energy and alacrity.

Adult↗
PubMed1989

Non-genic inheritance of cellular handedness.

Ciliates exhibit an asymmetry in arrangement of surface structures around the cell which could be termed handedness. If the usual order of placement of structures defines a 'right-handed' (RH) cell, then a cell with this order reversed would be 'left-handed' (LH). Such LH forms appear to be produced in Tetrahymena thermophila through aberrant reorganization of homopolar doublets back to the singlet condition. Four clones of LH forms were selected and subjected to genetic analysis to test whether this drastic phenotypic alteration resulted from a nuclear genetic change. The results of this analysis indicate that the change in handedness is not due to a genetic change in either the micronucleus or macronucleus. The LH form can, under certain circumstances, revert to the RH form, but typically it propagates itself across both vegetative and sexual generations with similar fidelity. While this analysis does not formally rule out certain possibilities of nuclear genic control involving regulatory elements transmitted through the cytoplasm, when the circumstances of origin and propagation of the LH condition are taken into account direct cortical perpetuation seems far more likely. Here we outline a conceptual framework centred on the idea of longitudinally propagated positional information; the positive evidence supporting this idea as well as further application of the idea itself are presented in the accompanying paper.

Animals↗
PubMed1989

Maintenance and regulation of cellular handedness in Tetrahymena.

The left-handed phenotype of Tetrahymena thermophila (LH) is a global mirror image of its right-handed counterpart (RH). LH cells are 'wound' in the opposite direction from that of RH cells with respect to the placement of all structures that are asymmetrically disposed on the cell circumference. However, the local geometry of ciliary rows, including the asymmetrically placed microtubule bands and other accessory structures, is identical in RH and LH cells. Populations of LH cells grow more slowly than those of RH cells, probably because of nutritional problems due to faulty construction of the cell mouth. LH cells, like RH cells, conjugate in a homopolar configuration, while LH cells mate with RH cells in a heteropolar union which suffices to initiate the conjugal nuclear events but is insufficient to allow survival of progeny. Subclonal analyses indicate that reversion of the LH to the RH form is relatively rare. However, the frequency of reversion is greatly increased by conditions that promote the formation of doublets by fission arrest. An analysis of intermediate doublet forms in such cultures strongly suggests that reversion takes place through a specific pathway, with LH-LH doublets regulating to LH-RH forms that then may give rise to RH singlets. The origin and fate of the LH-RH intermediate forms can be explained by applying a modified polar coordinate model of positional information with the proviso that there is a preferred direction for the intercalation of new positional values.

Animals↗
PubMed1979

Patients without communities: whose responsibility?

The authors conducted a study at an urban state hospital to determine if a patient's place of residence--within or outside the hospital's service district--was reflected in the admission rates or the quality of care received. No differences between in-district and out-of-district patients could be found on any parameter studied. The authors believe the results support the unique role of the state hospital as a facility that accepts its mandate as a referral of last resort.

Attitude of Health Personnel↗