PubMed Health⌕ Search

Biomedical subjects

A Melnyk

Publications and source records attributed to A Melnyk.

At least 19 recordsLinked to original sources
PubMed2001

Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus.

The bHLH-PAS transcription factor SIM1 is required for the development of the paraventricular nucleus (PVN) of the hypothalamus. Mice homozygous for a null allele of Sim1 (Sim1(-/-)) lack a PVN and die perinatally. In contrast, we show here that Sim1 heterozygous mice are viable but develop early-onset obesity, with increased linear growth, hyperinsulinemia and hyperleptinemia. Sim1(+/-) mice are hyperphagic but their energy expenditure is not decreased, distinguishing them from other mouse models of early-onset obesity such as deficiencies in leptin and melanocortin receptor 4. Quantitative histological comparison with normal littermates showed that the PVN of Sim1(+/-) mice contains on average 24% fewer cells without a selective loss of any identifiable major cell type. Since acquired lesions in the PVN also induce increased appetite without a decrease in energy expenditure, we propose that abnormalities of PVN development cause the obesity of Sim1(+/-) mice. Severe obesity was described recently in a patient with a balanced translocation disrupting SIM1. Pathways controlling the development of the PVN thus have the potential to cause obesity in both mice and humans.

Adipose Tissue↗
PubMed2000

A randomized trial of two treatments for mild traumatic brain injury: 1 year follow-up.

The purpose of this study was to provide 1 year follow-up data to a previous paper that compared single-session (SS) treatment to treatment-as-needed (TAN) outcomes for mild traumatic brain injury (MTBI) survivors at 3 months post-injury. Participants were 105 adults with MTBI who were recruited from consecutive admissions to two hospital emergency wards, and randomly assigned to either the SS or TAN modality. No group differences in outcome were evident at 12 months post-injury. As well, improvements seen in the groups after 3 months were maintained at 12 months. As improvements between 3 and 12 months were negligible, self-reported improvement after a treated MTBI typically occurred within the first 3 months. Brief educational intervention given soon after MTBI appears to be as helpful as more intensive treatment for most MTBI survivors for at least 12 months post-injury.

Adult↗
PubMed2000

Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes.

Multilocular, mitochondria-rich adipocytes appear in white adipose tissue (WAT) of rats treated with the beta3-adrenoceptor agonist, CL-316243 (CL). Objectives were to determine whether these multilocular adipocytes derived from cells that already existed in the WAT or from proliferation of precursor cells and whether new mitochondria contained in them were typical brown adipocyte mitochondria. Use of 5-bromodeoxyuridine to identify cells that had undergone mitosis during the CL treatment showed that most multilocular cells derived from cells already present in the WAT. Morphological techniques showed that at least a subpopulation of unilocular adipocytes underwent conversion to multilocular mitochondria-rich adipocytes. A small proportion of multilocular adipocytes ( approximately 8%) was positive for UCP1 by immunohistochemistry. Biochemical techniques showed that mitochondrial protein recovered from WAT increased 10-fold and protein isolated from brown adipose tissue (BAT) doubled in CL-treated rats. Stained gels showed a different protein composition of new mitochondria isolated from WAT from that of mitochondria isolated from BAT. Western blotting showed new mitochondria in WAT to contain both UCP1, but at a much lower concentration than in BAT mitochondria, and UCP3, at a higher concentration than that in BAT mitochondria. We hypothesize that multilocular adipocytes present at 7 days of CL treatment have two origins. First, most come from convertible unilocular adipocytes that become multilocular and make many mitochondria that contain UCP3. Second, some come from a cell that gives rise to more typical brown adipocytes that express UCP1.

Adipocytes↗
PubMed1998

Temperature-dependent feeding: lack of role for leptin and defect in brown adipose tissue-ablated obese mice.

The objective was to characterize the ability of control and transgenic brown adipose tissue (BAT)-ablated uncoupling protein diphtheria toxin A chain (UCP-DTA) mice to adjust food intake in relation to changes in environmental temperature and to assess the involvement of leptin in this adjustment. We measured serum leptin in mice from a previous study of UCP-DTA mice raised at thermoneutrality (35 degrees C) or at the usual rearing temperature (24 degrees C) from weaning [Melnyk, A., M. -E. Harper, and J. Himms-Hagen. Am. J. Physiol, 272 (Regulatory Integrative Comp. Physiol. 41): R1088-R1093, 1997] and extended the study by acclimating control and obese UCP-DTA mice at 18 wk of age to cold (14 degrees C) for up to 14 days. Leptin levels did not change in control mice at 14 degrees C; however, food intake increased threefold within 1 day and remained at this level. Serum leptin level was elevated in UCP-DTA mice at 24 degrees C compared with control mice at 24 degrees C; this elevated level decreased within 1 day at 14 degrees C and was not different from the level in control mice by 14 days. Food intake of UCP-DTA mice that were hyperphagic at 24 degrees C did not change during 7 days at 14 degrees C, then increased slowly. Similar low leptin levels were present in control mice raised at 24 or 35 degrees C and in UCP-DTA mice raised at 35 degrees C. Food intake of control mice raised at 24 degrees C was two times that of control mice raised at 35 degrees C. UCP-DTA mice raised at 35 degrees C ate the same low amount as control mice raised at 35 degrees C. UCP-DTA mice at 24 degrees C were hyperphagic relative to control mice at 24 degrees C yet had elevated leptin levels in their serum. Two principal conclusions are drawn. First, adjustment of food intake over a fourfold range by control mice acclimated to temperatures from 35 down to 14 degrees C is independent of changes in serum leptin levels. Second, this adjustment of food intake in relation to temperature is defective in the UCP-DTA mouse; the defect leads to hyperphagia at 24 degrees C and a failure to increase food intake as rapidly as control mice when exposed to 14 degrees C. Because lack of UCP-1-mediated thermogenesis in BAT of knockout mice is known not to induce hyperphagia, we propose that deficiency of UCP-1-expressing brown adipocytes in BAT of UCP-DTA mice results in lack of a satiety factor, secreted by these cells in BAT of control mice in inverse relationship to sympathetic nervous system activity.

Adipose Tissue, Brown↗
PubMed1997

Evaluation of the Revised European-American Lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkin's lymphoma.

The Revised European-American Lymphoma (REAL) classification has been criticized for its emphasis on the unproven clinical relevance of immunophenotype. A worse prognosis for peripheral T-cell non-Hodgkin's lymphomas (PTCLs) has been inconsistently reported in part because the definition of PTCL has been imprecise (eg, T-cell-rich B-cell non-Hodgkin's lymphomas [TCRBCLs] have been misdiagnosed as PTCLs in the past) and because its correlation with other known prognostic factors has not been studied by multivariate analysis. We analyzed six protocols from 1984 to 1995 with Working Formulation intermediate grade and immunoblastic lymphomas (exclusive of mantle cell) and selected only those cases in which immunophenotyping was performed and was conclusive. Of a total of 560 evaluable patients, 68 were PTCLs (12%) and the remaining 492 (88%) were B-cell non-Hodgkin's lymphomas, including 16 TCRBCLs (3% of total). The 5-year failure-free survival (FFS) for PTCLs and B-cell large-cell lymphomas (BCLCLs) is 38% and 55%, respectively (P < .0001) and the 5-year overall survival (OS) is 39% and 262%, respectively (P < .001). The M.D. Anderson prognostic tumor score (MDATS) and International Prognostic Index (IPI) for all patients was calculated. With MDATS of less than 3 (good prognosis), the 5-year FFS for PTCL and BCLCL is 56% and 69%, respectively (P = .01), and the 5-year OS is 64% and 77%, respectively (P = .06). With MDATS of greater than 2 (poor prognosis), 5-year FFS for PTCL and BCLCL is 26% and 38%, respectively (P = .03), and the 5-year OS is 24% and 41%, respectively (P = .02). With an IPI of less than 3 (good prognosis), the 5-year FFS for PTCL and BCLCL is 49% and 64%, respectively (P = .001), and the 5-year OS is 55% and 71%, respectively (P = .013). With an IPI greater than 2 (poor prognosis), the 5-year FFS for PTCL and BCLCL is 11% and 35%, respectively (P = .044), and the 5-year OS is 10% and 40%, respectively (P = .011). Multivariate analysis shows that MDATS, IPI, and T-cell phenotype are totally independent and are the most significant predictors of FFS and OS. The 68 PTCLs include 45 PTCLs unspecified, 10 Ki-1 anaplastic (ALCL), 8 angioimmunoblastic, and 5 angiocentric lymphomas. Angiocentrics were usually refractory (1 of 5 remissions only). ALCL rarely relapsed late. We conclude that the immunophenotypic basis of the REAL classification is clinically relevant and that, although other prognostic features also influence outcome, the T-cell phenotype still remains an independent and significant prognostic factor.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Raising at thermoneutrality prevents obesity and hyperphagia in BAT-ablated transgenic mice.

Transgenic mice with ablation of brown adipocytes induced by brown adipocyte-specific expression of diphtheria toxin A chain (DTA) driven by the uncoupling protein (UCP) promoter (UCP-DTA mice) become obese and hyperphagic (Lowell, B. B., V. S. Susulic, A. Hamann, J. A. Lawitts, J. Himms-Hagen, B. B. Boyer, L. P. Kozak, and J. S. Flier. Nature 366: 740-742, 1993). A deficit in energy expenditure for brown adipose tissue (BAT) thermogenesis in these mice is presumed to contribute to the development of obesity. The objective of the present study was to obviate any deficit in BAT thermogenesis by raising transgenic and control mice at thermoneutrality (35 degrees C), where both would have equally inactive BAT, to see whether this would prevent the obesity and the hyperphagia. Transgenic and control mice were raised from weaning (3 wk of age) to 8 wk of age at either 24 or 35 degrees C. Raising at 35 degrees C completely prevented development of obesity of UCP-DTA mice, as indicated by their normal carcass fat, normal weights of four major white adipose tissue depots, and normal size of white adipocytes. As seen before, transgenic mice raised at 24 degrees C had excess weight gain by 6 wk of age and by 8 wk had doubled carcass fat, an obesity characterized by increased white adipocyte size with no increase in number of adipocytes. The treatment also prevented hyperphagia of UCP-DTA mice, consistent with the hypothesized role of BAT thermogenesis in control of thermoregulatory feeding (Himms-Hagen, J. Proc. Soc. Exp. Biol. Med. 208: 159-169, 1995). UCP-DTA mice thus differ from genetically obese mice (ob/ob, db/db) for which raising at thermoneutrality is known not to prevent either the obesity or the hyperphagia. Both the obesity and the hyperphagia of UCP-DTA mice appear to be due to their deficit in BAT thermogenesis.

Adipose Tissue, Brown↗
PubMed1996

Ukrain monotherapy in malignant melanoma (case report).

A patient with a metastasizing malignant melanoma (stage III) was treated with Ukrain monotherapy. Before and during the first Ukrain course of treatment the patient excreted melanin in the urine. After the third course melanin was no more detectable and the patient has been without any symptoms of disease for the last 12 years.

Adult↗
PubMed1996

Ukrain therapy of recurrent breast cancer with lung metastases (case report).

A recurrent breast cancer with lung metastases was treated with the new anticancer drug Ukrain. The first two courses led to subjective improvement of the general condition as well as work capability; appetite improved and shortness of breath disappeared. After the sixth course of Ukrain therapy objective improvement was found clinically on X-ray, in haematological and biochemical data and improved tumour markers. Lymph nodes and lung metastases disappeared. The patient showed a full clinical remission.

Adult↗
PubMed1996

Ukrain treatment in carcinoma of the cervix (case report).

A grade IV Papanicolaou cervical cancer was treated with endocervical cone biopsy (electrocoagulation) in a 28 year-old lady. Three years later examination revealed cervical carcinoma in situ and a conization was recommended, which the patient refused. She was treated with Ukrain instead. The grading regressed steadily and after one year of Ukrain therapy all stagings were normal. Three years after the start of Ukrain therapy she gave birth to a healthy child. Eight years later she has no recurrence and is healthy.

Adult↗
PubMed1996

Combined therapy with Ukrain and chemotherapy in ovarian cancer (case report).

A patient with adenocarcinoma in the right ovary with lymphangitis carcinomatosa, staged as G II-G III pT3, pNX, pMX, was treated after palliative surgery by chemotherapy and, simultaneously, with Ukrain. Two and a half years after treatment the patient is without any signs of tumour recurrence. Her condition is excellent.

Adenocarcinoma↗
PubMed1996

Ukrain treatment in a patient with non-seminomatous germ-cell tumour of testis (case report).

A 31 year old patient with non-seminomatous germ-cell tumour of the testis was treated with Ukrain following operation and gamma-radiotherapy. 20 mg Ukrain ampoules were injected i.v. twice weekly with a total dose of 200 mg for each of three courses of treatment. Within the period of 24 months observation no recurrence or metastases were found. The results testify that Ukrain in complex treatment of patients with non-seminomatous germ-cell tumours of the testis can contribute to optimisation of immune status which improves the prognoses and results of treatment.

Adult↗
PubMed1996

Ukrain therapy in a frontal anaplastic grade III astrocytoma (case report).

Ukrain, a semisynthetic thiophosphoric acid compound of alkaloid chelidonine from Chelidonium majus L. (1) causes regression of various tumours. Among other effects, its action seems to depend on the stimulation of the immune system which very often is deficient in cancer patients. Its use in a patient with subtotal extirpation of a frontal anaplastic grade III astrocytoma seems to have reduced growth speed significantly.

Adult↗
PubMed1995

Resistance to aging-associated obesity in capsaicin-desensitized rats one year after treatment.

Previous studies demonstrated reduced weight of abdominal white adipose tissue depots and of carcass fat in capsaicin-desensitized (Cap-Des) rats up to 8 months after treatment. The objective of the present study was to find out whether aging-associated obesity and hyperplasia of retroperitoneal white adipose tissue was prevented in older (13.5 months old) Cap-Des rats, one year after treatment with Cap (done when they were 1.5 months old). The prevalence of obesity is known to increase in rats by this age. Abdominal white adipose tissue depots weighed less in old Cap-Des rats, both epididymal (9% less) and retroperitoneal (30% less). The number of mature white adipocytes was 28% less in the retroperitoneal depot but was not significantly different in the epididymal depot. Adipocyte size was not different. Carcass fat was less, both total and as percent of body weight. Food intake was normal for their reduced body size. The exponential increase in retroperitoneal white adipose tissue weight characteristic of aging rats that are becoming obese was virtually absent in Cap-Des rats. We conclude that lack of function of capsaicin-sensitive afferent autonomic nerves, known to be destroyed in Cap-Des rats, results in an alteration in energy balance conducive to leanness. We suggest that the attenuated age-associated increase in circulating CGRP (derived mainly from capsaicin-sensitive nerves) in the Cap-Des rat results in a lower degree of aging-associated insulin-resistance, hence in a lesser degree of obesity.

Adipose Tissue↗
PubMed1995

Three-hour paclitaxel infusion in patients with refractory and relapsed non-Hodgkin's lymphoma.

PURPOSE: Paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) is a novel antimicrotubule agent with anti-tumor activity against ovarian and breast carcinomas. Its activity when administered as a 3-hour intravenous infusion in patients with relapsed non-Hodgkin's lymphoma (NHL) has not been studied. PATIENTS AND METHODS: Patients with relapsed NHL were treated with a 3-hour infusion of 200 mg/m2 of Taxol every 3 weeks in an outpatient setting. All patients received premedication (dexamethasone, diphenhydramine, and cimetidine) to prevent allergic reactions. Responses were assessed after two courses of therapy, and patients who achieved at least partial remission (PR) continued to receive Taxol for a maximum of eight courses. RESULTS: Of 60 eligible patients, 54 (90%) were assessable for treatment toxicity and 53 (88%) were for treatment response (22 with primary refractory and 31 with relapsed disease). Twelve patients (23%) achieved a PR (n = 6) or complete remission (CR; n = 6) (95% confidence interval, 12% to 36%). Responses were observed in intermediate-grade (31%), low-grade (14%), and mantle-cell (17%) lymphomas. In the intermediate-grade lymphomas, there was a trend for a higher response rate in relapsed versus primary refractory disease (54% v 13%; P = .08). Treatment-related toxicity included alopecia (100%), peripheral neuropathy (37%), myalgia or arthralgia (25%), and neutropenic fever (11%). None of the patients had allergic reactions or cardiac toxicity. CONCLUSION: At this dose and schedule, Taxol is an active agent in patients with relapsed NHL and can be safely administered in an outpatient setting. Combination programs with Taxol should be investigated for treatment of NHL.

Adult↗
PubMed1990

T-cell acute lymphoblastic leukemia with t(1;18)(p36;q22).

An 8-year-old white boy with a T-cell acute lymphoblastic leukemia (T-ALL) developed chromosomal abnormalities t(1;18)(p36;q22) and del (6)(q21) at the first bone marrow relapse. Rearrangements of the chromosome region 1p36 have been reported previously in adults with T-ALL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Complex translocations in a patient with chronic myelocytic leukemia: t(9;22;17) and t(10;18;19) after two failed bone marrow transplantations.

A 6-year-old white boy with chronic myelogenous leukemia (CML) (adult type) developed complex translocations after a bone marrow transplant (BMT): t(9;22;17)(q34;q11;p12) t(10;18;19)(p11;q11;p12) and in the accelerated phase. The patient relapsed after his BMT and underwent a second BMT after a documented blast crisis. The previous karyotypic translocations persisted.

Bone Marrow Transplantation↗