Biomedical subjects

M Kovacs

Publications and source records attributed to M Kovacs.

At least 19 recordsLinked to original sources

PubMed2006

Association study of the adrenergic receptors and childhood-onset mood disorders in Hungarian families.

The adrenergic system has been implicated in the etiology of depression based on a number of lines of evidence, particularly, the mechanism of some classes of antidepressants which increase the synaptic levels of norepinephrine. Further, several genome scans for mood disorders, both unipolar and bipolar, have indicated linkage to the chromosomal regions of 5q23-q33.3, 8p12-p11.2, 4p16, and 10q24-q26, the location of the adrenergic receptors alpha1B (ADRA1B), beta3 (ADRB3), alpha2C (ADRA2C), alpha2A (ADRA2A), and beta1 (ADRB1). In this manuscript, we report on the relationship of the adrenergic receptors and depression using a family based association approach and 189 families (223 affected children) with childhood-onset mood disorder (COMD) collected in Hungary. We found no significant evidence for an association with any of the 24 markers, in total, tested across these genes using single marker analysis or haplotypes of markers across these genes. The results in the present sample indicate that these nine genes are unlikely to be major susceptibility genes contributing to COMD.

Adolescent↗

PubMed2006

Distribution and elimination of fumonisin analogues in weaned piglets after oral administration of Fusarium verticillioides fungal culture.

The distribution and elimination of fumonisins after oral administration of 50 mg FB(1), 20 mg FB(2) and 5 mg FB(3) per animal day(-1) for 22 days was studied in weaned barrows. At the end of the trial, the lung, heart, liver, kidney, spleen, brain, serum, bile, muscle, fat, urine and faeces samples were collected and their content of fumonisins (FB(1), FB(2)) determined by LC-MS. The highest FB(1) concentrations were found in the liver (99.4 +/- 37.5 ng g(-1)) and kidneys (30.6 +/- 10.1 ng g(-1)), whilst the highest average amount of FB(2) was in the liver (1.4 +/- 2.3 ng g(-1)) and fat (2.6 ng g(-1) +/- 4.8) samples. Comparing the FB(1)/FB(2) ratio in different organs (19/1), it was found that the ratio in the abdominal and subcutaneous fat samples (4/1) was markedly different from those in all other tissues, namely the relative proportion of FB(2) was higher in latter cases. Of the total quantity of FB(1), the 13% taken up during 5 days was excreted unchanged with the faeces and urine. On average, in the urine and faeces, FB(1) was detected in nine- and 14-fold quantities, as compared with FB(2).

Adipose Tissue↗

PubMed2005

Association study of CREB1 and childhood-onset mood disorders.

Several lines of evidence suggest that the cellular pathways involved in synaptic plasticity contribute to the risk of depression. These findings include the evidence that chronic antidepressant treatment upregulates the cAMP signal transduction cascade resulting in increased expression and function of the cAMP responsive element binding protein (CREB), a transcription factor that increases the expression of key growth factors involved in synaptogenesis and neurogenesis. Recently, linkage to CREB1 was reported for early-onset depression in families recruited from the Pittsburgh area. This finding was significant only in female sibling pairs from those families. Two specific DNA variants, -656G/A and a C insertion/deletion in intron 8, were identified in CREB1 that co-segregated with depression in two of the families. We sought to investigate the relationship of CREB1 to childhood-onset mood disorders (COMD) using a sample of 195 nuclear families (225 affected children) collected in Hungary. We genotyped the two CREB1 DNA variants previously identified as linked to depression as well as three additional polymorphisms spanning the gene. In addition, we genotyped the -656G/A DNA change and the intron 8 polymorphism in a sample of 112 probands with mood disorders collected in the Pittsburgh area and matched controls, and examined the distribution of alleles. The -656A allele was not observed in our samples and there was no evidence for association of the intron 8 polymorphism in either the sample from Pittsburgh (chi(2) = 0.061, 1 d.f., P = 0.803) or Hungary (chi(2) = 0.040, 1 d.f., P = 0.842). We found no evidence for an association with the other three polymorphisms or with the haplotypes of these markers. Further, we found no sex-specific relationship. Our results, therefore, do not support the previous evidence for this gene as a major factor contributing to depression.

Adolescent↗

PubMed2005

Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. BDNF markers included the (GT)n microsatellite, Val66Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val66Met polymorphism demonstrated significant overtransmission of the val allele (chi2=7.12, d.f.=1, P=0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT)n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z=2.095, P=0.036). Significant haplotypes involved Val66Met and BDNF2 (P=0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val66Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.

Adult↗

PubMed2004

Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals. BDNF gene polymorphisms have been associated with bipolar disorder. We tested two genetic polymorphisms of BDNF for their association with childhood-onset mood disorders (COMD) within the context of a case-control design. Two BDNF polymorphisms, a dinucleotide repeat (GT)(n), and a single nucleotide polymorphism (SNP) in the coding region, val66met, were genotyped in 99 adults with a history of COMD and matched psychiatrically healthy controls. A genomic control (GC) method was used to evaluate population substructure. Alleles at (GT)(n) were highly associated with COMD in this sample (chi(2) = 17.8; d.f. = 5; P = 0.0032). The odds of carrying the 168 bp allele were 3.94 times greater for cases than controls (CI = 1.72-9.04). Alleles of val66met were not significantly associated with COMD. GC analysis suggested population substructure was not a confounder of association. Analysis of haplotypes, in which (GT)(n) was treated as a binary variable (long vs. short alleles), provided significant evidence that the haplotype val/short contributes to liability to COMD. The BDNF (GT)(n) marker and the val/short haplotype are associated with COMD in this sample, in accordance with the previously described neurotrophic hypothesis of depression and some previous studies of association for bipolar disorder and neuroticism.

Adolescent↗

PubMed2004

BDNF and COMT polymorphisms: relation to memory phenotypes in young adults with childhood-onset mood disorder.

Recent investigations in several species have suggested a role for brain-derived neurotrophic factor (BDNF) in memory, which may be mediated by the influence of BDNF on neuronal plasticity in the hippocampus. BDNF polymorphisms have also been associated with mood disorders. Catechol-O-methyltransferase (COMT) metabolizes dopamine and has been implicated in prefrontal function, another area of the brain relevant for memory. In a sample of 63 young adults with a history of childhood-onset mood disorder, we typed three BDNF polymorphisms, including the BDNF Val66Met single nucleotide polymorphism (SNP), and the COMT Val108/158Met SNP. Multivariate analysis of variance was used to test the association between BDNF and COMT markers and measures of declarative memory. Variants at the three BDNF markers and one COMT marker were not associated with declarative memory function p-values ranged from 0.25 to 0.98. Higher IQ (F = 6.18, df = 4, 58, p = 0.0003) and female gender (F = 4.41, df = 4, 58, p = 0.0035) were associated with more optimal performance on the memory tasks. This study did not provide evidence supporting an association between BDNF and COMT genes and declarative memory phenotypes.

Adolescent↗

PubMed2002

Targeted cytotoxic analogue of luteinizing hormone-releasing hormone (LH-RH) only transiently decreases the gene expression of pituitary receptors for LH-RH.

A cytotoxic analogue of LH-RH, AN-207, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to carrier [D-Lys6]LH-RH, was developed for targeted therapy of cancers expressing LH-RH-receptors. To determine its possible side-effects on the pituitary gland, we investigated the gene expression of pituitary LH-RH-receptors and LH secretion in ovariectomized female and normal male rats after treatment with the maximum tolerated dose of AN-207. The effect of AN-207 on the gene expression of the pituitary GH-RH-receptors and GH secretion was also assessed in male rats. Five hours after a single i.v. injection of AN-207 at 175 nmol/kg, there was a 39-51% decrease in mRNA expression for the pituitary LH-RH-receptors in male and female rats. The carrier, at an equimolar dose, caused a similar reduction (37-39%), whereas the cytotoxic radical AN-201, at an equitoxic dose (110 nmol/kg), produced only a 12-24% decrease (NS) in the mRNA expression of LH-RH-receptors. AN-207 and the carrier analogue induced a comparable 90-100-fold increase in serum LH concentrations in male rats, and the same 12-fold elevation in OVX rats at 5 h. Seven days after treatment with AN-207, the mRNA levels for the LH-RH receptors and the serum LH concentration were back to normal in both sexes. AN-207, the carrier, and AN-201 had no significant effect on the expression of mRNA for GH-RH-receptors in the pituitary. In vitro, a continuous perfusion of pituitary cells with 10 nM AN-207 did not affect the hormone-releasing function of the targeted LH cells or the nontargeted GH cells. Our results demonstrate that cytotoxic LH-RH analogue AN-207, at the maximum tolerated dose causes only a transient decrease in the gene expression of the pituitary LH-RH receptors, and the levels of mRNA for LH-RH receptor fully recover within 7 days. Moreover, the carrier hormone moiety, and not the cytotoxic radical in AN-207 is responsible for this transient suppression. Our findings suggest that the therapy with cytotoxic LH-RH analogues will not inflict permanent damage to pituitary function.

Animals↗

PubMed2002

Lamprey gonadotropin hormone-releasing hormone-III has no selective follicle-stimulating hormone-releasing effect in rats.

Lamprey gonadotropin releasing-hormone (LGnRH)-III, a hypothalamic neurohormone recently isolated from sea lamprey, was reported to have a selective stimulatory effect on follicle-stimulating hormone (FSH) release in rats and suggested to be the mammalian FSH-releasing factor. In this study, we determined the relative luteinizing hormone (LH)- and FSH-releasing potency of LGnRH-III compared to mammalian gonadotropin-releasing hormone (LHRH) in normal female rats, ovariectomized (OVX) and oestrogen/progesterone substituted rats and the superfused rat-pituitary cell system. The specificity of LGnRH-III for the mammalian LHRH receptor was investigated by blocking the receptor with an LHRH antagonist, MI-1544. In vitro, LGnRH-III dose-dependently stimulated both LH and FSH secretion from rat pituitary cells at 10(-7) to 10(-5) M concentrations, while LHRH stimulated gonadotropin secretion at a 1000-fold lower doses (10(-10) to 10(-8) M). The difference between its LH- and FSH-releasing potency was similar to that of LHRH. LGnRH-III bound to high affinity binding sites on rat pituitary cells with a Kd of 6.7 nM, B(max)=113 +/- 27 fmol/mg protein. In vivo, LGnRH-III also stimulated both LH and FSH secretion in a dose-dependent manner and, similar to LHRH, induced a greater rise in the serum LH than the FSH level. In normal cycling rats, it showed 180-650-fold weaker potency than LHRH in stimulating LH secretion and 70-80-fold weaker effect in stimulating FSH secretion. In OVX rats, LGnRH-III demonstrated a similarly weak effect on both gonadotropins. It was found to be 40-210-fold less potent than LHRH regarding LH release and 50-160-fold weaker regarding FSH release. LHRH-receptor antagonist MI-1544 prevented both the LH- and the FSH-releasing effect of LGnRH-III both in vitro and in vivo. These results do not support the hypothesis that LGnRH-III might be the mammalian FSH-releasing factor but demonstrate that it is a weak agonist for the pituitary LHRH receptor and stimulates both gonadotropins in a dose-dependent fashion.

Animals↗

PubMed2002

Inhibitory effects of antagonistic analogs of GHRH on GH3 pituitary cells overexpressing the human GHRH receptor.

GH3 rat pituitary tumor cells produce GH and prolactin (PRL), but lack the GHRH receptor (GHRH-R). We expressed human GHRH-R (hGHRH-R) in GH3 cells using recombinant adenoviral vectors and studied the effects of GHRH antagonists. The mRNA expression of the GHRH-R gene in the cells was demonstrated by RT-PCR. An exposure of the GH3 cells infected with hGHRH-R to 10(-10), 10(-9) and 10(-8) m hGHRH for 1 or 2 h in culture caused a dose-dependent elevation of the intracellular cAMP concentration and the cAMP efflux. Exposure to hGHRH also elicited dose-dependent increases in GH and PRL secretion from these cells. Neither the uninfected nor the antisense hGHRH-R-infected control cells exhibited cAMP, GH and PRL responses to GHRH stimulation. GHRH antagonists JV-1-38 and jv-1-36 applied at 3x10(-8) m for 3 h, together with 10(-9) m GHRH, significantly inhibited the GHRH-stimulated cAMP efflux from the hGHRH-R-infected cells by 36 and 80% respectively. The more potent antagonist JV-1-36 also decreased the intracellular cAMP levels in these cells by 55%. Exposure to JV-1-36 for 1 h nullified the stimulatory effect of GHRH on GH secretion and significantly inhibited it by 64 and 77% after 2 and 3 h respectively. In a superfusion system, GHRH at 10(-10), 10(-9) and 10(-8) m concentrations induced prompt and dose-related high cAMP responses and smaller increases in the spontaneous GH secretion of the hGHRH-R-infected cells. Antagonists JV-1-36 and JV-1-38 applied at 3x10(-8) m for 15 min, together with 10(-9) m GHRH, inhibited the GHRH-stimulated cAMP response by 59 and 35% respectively. This work demonstrates that GHRH antagonists can effectively inhibit the actions of GHRH on the hGHRH-R. Our results support the view that this class of compounds would be active clinically.

Animals↗

PubMed2001

Activity of oral fludarabine phosphate in previously treated chronic lymphocytic leukemia.

PURPOSE: A prospective, multicenter, open-label phase II clinical trial was conducted to assess the efficacy and safety of oral fludarabine phosphate. Reference to an historical group of patients treated with the intravenous (IV) formulation allowed the investigators to compare the two formulations. PATIENTS AND METHODS: Efficacy was assessed using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and National Cancer Institute (NCI) criteria for complete remission (CR), partial remission (PR), stable disease, or disease progression. Safety monitoring included World Health Organization (WHO) toxicity grading for all adverse events. RESULTS: Seventy-eight (96.3%) of 81 recruited patients with previously treated B-cell chronic lymphocytic leukemia (CLL) received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. According to IWCLL criteria, the overall remission rate was 46.2% (CR, 20.5%; PR, 25.6%). The comparative figures using NCI criteria were 51.3% (CR, 17.9%; PR, 33.3%). Overall, 30 incidents of severe adverse events were reported for 22 patients. WHO grade 3 or grade 4 hematologic toxicities included granulocytopenia (53.8%), leukocytopenia (28.2%), thrombocytopenia (25.6%), and anemia (24.4%). Gastrointestinal adverse events were more common with the oral formulation than previously reported with IV fludarabine phosphate. However, these events were generally mild to moderate. CONCLUSION: This study demonstrates that oral fludarabine phosphate has similar clinical efficacy to the IV formulation and a safety profile that is both predictable and essentially similar to that of the IV formulation.

Administration, Oral↗

PubMed2001

The anti-emetic action of the neurokinin(1) receptor antagonist CP-99,994 does not require the presence of the area postrema in the dog.

Microinjection and ligand binding studies have implicated NK(1) receptors in the area postrema (AP) in the emetic response to intragastric copper sulphate that is mediated by abdominal vagal afferents. Because these afferents terminate in the brainstem in the nucleus tractus solitarius in close proximity to the AP or in the AP itself, the results of such studies may be difficult to interpret. The present study has demonstrated in the dog that the emetic response to intragastric copper sulphate is unaffected by AP ablation, demonstrated functionally by absence of an emetic response to apomorphine (100 microg kg(-1) i.v.). In AP ablated animals the selective NK(1) receptor antagonist CP-99, 994 (1 mg kg(-1) i.v.) blocked the emetic response to copper sulphate as it did in intact animals. The results demonstrate that the AP is not involved in the blockade of the emetic response to intragastric copper sulphate by an NK(1) receptor antagonist and hence provides further support for other sites proposed such as the nucleus tractus solitarius and central pattern generator.

Animals↗

PubMed2001

Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy.

PURPOSE: To evaluate efficacy, safety, and quality of life (QOL) changes with epoetin alfa therapy for anemia in patients with nonmyeloid malignancies. PATIENTS AND METHODS: Anemic cancer patients were enrolled onto this prospective, open-label study from 34 centers across Canada. The trial had two cohorts: patients who were and were not receiving chemotherapy during the 16-week study. All patients initially received epoetin alfa 150 IU/kg subcutaneously three times per week. The dose was doubled after 4 weeks for patients who did not experience sufficient response. RESULTS: Of the 183 patients enrolled in the nonchemotherapy cohort, statistically significant and clinically relevant improvements in QOL were observed with epoetin alfa therapy using both the FACT-An questionnaire and linear analog scale assessment. Hemoglobin levels increased significantly (P <.001; mean increase 2.5 g/dL from baseline to end of study) and these increases were positively correlated with improved QOL and change in Eastern Cooperative Oncology Group (ECOG) scores. There was a significant reduction in the percentage of patients who required blood transfusions. The 218 patients in the chemotherapy cohort also experienced significant improvements in QOL, decreased transfusion use, and increased hemoglobin levels that correlated with QOL improvements and change in ECOG scores. Epoetin alfa was well-tolerated in both cohorts. CONCLUSION: Epoetin alfa administered to patients with cancer-related anemia for up to 16 weeks resulted in significantly improved QOL, increased hemoglobin levels, and decreased transfusion use. These benefits were observed in cancer patients who were not receiving chemotherapy as well as those who were.

Aged↗

PubMed2001

Comparison of mechanisms of action of luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix and LHRH agonist triptorelin on the gene expression of pituitary LHRH receptors in rats.

The mechanisms through which luteinizing hormone (LH)-releasing hormone (LHRH) antagonists suppress pituitary gonadotroph functions and LHRH-receptor (LHRH-R) expression are incompletely understood. Consequently, we investigated the direct effect of LHRH antagonist cetrorelix in vitro on the expression of the pituitary LHRH-R gene and its ability to counteract the exogenous LHRH and the agonist triptorelin in the regulation of this gene. We also compared the effects of chronic administration of cetrorelix and triptorelin on the LHRH-R mRNA level and gonadotropin secretion in ovariectomized (OVX) and normal female rats. The exposure of pituitary cells in vitro to 3-min pulses of 1 nM LHRH or 0.1 nM triptorelin for 5 h increased the LHRH-R mRNA level by 77-88%. Continuous perfusion of the cells with 50 nM cetrorelix did not cause any significant changes, but prevented the stimulatory effect of LHRH pulses on the receptor mRNA expression. In OVX rats, 10 days after administration of a depot formulation of cetrorelix, releasing 100 microg of peptide daily, the elevated LHRH-R mRNA level was decreased by 73%, whereas daily injection of 100 microg of triptorelin caused a 41% suppression. In normal female rats, cetrorelix treatment suppressed the LHRH-R mRNA level by 33%, but triptorelin increased it by 150%. The highly elevated serum LH levels in OVX rats and the normal LH concentration of cycling rats were rapidly and completely suppressed by cetrorelix. Triptorelin decreased the serum LH in OVX rats to the precastration level, but had no effect on basal LH in normal rats. Our results confirm that LHRH antagonists, such as cetrorelix, inhibit the gene expression of pituitary LHRH-R indirectly, by counteracting the stimulatory effect of LHRH. A rapid suppression of serum LH by LHRH antagonists would be advantageous in the treatment of sex hormone-dependent tumors and other conditions.

Animals↗

PubMed2001

The dynamics of the relay loop tryptophan residue in the Dictyostelium myosin motor domain and the origin of spectroscopic signals.

Steady-state and time-resolved fluorescence measurements were performed on a Dictyostelium discoideum myosin II motor domain construct retaining a single tryptophan residue at position 501, located on the relay loop. Other tryptophan residues were mutated to phenylalanine. The Trp-501 residue showed a large enhancement in fluorescence in the presence of ATP and a small quench in the presence of ADP as a result of perturbing both the ground and excited state processes. Fluorescence lifetime and quantum yield measurements indicated that at least three microstates of Trp-501 were present in all nucleotide states examined, and these could not be assigned to a particular gross conformation of the motor domain. Enhancement in emission intensity was associated with a reduction of the contribution from a statically quenched component and an increase in a component with a 5-ns lifetime, with little change in the contribution from a 1-ns lifetime component. Anisotropy measurements indicated that the Trp-501 side chain was relatively immobile in all nucleotide states, and the fluorescence was effectively depolarized by rotation of the whole motor domain with a correlation time on 50-70 ns. Overall these data suggest that the backbone of the relay loop remains structured throughout the myosin ATPase cycle but that the Trp-501 side chain experiences a different weighting in local environments provided by surrounding residues as the adjacent converter domain rolls around the relay loop.

Adenosine Diphosphate↗

PubMed2001

Luteinizing hormone-releasing hormone (LH-RH) antagonist Cetrorelix down-regulates the mRNA expression of pituitary receptors for LH-RH by counteracting the stimulatory effect of endogenous LH-RH.

The mechanisms through which LH-RH antagonists suppress gonadotroph functions and LH-RH receptor (LH-RH-R) production are incompletely understood. To elucidate these mechanisms, we investigated the effects of Cetrorelix on the mRNA expression of pituitary LH-RH-R and luteinizing hormone (LH) secretion in three experimental systems with different pituitary LH-RH environments. Ovariectomy induced 3.61-fold and 6.34-fold increases in the mRNA expression of pituitary LH-RH-R in rats after 11 and 21 days, respectively. After (5 h) a single injection of 100 microg Cetrorelix, no significant decrease occurred in the mRNA levels of pituitary LH-RH-R in ovariectomized (OVX) rats with high pituitary exposure to LH-RH, but there was a significant 23.2% reduction in cycling rats with normal hypophysial LH-RH environment. Prolonged treatment for 10 days with a Cetrorelix depot formulation releasing 100 microg/day decreased the concentration of mRNA for pituitary LH-RH-R by 72.6% in OVX rats, but only by 32.9% in normal rats. The decline in serum LH was 98.7% in OVX rats and 63.2% in normal rats, resulting in a minimal 0.1--0.2 ng/ml LH concentration in both groups. A continuous exposure of pituitary cells to 100 nM Cetrorelix in the superfusion system, which is devoid of LH-RH, did not cause any significant changes in LH-RH-R mRNA level. These studies demonstrate that prolonged exposure to Cetrorelix in vivo, but not in vitro, down-regulates the mRNA expression of the pituitary receptors for LH-RH. Our findings indicate that LH-RH antagonists exert their inhibitory effects on the gene expression of pituitary LH-RH-R by counteracting the stimulatory effect of endogenous LH-RH.

Animals↗

PubMed2001

Hypothalamic hormones and cancer.

The use of peptide analogs for the therapy of various cancers is reviewed. Inhibition of the pituitary-gonadal axis forms the basis for oncological applications of luteinizing hormone-releasing hormone (LH-RH) agonists and antagonists, but direct effects on tumors may also play a role. Analogs of somatostatin are likewise used for treatment of various tumors. Radiolabeled somatostatin analogs have been successfully applied for the localization of tumors expressing somatostatin receptors. Studies on the role of tumoral LH-RH, growth hormone-releasing hormone (GH-RH), and bombesin/GRP and their receptors in the proliferation of various tumors are summarized, but the complete elucidation of all the mechanisms involved will require much additional work. Human tumors producing hypothalamic hormones are also discussed. Treatment of many cancers remains a major challenge, but new therapeutic modalities are being developed based on antagonists of GH-RH and bombesin, which inhibit growth factors or their receptors. Other approaches consist of the use of cytotoxic analogs of LH-RH, bombesin, and somatostatin, which can be targeted to receptors for these peptides in various cancers and their metastases. These new classes of peptide analogs should lead to a more effective treatment for various cancers.

Animals↗

PubMed2001

Risk stratification and outcomes of transluminal endografting for abdominal aortic aneurysm: 7-year experience and long-term follow-up.

PURPOSE: To determine early and late outcomes of transluminal endografting (TE) in patients with abdominal aortic aneurysm (AAA), stratified by predicted risk of procedure-related mortality with conventional operation. MATERIALS AND METHODS: A retrospective study was conducted in consecutive risk-stratified AAA patients undergoing TE at a not-for-profit cardiovascular referral center from March 1994 through November 2000 with follow-up through February 2001. With use of conventional risk strata (0 = low, 1 = minimal, 2 = moderate, and 3 = high), predicted procedure-related mortalities were 0%-1% in stratum 0 (n = 40), 1%-3% in stratum 1 (n = 118), 3%-8% in stratum 2 (n = 116), and 8%-30% in stratum 3 (n = 31). Main outcome measures were: (i) TE procedural success, (ii) procedure-related mortality, (iii) major nonfatal complications, (iv) composite adverse outcome (ii + iii), (v) length of stay (LOS), (vi) freedom from AAA rupture, (vii) late survival, (viii) late complications, and (ix) endoleaks and their classification and management. RESULTS: Women were significantly less likely than men to qualify for and undergo endografting: 24 of 91 (26.4%) women underwent TE, compared to 281 of 684 (41.1%) men. Of 305 attempted TE procedures, 291 (95.4%) were successful, four (1.3%) were urgently converted to open repair, and 10 (3.3%) were aborted. Procedure-related mortalities occurred in eight cases (2.6%) overall and one of 40 (2.5%), one of 118 (0.8%), four of 116 (3.4%), and two of 31 (6.5%) cases for risk strata 0-3, respectively. Perioperative survivors were significantly younger than nonsurvivors (74.3 y +/- 9 vs 81.6 y +/- 5.1; P =.0087). Forty-six patients (15.1%) had major complications. Composite adverse outcome was worse for patients in stratum 3 than those in stratum 1 (P =.0296) and those in strata 0, 1, and 2 combined (P =.026). Procedure-related mortality declined with institutional experience, from 4% among the first 100 patients undergoing TE to 1% among the last 105. For strata 0-3, median LOS were 2, 3, 3, and 4 days, respectively. Seventy patients (22.9%) had 75 endoleaks, of which 30 necessitated additional procedures, 17 self-resolved, and 22 were untreated as of March 1, 2001. Five patients with endoleak died of unrelated causes. One late-onset type IA endoleak (26 mo) resulted in the only AAA rupture and death in the follow-up period among the 291 patients who underwent successful transluminal endograft implantation. Actuarial survival rates at 1 year after TE were 90.3% +/- 1.9% for the overall study group and 97.5% +/- 2.5%, 94% +/- 2.5%, 86.9% +/- 3.3%, and 81.3% +/- 7.7% for risk strata 0-3, respectively. At 5 years, overall actuarial survival was 69.6% +/- 6.1%. Thirty-eight late deaths were attributable to post-TE AAA rupture (n = 1), AAA rupture late after failed TE with no further treatment (n = 1), other cardiovascular disorders (n = 7), cancer (n = 15), other causes (n = 10), and unknown causes (n = 4). Late deaths occurred in risk strata 0-3 at the following rates: two of 40 (5%), 10 of 118 (8.5%), 16 of 116 (13.8%), and 10 of 31 (32.3%), respectively (stratum 0 vs stratum 3, P =.0017; stratum 1 vs stratum 3, P =.003). CONCLUSIONS: TE is safe and confers durable protection against AAA rupture in treated populations. Still, protection is not absolute in patients with endoleaks, because late AAA enlargement and even rupture can occur. Given current knowledge, technology, and practice, careful patient selection and close surveillance of patients after implantation of transluminal endografts is essential.

Age Distribution↗

PubMed2001

Gender and the course of major depressive disorder through adolescence in clinically referred youngsters.

OBJECTIVES: To determine whether there are gender differences among psychiatrically referred young patients in the presenting features and subsequent course of major depressive disorder (MDD) through adolescence. METHOD: The subjects were 92 participants in a longitudinal follow-up study that included repeated standardized psychiatric evaluations. Gender effects were examined on features of MDD as patients progressed from late childhood (mean age 11 years) to late adolescence (mean age 17 years). RESULTS: Salient features of MDD did not differ for girls versus boys, including age at MDD onset, recovery from the index episode, risk of a new episode, and rates of various comorbid disorders in the index and recurrent episodes. Rates of selected symptoms and severity of the depressive syndrome also were comparable for boys and girls throughout their development. CONCLUSIONS: Gender differences have been documented in epidemiological and community samples with respect to rates and correlates of depressed mood and some features of depressive disorders. However, the study of gender differences among clinically referred depressed youths has only recently gained momentum. The present findings complement existing reports suggesting a lack of compelling gender effects on salient presenting features and adolescent outcomes of MDD in clinically referred youths. Additional work is needed to determine whether gender effects are detectable on other clinical parameters of MDD during adolescence or further along in development.

Adolescent↗