Disposition of methylglyoxal bis(guanylhydrazone) (MGBG,NSC-32946) in man

Summary A high-pressure liquid chromatographic method was utilized to determine the concentration of the antileukemic agent methylgloxal bis(guanylhydrazone) (MGBG, NSC-32946) in tissue samples obtained at autopsy from patients who received MGBG. In a patient with cholangiocarcinoma who received one course of MGBG (500 mg/m²), the highest drug concentration was found in normal liver tissue. However, the drug concentration in intrahepatic tumor tissue was only 10% of that found in uninvolved liver. In a patient with acute myelogenous leukemia (AML) who received 12 courses of MGBG therapy, highly infiltrated lymph node tissue was found to contain the highest concentration of MGBG. High concentrations of the drug were also found in liver, spleen, kidney, adrenal, and thyroid. The drug penetrated well into normal brain tissue. After repeated administration, high drug concentrations were found in cerebral and cerebellar gray matter. These studies suggest that there is no selective uptake of MGBG into solid tumors early after drug administration and provide a pharmacologic rationale for testing this agent against endocrine and intracerebral tumors in man.The abbreviations used in this paper are MGBG methylglyoxal bis(guanylhydrazone) - TCA trichloroacetic acid - PCA perchloric acid - KOH potassium hydroxide - HPLC high-pressure liquid chromatography     

An immunohistochemical study of human fetal liver in the Meckel-Gruber syndrome

AIMS: The ductal plate abnormality of the liver in fetuses with the Meckel-Gruber syndrome has been well characterised, but its aetiology remains unknown. We have analysed liver structure in six fetuses with this syndrome, using routine histology, immunocytochemistry, and electron microscopy. METHODS: Liver tissue from six fetuses of 11-27 weeks gestational age was examined by immunoperoxidase staining with antigens to cyokeratin (AE1/3) and polyclonal CEA. We also examined the ultrastructure of the syndromic fetal liver. The findings were compared with livers of control fetuses obtained from miscarriages, of similar size and gestational age but without dysmorphic features or developmental anomalies. RESULTS: The ductal plate abnormality was present in all the fetuses with the Meckel-Gruber syndrome. There were abnormalities of biliary excretion in all syndromic fetuses. Ultrastructural studies of the portal tract revealed abnormal collagen bundles in the Meckel-Gruber syndrome. CONCLUSIONS: Our findings, in conjunction with other reports in the literature, suggest that the ductal plate abnormality may be caused by failure of anastomosis of the intra- and extrahepatic biliary systems, perhaps in association with abnormalities of the portal tract stroma and biliary excretion.     

Psychiatric comorbidity in adult attention deficit hyperactivity disorder: findings from multiplex families

OBJECTIVE: Patterns of psychiatric comorbidity were assessed in adults with and without attention deficit hyperactivity disorder (ADHD) identified through a genetic study of families containing multiple children with ADHD. METHOD: Lifetime ADHD and comorbid psychopathology were assessed in 435 parents of children with ADHD. Rates and mean ages at onset of comorbid psychopathology were compared in parents with lifetime ADHD, parents with persistent ADHD, and those without ADHD. Age-adjusted rates of comorbidity were compared with Kaplan-Meier survival curves. Logistic regression was used to assess additional risk factors for conditions more frequent in ADHD subjects. RESULTS: The parents with ADHD were significantly more likely to be unskilled workers and less likely to have a college degree. ADHD subjects had more lifetime psychopathology; 87% had at least one and 56% had at least two other psychiatric disorders, compared with 64% and 27%, respectively, in non-ADHD subjects. ADHD was associated with greater disruptive behavior, substance use, and mood and anxiety disorders and with earlier onset of major depression, dysthymia, oppositional defiant disorder, and conduct disorder. Group differences based on Kaplan-Meier age-corrected risks were consistent with those for raw frequency distributions. Male sex added risk for disruptive behavior disorders. Female sex and oppositional defiant disorder contributed to risk for depression and anxiety. ADHD was not a significant risk factor for substance use disorders when male sex, disruptive behavior disorders, and socioeconomic status were controlled. CONCLUSIONS: Adult ADHD is associated with significant lifetime psychiatric comorbidity that is not explained by clinical referral bias.     

Short-term postoperative GnRH analogue or danazol treatment after conservative surgery for stage III or IV endometriosis before ovarian stimulation: a prospective, randomized study

OBJECTIVE: To assess the effect of short-term use of a gonadotropin releasing hormone (GnRH) analogue for 3 months before ovarian stimulation in patients with stage III and IV endometriosis after conservative surgery. STUDY DESIGN: Eleven patients were randomly selected to receive intramuscular injections of GnRH analogue, leuprolide acetate (3.75 mg), every 28 days, or 400 mg danazol orally 2 times per day for 3 months before ovarian stimulation after conservative laparoscopic or laparotomy surgeryfor stage III and IV symptomatic endometriosis (group 1), as compared with 30 patients who had received no postoperative treatment with GnRH analogue or danazol but underwent ovarian stimulation immediately after thefirst menses within 3 months postoperatively (group 2). RESULTS: Although the number of oocytes retrieved and number of embryos per cycle were significantly higher in group 1, the pregnancy rate per cycle in group 1 was not significantly different from that in group 2 (18% vs. 20%). The cumulative pregnancy rate at 12 months was 54.5% and 56.7% in group 1 and group 2, respectively. With regard to recurrence of disease after 24 months of follow-up, group 2 had a statistically significantly higher recurrence rate (13.3%) than did group 1 (0%). CONCLUSION: Short-term use of GnRH analogue before ovarian stimulation in women with stage III or IV endometriosis confers no definite benefits on pregnancy rates per cycle when compared with patients who received ovarian stimulation within 3 months after conservative surgery.     

Ecological validity of walking speed assessment after traumatic brain injury: a pilot study

OBJECTIVE: To assess the ecological validity of walking speed measurement after traumatic brain injury (TBI). PARTICIPANTS: Ten people with TBI who could walk independently and were participating in a rehabilitation program. DESIGN: Walking speed on 3 clinical gait tests (comfortable and fast pace over a 10-m distance and a 6-minute walk test) in 3 "natural" environments (a corridor in a brain injury rehabilitation unit, a car park of a metropolitan shopping center, and inside a metropolitan shopping center). Normative data were collected for 275 able-bodied pedestrians as they walked in the 3 natural environments. RESULTS: For subjects with TBI, agreement between the speeds used in the clinical gait tests and the natural environments was poor (intraclass correlation coefficient [ICC] values ranged from -0.24 to 0.63). The closest speed match was the comfortable paced 10-m walk test and walking in a corridor of a brain injury rehabilitation unit (ICC 0.63). Able-bodied pedestrians walked at significantly faster speeds than did subjects with TBI in all 3 natural environments. CONCLUSIONS: Comfortable walking speed appears to have the highest ecological validity of the clinical gait tests investigated. Practice in natural and more complex environments should be incorporated into walking rehabilitation programs for people with TBI.     

A novel in vivo procedure for volumetric flow measurements

We report on a novel procedure for invasive volumetric blood flow measurements using a commercially available Doppler flow wire system, which could, until now, only measure flow velocity. We here describe a method applicable in vivo to generate both velocity and cross-sectional area information from the same pulsed-wave Doppler signal for volumetric flow assessment. We demonstrate its feasibility and validation in vivo in pig coronary arteries. Our Doppler-derived volumetric flow measurements were compared with the respective transit-time flow and showed an excellent correlation (r = 0.969; p < 0.0001). Agreement between transit-time and Doppler-derived flow measurements could be observed for flow conditions ranging from 30 to 180 mL/min. The mean values for the two methods were 71.4 +/- 43.7 mL/min and 71.3 +/- 42.2 mL/min, respectively. We conclude that this technique might possibly be introduced into future clinical practice as an invasive procedure of choice for the assessment of volumetric blood flow.     

Very slight chance of other metastases in axillary nodes of breast cancer patients with a small sentinel node metastasis without extranodal tumor growth

OBJECTIVE: To determine in patients with mammary carcinoma and a sentinel node metastasis whether pathological parameters of the sentinel node metastasis and the primary tumour might have predictive value with respect to the presence of metastases in other axillary nodes. DESIGN: Prospective. METHOD: The study group consisted of the first 100 consecutive patients with a sentinel node metastasis, who subsequently underwent a complete axillary dissection. The patients with metastases in the non-sentinel nodes were compared to those without such metastases regarding the size of the largest sentinel node metastasis and the presence of extranodal tissue invasion near any such node, and size, and type of the primary tumour. RESULTS: The median size of the metastases in the sentinel lymph node in the two groups was 3 mm versus 13 mm respectively (p < 0.001) and the frequency of extranodal tissue invasion 3% versus 74% respectively (p < 0.001); the combination of these factors strongly predicted the presence of non-sentinel lymph node metastases in the axilla (94% area under the receiver operating characteristics curve). None of the 30 patients with a micrometastasis < or = 2.0 mm in the sentinel lymph node had metastases in the non-sentinel axillary lymph nodes. Metastases were present in the non-sentinel axillary lymph nodes in 29 of the 31 patients with extranodal tissue invasion near the sentinel node. CONCLUSION: In breast cancer patients with a sentinel lymph node metastasis < or = 2.0 mm and without extranodal tumour growth a complete axillary lymph node dissection might be unnecessary as the risk of additional metastases was very small.     

Array comparative genomic hybridization analysis of genomic alterations in breast cancer subtypes

In this study, we performed high-resolution array comparative genomic hybridization with an array of 4153 bacterial artificial chromosome clones to assess copy number changes in 44 archival breast cancers. The tumors were flow sorted to exclude non-tumor DNA and increase our ability to detect gene copy number changes. In these tumors, losses were more frequent than gains, and gains in 1q and loss in 16q were the most frequent alterations. We compared gene copy number changes in the tumors based on histologic subtype and estrogen receptor (ER) status, i.e., ER-negative infiltrating ductal carcinoma, ER-positive infiltrating ductal carcinoma, and ER-positive infiltrating lobular carcinoma. We observed a consistent association between loss in regions of 5q and ER-negative infiltrating ductal carcinoma, as well as more frequent loss in 4p16, 8p23, 8p21, 10q25, and 17p11.2 in ER-negative infiltrating ductal carcinoma compared with ER-positive infiltrating ductal carcinoma (adjusted P values < or = 0.05). We also observed high-level amplifications in ER-negative infiltrating ductal carcinoma in regions of 8q24 and 17q12 encompassing the c-myc and c-erbB-2 genes and apparent homozygous deletions in 3p21, 5q33, 8p23, 8p21, 9q34, 16q24, and 19q13. ER-positive infiltrating ductal carcinoma showed a higher frequency of gain in 16p13 and loss in 16q21 than ER-negative infiltrating ductal carcinoma. Correlation analysis highlighted regions of change commonly seen together in ER-negative infiltrating ductal carcinoma. ER-positive infiltrating lobular carcinoma differed from ER-positive infiltrating ductal carcinoma in the frequency of gain in 1q and loss in 11q and showed high-level amplifications in 1q32, 8p23, 11q13, and 11q14. These results indicate that array comparative genomic hybridization can identify significant differences in the genomic alterations between subtypes of breast cancer.     

Toxic proteins released from mitochondria in cell death

A plethora of apoptotic stimuli converge on the mitochondria and affect their membrane integrity. As a consequence, multiple death-promoting factors residing in the mitochondrial intermembrane space are liberated in the cytosol. Pro- and antiapoptotic Bcl-2 family proteins control the release of these mitochondrial proteins by inducing or preventing permeabilization of the outer mitochondrial membrane. Once released into the cytosol, these mitochondrial proteins activate both caspase-dependent and -independent cell death pathways. Cytochrome c was the first protein shown to be released from the mitochondria into the cytosol, where it induces apoptosome formation. Other released mitochondrial proteins include apoptosis-inducing factor (AIF) and endonuclease G, both of which contribute to apoptotic nuclear DNA damage in a caspase-independent way. Other examples are Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP-binding protein with low PI) and the serine protease HtrA2/OMI (high-temperature requirement protein A2), which both promote caspase activation and instigate caspase-independent cytotoxicity. The precise mode of action and importance of cytochrome c in apoptosis in mammalian cells has become clear through biochemical, structural and genetic studies. More recently identified factors, for example HtrA2/OMI and Smac/DIABLO, are still being studied intensively in order to delineate their functions in apoptosis. A better understanding of these functions may help to develop new strategies to treat cancer.