Baclofen for alcohol dependence: a preliminary open-label study

BACKGROUND: Recent preclinical and clinical studies have shown that the gamma-aminobutyric acid-B agonist baclofen may be an effective treatment for reducing alcohol consumption. This preliminary open-label investigation examined the tolerability and effect of a 30-mg daily baclofen dose for reducing drinking, subclinical anxiety and depressive symptoms, and craving in alcohol-dependent subjects. METHODS: Nine men and three women participated in a 12-week trial during which they took baclofen on a 10 mg thrice-daily regimen and received four sessions of motivational enhancement therapy. Each participant received a comprehensive physical and psychiatric screening before being enrolled. At each visit, side effects were monitored with a revised version of the Systematic Assessment of Treatment Emergent Events-General Inquiry, and drinking data were collected via the timeline follow-back interview. Participants also completed the Beck Depression Inventory, the Beck Anxiety Inventory, and the Penn Alcohol Craving Scale at each visit. RESULTS: Baclofen was reasonably tolerated. Two participants discontinued because of side effects. No serious adverse events were noted. Six other individuals did not complete the trial. Overall, there were statistically significant reductions in the number of drinks per drinking day and the number of heavy-drinking days, and there was an increase in the number of abstinent days. Significant decreases in anxiety and craving were also shown. CONCLUSIONS: These findings suggest that baclofen is reasonably tolerated in an alcohol-dependent population, although the high dropout rate in the study is of concern. Baclofen may be effective for the reduction of drinking, anxiety, and craving for some alcohol-dependent individuals. A larger-scale placebo-controlled study is needed to further explore these effects and to determine the characteristics of those who respond to this medication.     

Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid

The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-L-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals. Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM.     

Selective embolization of the splenic vein in patients with hepatic encephalopathy and splenorenal shunt

Obliteration of portal-systemic shunts is effective for portosystemic encephalopathy but is often associated with complications such as retention of ascites and worsening of esophageal varices. Selective embolization of the splenic vein was performed on six patients with hepatic encephalopathy and splenorenal shunts. Hepatic encephalopathy was not observed in four patients after the procedure. Neither retention of ascites nor rupture of esophageal varices was observed because postoperative elevation of portal venous pressure was not as great as that seen when shunt obliteration is performed. This procedure can be an effective and safe treatment option for hepatic encephalopathy with a splenorenal shunt.     

A surgical case of subdural hematoma with hemophilia A

A 54-year-old man presented with unconsciousness. Computed tomography revealed acute subdural hematoma. Emergency evacuation of hematoma was performed showing any excessive tendency to bleed or difficulty to stop bleeding during the operation. However transfusion of fresh frozen plasma was needed to stop continuous bleeding from the surgical wound after the operation. The patient underwent craniotomy again 18 days after the operation because he suffered hemorrhagic infarction and recurrence of acute subdural hematoma. After the second operation, a coagulability examination revealed that his activated partial thromboplastin test was prolonged (74.5 seconds) and his plasma factor VIII level was 20% of normal, so he was diagnosed as having mild hemophilia A. Cranioplasty was accomplished with replacement therapy, and he was discharged with mild recent memory disturbance and homonymous hemianopsia.     

Usefulness of Radio-guided Surgery Using Technetium-99m Methoxyisobutylisonitrile for Primary and Secondary Hyperparathyroidism

The efficacy of technetium-99m methoxyisobutylisonitrile (^99mTc-MIBI)-guided surgery for detecting abnormal parathyroid glands in patients with secondary hyperparathyroidism (2-HPT) was evaluated and compared with the results from the same examination in patients with primary hyperparathyroidism (1-HPT). The results were also compared with those found by ultrasonography (US) and preoperative ^99mTc-MIBI scintigraphy was also made. At operation ^99mTc-MIBI accumulated in 64 nodules of 15 cases of 2-HPT, and all of 60 parathyroid swellings were detected (true-positives 60, sensitivity 100%, accuracy 94%). In the cases of 1-HPT, ^99mTc-MIBI revealed 11 hot nodules in 10 cases, and the evaluation was true-positive 10, sensitivity 100%, and accuracy 91%. US and preoperative ^99mTc-MIBI scintigraphy in patients with 2-HPT had a sensitivity of 75% and 67% and an accuracy of 70% and 66%, respectively. The usefulness of ^99mTc-MIBI-guided surgery for detecting abnormal parathyroid tissue in 2-HPT patients was similar to that in 1-HPT patients but was superior to US and preoperative ^99mTc-MIBI scintigraphy. Intraoperative ^9mTc-MIBI for patients with 2-HPT is effective and makes the surgery easier, especially when the parathyroid glands are ectopic or when a few glands are markedly enlarged but the other glands are atrophied.     

Correlation between angiogenesis and reduction ratio measured using<Superscript>201</Superscript>Tl chloride single photon emission computed tomography in patients with oral cavity squamous cell carcinoma

OBJECTIVE: The aim of this study is to examine the correlation between tumor angiogenesis and response to preoperative radiotherapy evaluated using 201Tl single photon emission computed tomography (Tl SPECT) in oral cavity squamous cell carcinoma (SCC). METHODS: Tl SPECTs before and after preoperative radiotherapy were obtained from 11 patients diagnosed with SCC in oral cavity. Regions of interest were set around the tumor and scalp respectively, and the ratio of mean counts in the tumor to those in the scalp was calculated (T/N). Immunohistochemical staining for investigating microvessel density of pre-treatment biopsy specimen was performed using CD31 monoclonal antibody. We compared microvessel density with semi-quantitative parameters obtained using Tl SPECT (T/N at pre- an post-treatment, reduction ratio) and prognosis. RESULTS: The subgroup with higher microvessel density showed a significantly higher reduction ratio than the one with lower microvessel density. Regarding prognosis, the subgroup with locoregional recurrent disease exhibited a significantly higher microvessel density than the one without recurrence. CONCLUSIONS: In SCC of the oral cavity, there was a significant correlation between microvessel density and response to preoperative radiotherapy. Namely, it was revealed that change of 201Tl uptake after preoperative radiotherapy correlated with tumor angiogenesis of oral cavity SCC.     

Maternal-fetal interactions and birth order influence insulin variable number of tandem repeats allele class associations with head size at birth and childhood weight gain

Polymorphism of the insulin gene (INS) variable number of tandem repeats (VNTR; class I or class III alleles) locus has been associated with adult diseases and with birth size. Therefore, this variant is a potential contributory factor to the reported fetal origins of adult disease. In the population-based Avon Longitudinal Study of Pregnancy and Childhood birth cohort, we have confirmed in the present study the association between the INS VNTR III/III genotype and larger head circumference at birth (odds ratio [OR] 1.92, 95% CI 1.23-3.07; P = 0.004) and identified an association with higher cord blood IGF-II levels (P = 0.05 to 0.0001). The genotype association with head circumference was influenced by maternal parity (birth order): the III/III OR for larger head circumference was stronger in second and subsequent pregnancies (OR 5.0, 95% CI 2.2-11.5; P = 0.00003) than in first pregnancies (1.2, 0.6-2.2; P = 0.8; interaction with birth order, P = 0.02). During childhood, the III/III genotype remained associated with larger head circumference (P = 0.004) and was also associated with greater BMI (P = 0.03), waist circumference (P = 0.03), and higher fasting insulin levels in girls (P = 0.02). In addition, there were interactions between INS VNTR genotype and early postnatal weight gain in determining childhood BMI (P = 0.001 for interaction), weight (P = 0.005), and waist circumference (P = 0.0005), such that in the approximately 25% of children (n = 286) with rapid early postnatal weight gain, class III genotype-negative children among this group gained weight more rapidly. Our results indicate that complex prenatal and postnatal gene-maternal/fetal interactions influence size at birth and childhood risk factors for adult disease.     

Pulmonary metastases from uterine malignancies: results of surgical resection in 133 patients

OBJECTIVE: The long-term results of the surgical treatment for patients with pulmonary metastases from uterine malignancies were clarified. METHODS: A total of 133 patients who underwent pulmonary metastasectomy for uterine malignancies were enrolled in the Metastatic Lung Tumor Study Group of Japan between March 1984 and February 2002. These patients constituted the study population, and their clinical, pathologic, and prognostic data were retrospectively analyzed. RESULTS: The morbidity and mortality rates related to the operation were minimal (1% and 1%, respectively). The 5- and 10-year survivals after the surgical resection in all cases were 54.6% and 44.9%, respectively. The 5-year survivals for each histologic type were estimated to be 46.8% for squamous cell carcinoma (n = 58), 40.3% for cervical adenocarcinoma (n = 13), 75.7% for endometrial adenocarcinoma (n = 23), 86.5% for choriocarcinoma (n = 16), and 37.9% for leiomyosarcoma (n = 11). In the univariate analysis, the following were shown to be associated with poor survival: primary tumor in the cervix, short disease-free interval (<12 months), large number of resected metastases (> or =4), and large tumor size (> or =3 cm). After mutual adjustment, short disease-free interval (<12 months) alone was related to risk of death (hazard ratio = 2.26, 95% confidence interval = 1.06-4.78) for 105 patients, excluding patients with choriocarcinoma and miscellaneous histologic types. CONCLUSION: Pulmonary metastasectomy for uterine malignancies is a safe and acceptable treatment to improve survival. Patients with a disease-free interval of 12 months or more are good candidates for this treatment if there is adequate control of the primary tumor without extrapulmonary metastasis.