Advanced colorectal cancer is associated with impaired interleukin 12 and enhanced interleukin 10 production

Interleukin 12 (IL-12) is a heterodimeric cytokine that has been demonstrated to have a major role in stimulating a cell-mediated antitumor response. IL-10, a product of T helper 2 lymphocytes, is its most potent inhibitor. The aim of this study was to investigate whether patients with colorectal cancer had an imbalance in production of IL-12 and IL-10 preoperatively, and whether this was associated with advanced disease at surgery. Blood was obtained before surgery from 60 patients with colorectal cancer and from 30 controls. Peripheral blood mononuclear cells were incubated with Staphylococcus aureus Cowan's strain 1 in vitro for 24 h to assess IL-12 expression after stimulation, and serum was used for IL-10 measurement. IL-12 and IL-10 levels were assessed by ELISA. A single pathologist staged the tumors according to the tumor-node-metastasis (TNM) and Dukes' classifications. Patients with colorectal cancer had significantly lower levels of IL-12 (P <0.001) and higher levels of IL-10(P = 0.004) compared to controls. In addition, lower levels of IL-12 were detected in those patients who were node positive (P<0.05), had Dukes' C lesions (P < or = 0.001), and T3 or T4 lesions (P<0.033) when compared to controls. Patients with Dukes' B and C lesions (P<0.01) and T3 and T4 lesions (P<0.05) also had higher levels of IL-10 compared to controls. This study is the first to demonstrate that patients with colorectal cancer have decreased IL-12 production and increased serum IL-10. This suggests an impaired T helper 1 cell-mediated antitumor response and provides some justification for exogenous IL-12 therapy or anti-IL-10 therapy in these patients.     

PASAT performance and the pattern of uptake of 99mTc-exametazime in brain estimated with single photon emission tomography

The effect of the paced auditory serial addition test (PASAT) on the regional uptake of 99mTc-exametazime was determined by single photon emission computed tomography. Twenty insulin-treated diabetic outpatients were scanned at rest and during the performance of the PASAT task using split-dose injection of tracer. When resting and activation scans were compared there were significant decreases in tracer uptake in the right anterior cingulate and left posterior cingulate areas during PASAT activation. The findings are compared with previous studies which had implicated the anterior cingulate area in the mechanisms of attention in humans and other animals. The potentially confounding role of anxiety during attentional tasks is discussed.     

Limbic dysfunction in schizophrenia and mania. A study using 18F-labelled fluorodeoxyglucose and positron emission tomography

BACKGROUND: Diagnostic classes (derived from CATEGO) can be correlated with regional brain metabolism in patients with major psychiatric disorders. METHOD: Seventeen patients with schizophrenia, 15 with mania, 10 with depression and 10 healthy Volunteers were examined with positron emission tomography (PET) and 18F-labelled fluorodeoxyglucose, as a marker for glucose metabolism. The number of possible comparisons of regions of interest was reduced by principal-components analysis, and differences in factor scores were determined between diagnostic groups. RESULTS: Four independent factors, representing distributed brain systems, emerged: an anterior-posterior (1), a left-right temporal (2), a temporofrontal (3), and a mediofrontal (4) system, of which (1), (2) and (3) were abnormal in schizophrenia, (1) and (2) in mania, and (1) in depression. CONCLUSIONS: Abnormal patterns of metabolism could be detected, in decreasing order, in schizophrenia, mania and depression. Some of these abnormalities are likely to be due to medication, but others will be associated with structural or functional abnormalities of the frontolimbic system in the diagnostic groups.     

Scoring prevalence and severity in gonarthritis: the suitability of the Kellgren & Lawrence scale

OBJECTIVES: Infection with the high-risk strain of human papillomaviruses (HPVs) and the inactivation of the tumor suppressor gene p53 through mutation are important factors in cervical carcinogenesis. To know whether such events would occur in cervical carcinomas of Indians, 43 tumors (consisting of 36 of stage III B and 6 of stage II B) were screened for p53 and p16 gene mutations. METHODS: PCR followed by single-strand conformation polymorphism (SSCP) analysis were used to detect mutations in p53 and p16 genes and PCR for the presence of human papillomavirus genome. HPV status was ascertained by PCR amplification of parts of E6 and E7 genes using primers pU-1M and pU-2R and typing was carried out by restriction analysis. RESULTS: Of the 43 samples analyzed, 4 samples (9%) showed mobility shifts for p53 mutations; PCR products of the p16 gene did not show band shifts in SSCP analysis. HPV DNA was detected in 70% of the 43 samples analyzed: HPV 16 in 23 cases (53%), HPV 18 in 4 cases (13.3%), and HPV 33 in 1 case (3.3%). Two amplified HPV DNAs that were difficult to type with various restriction enzymes were cloned and the amplified regions were sequenced. One of these was 93% close to HPV 35 and the other was 80% close to HPV 58. Three samples had both p53 mutations and HPV genome. CONCLUSIONS: Our results indicate that HPV 16 infection was more common than HPV 18, the p53 mutations and HPV infection were not mutually exclusive events in the genesis of carcinoma of uterine cervix among Indian women, and p16 gene may not play a role in Indian cervical carcinomas.     

Ultralow concentrations of proenkephalin and [met5]-enkephalin differentially affect IgM and IgG production by B cells

Adenovirus-mediated gene transfer is a promising method for studies of vascular biology and potentially for gene therapy. Intravascular approaches for gene transfer to blood vessels in vivo generally require interruption of blood flow and have several limitations. We have used two alternative approaches for gene transfer to blood vessels in vivo using perivascular application of vectors. First, replication-deficient adenovirus expressing nuclear-targeted bacterial beta-galactosidase was injected into cerebrospinal fluid via the cisterna magna of rats. Leptomeningeal cells over the major arteries were efficiently transfected, and adventitial cells of large vessels and smooth muscle cells of small vessels were occasionally stained. When viral suspension was injected with the rat in a lateral position, the reporter gene was expressed extensively on the ipsilateral surface of the brain. Thus, adenovirus injected into cerebrospinal fluid provides gene transfer in vivo to cerebral blood vessels and, with greater efficiency, to perivascular tissue. Furthermore, positioning of the head may 'target' specific regions of the brain. Second, vascular gene delivery was accomplished by perivascular injection of virus in peripheral vessels. Injection of the adenoviral vector within the periarterial sheath of monkeys resulted in gene transfer to the vessel wall that was substantial in magnitude although limited to cells in the adventitia. Approximately 20% of adventitial cells expressed the transgene, with no gene transfer to cells in the intima or media. These approaches may provide alternative approaches for gene transfer to blood vessels, and may be useful for studies of vascular biology and perhaps vascular gene therapy.     

Angiosarcoma of the heart. A case study

Angiosarcoma of the heart is a rare neoplasm. The clinical manifestations are surprisingly consistent, but the diagnosis is rarely made before death. A patient with such a tumor was described here and the current literature was reviewed. Venous angiography and pericardiectomy are recommended in patients with hemorrhagic pericardial tamponade when the cause is unclear.     

Mass spectral study of derivatives of the four bilirubin-IX isomers

The beta, gamma and delta isomers of bilirubin-IX show a decreased stability as compared with the IXalpha isomer; characteristic mass spectra are obtained only for the tetrakis-(trimethylsilyl) derivatives of the IXalpha and IXgamma isomers. Hydrogenation of the vinyl substituents increases the thermal stability of the bilirubins and gives rise to a characteristic mass spectrum for the tetrakis-(trimethylsilyl) derivative of meso-bilirubin-IXdelta. The ethyl anthranilate azopigments derived from the four bilirubins yield characteristic mass spectra, except for the two unstable divinyl substituted azodipyrroles (mol. wt. 416), derived from bilirubin-IXbeta and IXdelta. The corresponding mol. wt. 420 azopigments derived from the hydrogenated bilirubins are thermally stable. Elucidation of mass spectral fragmentation pathways is facilitated by the varying positions of the substituents and by deuterium labelling, and permits the assignment of structures to the various isomeric azodipyrroles.     

The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone

OBJECTIVE: To compare the therapeutic effects of the alpha-glucosidase inhibitor miglitol (BAY m 1099), the sulfonylurea glibenclamide, and placebo on parameters of metabolic control and safety in patients with NIDDM that is inadequately controlled by diet alone. RESEARCH DESIGN AND METHODS: After a 4-week placebo run-in period, 201 patients in 18 centers in 4 countries were randomized in a double-blind manner to miglitol (50 mg t.i.d., followed by 100 mg t.i.d.), glibenclamide (3.5 mg q.d/b.i.d.), or placebo for 24 weeks. Efficacy criteria were changes from baseline of HbA1c, fasting and postprandial blood glucose and insulin levels, body weight, and serum triglycerides. RESULTS: Efficacy was assessed in 119 patients who completed the full protocol, and the results were similar to those obtained in 186 patients who fulfilled the validity criteria for analysis. Compared with placebo, mean baseline-adjusted HbA1c decreased by 0.75% (P = 0.0021) and 1.01% (P = 0.0001) in the miglitol and glibenclamide treatment groups, respectively. Blood glucose decreased slightly in the fasting state and considerably in the postprandial state in both treatment groups but not in the placebo group. Fasting insulin levels increased slightly (NS) in all treatment groups; however, postprandial insulin levels decreased with miglitol, while increasing markedly with glibenclamide (P = 0.0001 between all treatment groups). Gastrointestinal side effects (flatulence and diarrhea) occurred mostly in the miglitol-treated patients, while some glibenclamide-treated patients had symptoms suggestive of hypoglycemia. CONCLUSIONS: Miglitol monotherapy is effective and safe in NIDDM patients. Compared with glibenclamide, it reduced HbA1c less effectively and caused more gastrointestinal side effects. On the other hand, glibenclamide, unlike miglitol, tended to cause hypoglycemia, hyperinsulinemia, and weight gain, which are not desirable in patients with NIDDM.     

Hypoxia stimulates cytokine production by villous explants from the human placenta

It has been hypothesized that inadequate placentation in the hypertensive disorder of pregnancy known as preeclampsia creates foci of placental ischemia/hypoxia leading to the elaboration of factors that compromise systemic endothelial function to produce disease sequelae. As tumor necrosis factor-alpha (TNF alpha) and interleukin-1 (IL-1) are inflammatory cytokines capable of eliciting endothelial cell dysfunction, we investigated whether the production of these inflammatory cytokines by cultured villous explants from the human placenta was affected by incubation in reduced oxygen (2% O2). The term placenta produced TNF alpha, IL-6, and low levels of IL-1alpha and IL-1beta under standard tissue culture conditions. Hypoxia significantly increased TNF alpha, IL-1alpha, and IL-1beta production by 2-, 6-, and 23-fold, respectively, but did not affect IL-6 production. Further, cytokines were immunolocalized to the syncytiotrophoblast layer as well as to some villous core cells. Hypoxic regulation of placental TNF alpha and IL-1beta production also appeared to differ based on gestational age. Finally, treatment with either cobalt chloride or an iron chelator mimicked the hypoxic response, suggesting that stimulation of placental cytokine production may involve a heme-containing, O2-sensing protein. These results suggest that placental hypoxia can lead to the elaboration of inflammatory cytokines, which may contribute to the pathophysiology of preeclampsia.