Contraindications to metformin therapy in patients with NIDDM

OBJECTIVE: Treatment with metformin is occasionally associated with the development of severe lactic acidosis. However, this is usually observed in patients with major contraindications to the drug. In this study, we aimed to determine the prevalence of conditions currently regarded as either contraindications or cautions to the use of metformin in patients with NIDDM. RESEARCH DESIGN AND METHODS: The case notes of metformin-treated NIDDM patients (mean age 62 years) attending a United Kingdom university hospital diabetes clinic over a 3-month period were reviewed according to criteria reflecting a pragmatic view of current prescribing recommendations. RESULTS: Of 89 consecutive patients whose notes could be evaluated in detail, only 41 (46%) had no contraindications or cautions to metformin whatsoever. Concomitant chronic disorders associated with a potentially increased risk of hyperlactatemia were renal impairment (n = 2; plasma creatinine concentrations 1.7 and 2.3 mg/dl, respectively), cardiac failure (n = 2), and chronic liver disease (n = 2). Other potentially relevant disorders included ischemic heart disease (n = 20), clinical proteinuria (n = 14), peripheral vascular disease (n = 22), and pulmonary disease (n = 7). Multiple conditions (i.e., two, three, or four) were present in eight, five, and one patient(s), respectively. CONCLUSIONS: More than half the patients in our series had concomitant conditions or complications conventionally regarded as cautions or contraindications to metformin; approximately 10% had a multiplicity of such conditions. Regular surveillance is necessary to detect the development of complications such as renal impairment. Vigilance is also required in view of the increased risk of major intercurrent illnesses, which may independently disturb lactate metabolism in patients with NIDDM. Metformin should be withdrawn promptly under such circumstances.     

Comparison of the biodistribution and the efficacy of monoclonal antibody 323/A3 labeled with either 131I or 186Re in human ovarian cancer xenografts

The effects of arginine vasopressin (AVP) and oxytocin (OT) upon thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) release were studied in euthyroid rats. Intracerebroventricular (i.c.v.) infusion of AVP in doses of 0.5 ng or 5 ng led to significant increases in plasma levels of TSH as well as FT4 and FT3. The effects of OT injected i.c.v. in similar doses were not consistent (there was no parallel between the changes of respective hormones plasma levels). It may be concluded that vasopressin modulate the pituitary-thyroid system function; AVP is probably a physiological stimulator of TSH and thyroid hormones secretion.     

Mapping a quantitative trait locus involved in melanotic encapsulation of foreign bodies in the malaria vector, Anopheles gambiae

A Plasmodium-refractory strain of Anopheles gambiae melanotically encapsulates many species of Plasmodium, whereas wild-type mosquitoes are usually susceptible. This encapsulation trait can also be observed by studying the response of refractory and susceptible strains to intrathoracically injected CM-Sephadex beads. We report the results of broad-scale quantitative trait locus (QTL) mapping of the encapsulation trait using the bead model system. Interval mapping using the method of maximum likelihood identified one major QTL, Pen1. The 13.7-cM interval containing Pen1 was defined by marker AGH157 at 8E and AGH46 at 7A on 2R. Pen1 was associated with a maximum LOD score of 9.0 and accounted for 44% of the phenotypic variance in the distribution of phenotypes in the backcross. To test if this QTL is important for encapsulation of Plasmodium berghei, F2 progeny were infected with P. berghei and evaluated for degree of parasite encapsulation. For each of the two markers that define the interval containing Pen1, a significant difference of encapsulation was seen in progeny with at least one refractory allele in contrast with homozygous susceptible progeny. These results suggest that Pen1 is important for melanotic encapsulation of Plasmodium as well as beads.     

Supramedullary modulation of sympathetic vasomotor function

1. Supramedullary structures including the ventral medial prefrontal cortex (MPFC) and the midbrain cuneiform nucleus (CnF) project directly and indirectly to premotor sympatho-excitatory neurons of the rostral ventrolateral medulla (RVLM) that are critically involved in the generation of sympathetic vasomotor tone. 2. Electrophysiological studies have demonstrated that activation of depressor sites within the MPFC is associated with splanchnic sympathetic vasomotor inhibition and inhibition of the activity of RVLM sympathoexcitatory neurons. 3. Antidromic mapping and anatomical studies support the notion that a relay in the nucleus tractus solitarius is involved in the cardiovascular response to MPFC stimulation. 4. The midbrain CnF, which lies adjacent to the midbrain periaqueductal grey, is a sympathoexcitatory region of the midbrain reticular formation. Sympathoexcitatory responses evoked from the CnF are associated with short-latency excitation of RVLM neurons. 5. Cuneiform nucleus stimulation induces the expression of mRNA for the immediate early genes c-fos and NGFI-A in mid-brain, pontine and hypothalamic structures. 6. The MPFC and CnF are supramedullary structures with opposing modulatory influences on sympathetic vasomotor drive, whose roles in cardiovascular control mechanisms warrant further investigation.     

Short-pulse, eye-safe Nd:YAG laser using cavity-dumping

A short-pulse 1.444-μm laser based on Nd:YAG technology has been demonstrated. The 1.444-μm is eye-safe. With the cavity-dump technique, a pulse of 50 m× and 14 ns was obtained. The beam quality was excellent with an M² of 1.6 by the use of a telescopic resonator. Silicon-window polarizers were used to suppress the 1.06-μm radiation but showed 1.444-μm absorption as well     

Antimutagenic activity of casein against MNNG in the E. coli DNA repair host-mediated assay

The effect of caseinate and soy protein in the diet on the mutagenicity induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was assessed in-vivo and ex-vivo in the DNA-repair host-mediated assay and liquid suspension assay, respectively. Of the two proteins only casein showed a strong antimutagenic activity over the whole digestive tract, except in the stomach. It is suggested that the molecular structure of a protein determines its protective effect against mutagens: casein lacks secondary and tertiary structure so that amino acids are more readily available for interaction with the mutagen than with the amino acids in soy protein which is a globular protein.     

The human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel nuclear pore component Nup88

The oncogenic nucleoporin CAN/Nup214 is essential in vertebrate cells. Its depletion results in defective nuclear protein import, inhibition of messenger RNA export and cell cycle arrest. We recently found that CAN associates with proteins of 88 and 112 kDa, which we have now cloned and characterized. The 88 kDa protein is a novel nuclear pore complex (NPC) component, which we have named Nup88. Depletion of CAN from the NPC results in concomitant loss of Nup88, indicating that the localization of Nup88 to the NPC is dependent on CAN binding. The 112 kDa protein is the human homologue of yeast CRM1, a protein known to be required for maintenance of correct chromosome structure. This human CRM1 (hCRM1) localized to the NPC as well as to the nucleoplasm. Nuclear overexpression of the FG-repeat region of CAN, containing its hCRM1-interaction domain, resulted in depletion of hCRM1 from the NPC. In CAN-/- mouse embryos lacking CAN, hCRM1 remained in the nuclear envelope, suggesting that this protein can also bind to other repeat-containing nucleoporins. Lastly, hCRM1 shares a domain of significant homology with importin-beta, a cytoplasmic transport factor that interacts with nucleoporin repeat regions. We propose that hCRM1 is a soluble nuclear transport factor that interacts with the NPC.