A man with osteoblastic metastasis and hypocalcaemia

We report a case of an 80-year-old man with osteoblastic metastases from advanced carcinoma of the prostate presenting with a grand mal seizure resulting from severe hypocalcaemia. He had low serum phosphate and ionised calcium levels, elevated serum skeletal alkaline phosphatase and intact parathormone levels. 99mTc radioisotope bone scan revealed a "super bone scan" suggestive of osteomalacia. The serum 1, 25-dihydroxycholecalciferol level was unexpectedly elevated. The biochemical abnormalities persisted despite high dose calcium replacement, but improved with supraphysiological doses of 1,25 (OH)2 vitamin D3 (Rocaltrol) therapy. We hypothesise that the hypocalcaemia in this patient was due to vitamin D resistance secondary to a humoral factor secreted by the tumour.     

Genetic causes of familial hypercholesterolaemia in a Malaysian population

A total of 86 unrelated Malaysian patients with familial hypercholesterolaemia (FH) were studied for mutations in their low-density lipoprotein receptor (LDL-R) gene. Amongst them, 23 had a LDL-R gene mutation, while none having an Apolipoprotein B-3500 (Apo B-3500) mutation. Patients with the LDL-R gene defect appeared to have a higher level of low-density lipoprotein cholesterol (LDL-C), an increased incidence of xanthomas and coronary heart disease (CHD), but no relationships were found between the type of LDL-R gene mutations and their lipid levels or clinical signs of CHD. In contrast to Western data, our findings seemed to indicate a predominance of mutations in the ligand binding domain and an absence of Apo B-3500 gene mutation. The latter finding may offer a genetic basis as to why Asian patients with familial hypercholesterolaemia have lower LDL-C levels and less premature CHD than their Western counterparts.     

Serious toxicity associated with continuous nevirapine-based HAART in pregnancy

Objective  This study was designed to determine the safety of nevirapine (NVP)-based highly active antiretroviral therapy (HAART) in a cohort of HIV-positive pregnant women.
Design  This was a prospective cohort study of HIV-positive pregnant women.
Population and setting  All HIV-positive women treated with HAART during pregnancy from January 1997 to February 2004 at the British Columbia (BC) Women's Hospital in Vancouver, BC, Canada.
Methods  Demographic and clinical data were collected to compare antiretroviral drug toxicities in women treated antenatally with NVP-based or non-NVP-based HAART. Multivariate analyses were then used to investigate determinants of toxicity.
Results  From 1997 to 2004, 103 HIV-positive pregnant women received HAART. Equivalent numbers of women were initially treated with NVP-based (54%) and non-NVP-based (46%) HAART. The groups did not differ by clinical or demographic parameters and duration of HAART exposure was similar between groups. Toxicities necessitating treatment discontinuation were observed in 6 of 56 NVP-exposed women (2 cases each of grade 2, 3, and 4 toxicity) compared with 1 of 47 in the non-NVP-exposed women. First time use of NVP approached significance as a predictor for toxicity, with a toxicity rate of 12.5% (6/48) observed among those taking NVP for the first time (adjusted OR 2.68, 95% CI 0.49–14.6).
Conclusion  Continuous NVP use in pregnancy resulted in a relatively higher rate of toxicity, and all cases of NVP toxicity occurred in women exposed to NVP for the first time during pregnancy.     

Video capsule endoscopy for previous overt obscure gastrointestinal bleeding in patients using anti‐thrombotic drugs

Background and Aim: Little is known about the causes of overt obscure gastrointestinal bleeding (OGIB) in patients using anti‐thrombotic therapy. We aimed to describe video capsule endoscopy (VCE) findings and to identify factors associated with positive findings in these patients. Methods: We carried out a retrospective study of 56 patients who underwent VCE for evaluation of previous overt OGIB during anti‐thrombotic therapy. VCE studies were re‐evaluated by a gastroenterologist blinded to clinical details. Clinical data included in the multivariate analysis were sex, age, indication for and type of anti‐thrombotic therapy, hemodynamic instability on admission, type of blood loss, hemoglobin on admission, use of a proton pump inhibitor, NSAID use, time between bleeding episodes and VCE, and whether or not anti‐thrombotic therapy was resumed before the VCE study. Results: A probable cause for gastrointestinal bleeding was identified in 28 (50%) of the 56 studies. Angiodysplasia was found in 19 patients. Twenty‐two studies showed a possible cause in the small bowel. Multivariate logistic regression analysis showed that reinstitution of anti‐thrombotic therapy before VCE was carried out was the only independent predictor of positive VCE findings (OR: 8.61, 95% CI: 1.20–60.42, P = 0.032). Conclusions: Small intestinal angiodysplasia was the most common cause for overt OGIB. Reinstitution of withdrawn anti‐thrombotic drugs before the VCE examination was carried out was associated with positive VCE findings in multivariate analysis.     

Carrier detection in hemophilia A: a cooperative international study. I. The carrier phenotype

Eight laboratories in six countries cooperated to clarify several issues concerning the phenotypes of heterozygous carriers of hemophilia "A." Plasma levels of factor VIII (F.VIII:C, formerly VIII:C) and von Willebrand factor (VWF:Ag, formerly VIIIR:Ag) of carriers and normal women were determined by various "in-house" methods; a single lyophilized plasma standard was used for all assays. Analysis of the collated data from 336 carriers (296 obligatory carriers and 40 sporadic carriers) and 137 normal women showed that there was no difference in the F.VIII:C levels of "paternal" carriers (women who had obtained the abnormal gene from their fathers) and "maternal" carriers. Neither was there a difference in the VWF:Ag levels of normal women and either type of carrier. Age was found to have a significant effect on both F.VIII:C and VWF:Ag, values being higher at very young and very old ages, the minima occurring in the 25- to 30-year range. ABO blood type had a striking effect. Women of types A, B, and AB (designated non- O in the study), both normals and carriers, had significantly higher levels of both factors than did women of type O. Analysis by laboratories showed that differences in mean levels of both factors between laboratories were highly significant. It was concluded that age, ABO blood type, and laboratory variation should be taken into account in carrier detection.     

Differential effects of nitric oxide on erythroid and myeloid colony growth from CD34+ human bone marrow cells

Nitric oxide (NO) is a reactive molecule with numerous physiologic and pathophysiologic roles affecting the nervous, cardiovascular, and immune systems. In previous work, we have demonstrated that NO inhibits the growth and induces the monocytic differentiation of cells of the HL- 60 cell line. We have also demonstrated that NO inhibits the growth of acute nonlymphocytic leukemia cells freshly isolated from untreated patients and increases monocytic differentiation antigens in some. In the present work, we studied the effect of NO on the growth and differentiation of normal human bone marrow cells in vitro. Mononuclear cells isolated from human bone marrow were cultured in semisolid media and treated with the NO-donating agents sodium nitroprusside (SNP) or S- nitroso-acetyl penicillamine (SNAP) (0.25 to 1 mmol/L). Both agents decreased colony-forming unit-erythroid (CFU-E) and colony-forming unit- granulocyte macrophage (CFU-GM) formation by 34% to 100%. When CD34+ cells were examined, we noted that these cells responded to SNP and SNAP differently than did the mononuclear cells. At a concentration range of 0.25 to 1 mmol/L, SNP inhibited the growth of CFU-E by 30% to 75%. However, at the same concentration range, SNP increased the number of CFU-GM by up to 94%. At concentrations of 0.25 to 1 mmol/L, SNAP inhibited the growth of CFU-E by 33% to 100%. At a concentration of 0.25 mmol/L, SNAP did not affect CFU-GM. At higher concentrations, SNAP inhibited the growth of CFU-GM. Although SNP increased intracellular levels of cGMP in bone marrow cells, increasing cGMP in cells by addition of 8-Br-cGMP (a membrane permeable cGMP analogue) did not reproduce the observed NO effects on bone marrow colonies. These results demonstrate that NO can influence the growth and differentiation of normal human bone marrow cells. NO (generated in the bone marrow microenvironment) may play an important role modulating the growth and differentiation of bone marrow cells in vivo.     

P-Glycoprotein and transporter MRP1 reduce HIV protease inhibitor uptake in CD4 cells: potential for accelerated viral drug resistance?

BACKGROUND: The multidrug transporters P-glycoprotein (P-gp) and MRP1 are functionally expressed in several subclasses of lymphocytes. HIV-1 protease inhibitors interact with both; consequently the transporters could reduce the local concentration of HIV-1 protease inhibitors and, thus, influence the selection of viral mutants. OBJECTIVES: To study the effect of the expression of P-gp and MRP1 on the transport and accumulation of HIV-1 protease inhibitors in human lymphocytes and to study the effects of specific P-gp and MRP1 inhibitors. METHODS: The initial rate and the steady-state intracellular accumulation of radiolabelled ritonavir, indinavir, saquinavir and nelfinavir was measured in three human lymphocyte cell lines: control CEM cells, CEM-MDR cells, which express 30-fold more P-gp than CEM cells, and CEM-MRP cells, which express fivefold more MRP1 protein than CEM cells. The effect of specific inhibitors of P-gp (GF 120918) and MRP1 (MK 571) was also examined. RESULTS: Compared with CEM cells, the initial rates of uptake and the steady-state intracellular concentrations of all protease inhibitors are significantly reduced in CEM-MDR cells. The intracellular concentrations of the protease inhibitors are increased upon co-administration with GF 120918, in some cases to levels approaching those in CEM cells. The intracellular concentrations of the protease inhibitors are also significantly reduced in CEM-MRP cells. Co-administration with MK -571 can partially overcome these effects. CONCLUSIONS: The overexpression of multidrug transporters significantly reduces the accumulation of protease inhibitors at this major site of virus replication, which, potentially, could accelerate the acquisition of viral resistance. Targeted inhibition of P-gp may represent an important strategy by which this problem can be overcome.