The pharmacology of a new pasteurized antihemophilic factor concentrate derived from human blood plasma

The pharmacology of a new pasteurized factor VIII (FVIII) concentrate derived from human blood plasma was studied in 23 adults with hemophilia A. In Part 1 of the study involving six nonbleeding subjects, the mean increase in FVIII activity was 1.43 +/- 0.34 U per ml 10 minutes after an intravenous dose of 50 U per kg. The intravascular survival kinetics in these six patients showed a biphasic decay curve with an initial mean half-life of 5.1 +/- 1.2 hours probably representing early redistribution, and a late half-life of 13.3 +/- 4.9 hours. In Part 2 of the study, the activity at 10 minutes was measured in another 17 patients, as well as in one patient already studied in Part 1. The mean increase in activity with the 24 observations was 1.13 +/- 0.37 U per ml with a mean FVIII dosage of 51.0 +/- 2.6 U per kg of body weight. Only one patient had an allergic reaction, which did not recur when the patient was given a second lot.     

In vitro and in vivo activity of murine lymphokine-activated killer cells after cryopreservation

The in vitro and in vivo effects of cryopreservation on the cytotoxic activity of murine lymphokine-activated killer (LAK) cells were studied. LAK cells were generated by incubation of spleen lymphocytes of BALB/c mice for 3 days with recombinant interleukin-2 (rIL-2) and subsequent cryopreservation. Cytotoxicity was determined in a 51Cr release assay. After thawing, cytotoxic activity was reduced (40.4% 51Cr release at an effector:target cell ratio of 40:1 as compared to 68.5% 51Cr release before freezing) and could be restored to precryopreserved levels by reincubation with rIL-2 for 2 days after thawing (78.8% 51Cr release). These cells were then tested in BALB/c mice injected with RAW 112 cells, a pre-B-cell lymphoma line. The results demonstrate that the survival rate of mice injected with cryopreserved and restimulated LAK cells (50% survival greater than 180 days after injection) did not differ significantly from that of mice injected with fresh unfrozen LAK cells (60% survival greater than 120 days, 50% survival greater than 180 days). Cryopreserved LAK cells have potential use in adoptive immunotherapy.     

Chronic treatment with tempol does not significantly ameliorate renal tissue hypoxia or disease progression in a rodent model of polycystic kidney disease

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Is chromium from stainless steel utensils responsible for epidemic of type 2 diabetes?

Type 2 diabetes prevalence is rising rapidly in developing world especially in India in last few decades. ‘Thrifty phenotype’ and ‘westernization of lifestyle’ is used to explain this epidemic. Chromium is an important modulator in insulin and glucose metabolism. Preconceptional chromium exposure has been demonstrated to raise the corticosterone and glucose levels in offspring of rodent model. Chromium is chelated when acidic food is stored in the stainless steel utensils. Chromium levels are shown to be high in Asian Indians. The hyperinsulinemia and insulin resistance is demonstrated in Indians from the newborn stage. We hypothesize that increased exposure to chromium in preconceptional and/or fetal stage leads to altered epigenetic control and altered endocrine and metabolic functioning. Increasing urbanization has led to increasing use of stainless steel and resultant exposure to chromium is at the least partly responsible for rising prevalence of type 2 diabetes. If proven avoiding or modifying the use of stainless steel utensils will halt the present epidemic of type 2 diabetes.     

A new autosomal recessive disorder of bilateral frontotemporal pachygyria without microcephaly: report of a case and review of literature

Pachygyria is a disorder of neuronal migration. We report an Indian family with four siblings with developmental delay, infrequent seizures, normal head size and mild to moderate mental retardation. Two of them had bilaterally symmetrical frontotemporal pachygyria. Dysmorphism and neurological signs were absent in the affected subjects. Affected male and female siblings with normal parents suggests autosomal recessive mode of inheritance. We believe these cases represent a new autosomal recessive disorder of neuronal migration. Other similar cases of lissencephaly are reviewed.     

Selection of replicon variants resistant to ACH-806, a novel hepatitis C virus inhibitor with no cross-resistance to NS3 protease and NS5B polymerase inhibitors

We have discovered a novel class of compounds active against hepatitis C virus (HCV), using a surrogate cellular system, HCV replicon cells. The leading compound in the series, ACH-806 (GS-9132), is a potent and specific inhibitor of HCV. The selection of resistance replicon variants against ACH-806 was performed to map the mutations conferring resistance to ACH-806 and to determine cross-resistance profiles with other classes of HCV inhibitors. Several clones emerged after the addition of ACH-806 to HCV replicon cells at frequencies and durations similar to that observed with NS3 protease inhibitors and NS5B polymerase inhibitors. Phenotypic analyses of these clones revealed that they are resistant to ACH-806 but remain sensitive to other classes of HCV inhibitors. Moreover, no significant change in the susceptibility to ACH-806 was found when the replicon cellular clones resistant to NS3 protease inhibitors and NS5B polymerase inhibitors were examined. Sequencing of the entire coding region of ACH-806-resistant replicon variants yielded several consensus mutations. Reverse genetics identified two single mutations in NS3, a cysteine-to-serine mutation at amino acid 16 and an alanine-to-valine mutation at amino acid 39, that are responsible for the resistance of the replicon variants to ACH-806. Both mutations are located at the N terminus of NS3 where extensive interactions with the central hydrophobic region of NS4A exist. These data provide evidence that ACH-806 inhibits HCV replication by a novel mechanism.     

Arch height and first metatarsal joint axis orientation as related variables in foot structure and function

BACKGROUND: This study investigated the association of arch height combined with first metatarsal joint axis vertical (V) orientation to the size of the 1-2 intermetatarsal angle (IMA) and first metatarsal adduction/abduction position simulating foot postures during gait, kinematics commonly affected by bunion. MATERIALS AND METHODS: Nine cadaver specimens were mounted in a loading frame. Measures of arch height ratio and IMA were made. With the foot placed in positions seen during normal gait cycle an electromagnetic device measured displacement of the relative angle of rotations between the first metatarsal and navicular, and helical axis (HA) parameters. Canonical correlation analysis assessed the relationship among the variables. RESULTS: A negative relationship (r = -0.73) was found between arch height and first metatarsal HA V-orientation. When considered as combined variables, arch height and metatarsal HA V-orientation accounted for 69% of the variance of IMA and change in first metatarsal adduction/abduction position. CONCLUSION: Orientation of the first metatarsal joint axis was highly variable between specimens but correlated with arch height. The conjoined factors of arch height and first metatarsal HA V-orientation accounted for most of the variance of IMA and change in first metatarsal adduction/abduction position during the sequence of foot position during simulated gait. CLINICAL RELEVANCE: These findings suggest that orthotic arch support could reorient the metatarsal joint axis out-of-vertical and in effect, limit the first metatarsal from displacing into an adducted bunion deformity. These findings could help to explain the pathogenesis of bunions.