Publications

BACKGROUND

With advances in antiretroviral therapy, many human immunodeficiency virus (HIV)-infected individuals are living longer and developing end-stage renal or hepatic disease requiring transplantation. Maintaining the viability of the transplant and suppressing HIV replication requires concomitant use of immunosuppressants (e.g., cyclosporine) and antiretrovirals (e.g., protease inhibitors or nonnucleoside reverse transcriptase inhibitors), which leads to drug interactions. To assist in appropriate clinical management of HIV-infected transplant recipients, the authors describe the pharmacokinetic interactions between cyclosporine and the antiretroviral medications, and required modifications of cyclosporine dosing.

METHODS

Eighteen HIV-infected subjects with end-stage kidney or liver disease underwent transplantation. Subjects had pharmacokinetic studies before transplantation and for up to 2 years posttransplantation (at weeks 2-4, 12, 28, 52, and 104). Protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and cyclosporine concentrations were measured by liquid chromatography-mass spectrometry in plasma and whole blood, respectively.

RESULTS

Subjects using protease inhibitors and cyclosporine had a threefold increase in cyclosporine area under the curve (4,190+/-2,180-11,900+/-1,600 ng*hr/mL, P<0.01), necessitating an 85% reduction in cyclosporine dose over a 2-year period (1.3+/-1.5-0.2+/-0.0 mg/kg/dose), leading to a progressive increase in oral cyclosporine bioavailability (R=0.92, P<0.02). Subjects on nonnucleoside reverse-transcriptase inhibitors showed minimal interactions with cyclosporine, and subjects on both HIV treatments had intermediate responses.

CONCLUSIONS

HIV-infected transplant recipients on protease inhibitors require markedly lower doses of cyclosporine, with continued lowering of the cyclosporine dose over time and ongoing cyclosporine trough monitoring because of progressively increasing cyclosporine bioavailability. Medication changes must be carefully managed to avoid insufficient immunosuppression or toxicity resulting from drug interactions.

The purpose of this literature review is to examine recent advances in technique and technology of endoscopic mucosal resection of superficial early cancers of the upper gastrointestinal tract. Endoscopic mucosal resection (EMR) of superficial early cancers of the upper gastrointestinal tract is standard technique in Japan and is increasingly used in Western countries. Newer techniques of EMR allow removal of larger lesions en-bloc. These minimally invasive techniques, when applied correctly, allow safe and efficacious treatment in situations that would otherwise require major surgery. Through the establishment of long-term outcomes data, standardization of endoscopic and pathologic reporting, and newer EMR technology and techniques, the future treatment of early cancers in the upper gastrointestinal tract may be achieved primarily through the endoscope.

BACKGROUND

Neutrophilic airway inflammation, as defined by cell counts in respiratory tract lining fluid (RTLF), is a key end point in many studies of respiratory toxicity in both healthy and asthmatic subjects. BAL and sputum induction (SI) are the most common methods of sampling RTLF in such studies. However, the comparability of these methods (BAL and SI) after experimental treatment has not been investigated in a head-to-head controlled trial.

METHODS

To determine whether BAL and SI are comparable and can be used in place of each other in the assessment of neutrophilic airway inflammation after ozone (O(3)) exposure, we exposed 13 asthmatic subjects to either 0.2 ppm of O(3) or filtered air (FA) followed by either BAL or SI. Subjects then underwent the alternate (O(3) or FA) exposure followed by the same method of RTLF sampling. Next, subjects repeated the same exposure protocol with the alternate method of RTLF sampling. Differences in inflammatory indexes including the percentage of polymorphonuclear neutrophils (%PMNs) between the exposures were then correlated by regression analysis.

RESULTS

The %PMNs in sputum was poorly correlated with that in BAL fluid (R = 0.12). The correlation between the %PMNs in sputum and in the bronchial fraction of BAL (BFx) fluid, however, was somewhat higher (R = 0.50). Furthermore, the uncertainty of the estimate of %PMN values in BFx fluid and BAL fluid based on those of sputum values, using regression models, was almost as great as the magnitude of the O(3) effect itself (ie, 9.7% and 5.5% estimate errors for O(3) effects of 17.0% and 7.5%, respectively).

CONCLUSION

We concluded that SI and BAL indexes are not directly interchangeable in the assessment of O(3)-induced airway inflammation in asthmatic subjects.

The small GTPase accelerators regulator of G protein signalling (RGS) proteins are important regulators of proximal signalling from G protein coupled receptors. Although natural killer (NK) cells express a number of G-protein coupled receptors, expression of RGS proteins has not been investigated. We analysed the expression of RGS proteins in rat NK cells, and detected mRNA for RGS1, RGS2, RGS5, RGS8, RGS16, and RGS18. Interestingly, when we included a panel of different leucocyte subsets, we found that RGS8 was selectively expressed by NK cells. NK cells are under control of both activating and inhibitory receptors and, utilizing a xenogeneic system where the mouse activating Ly49D or inhibitory Ly49A receptors were transfected into the rat RNK-16 cell line, the potential regulation of RGS proteins by single NK cell receptors was studied. We found that ligation of Ly49D led to a rapid and transient increase in message for RGS2, while Ly49A ligation up-regulated RGS2, RGS16, and RGS18 mRNA. Both receptors also induced a prolonged increase in RGS2 endogenous protein levels. These findings suggest that RGS proteins may be influenced by or involved in NK cell receptor events, suggesting a crosstalk between G-protein coupled receptors and NK cell receptors.