Recent Publications by CFE Educators

BACKGROUND

Numerous studies have tested for associations between common variants of the angiotensin-converting enzyme gene (ACE) and late-onset Alzheimer disease (AD), but results have been inconclusive.

METHODS

Relevant studies were systematically identified, and data were abstracted according to predefined criteria.

RESULTS

The odds ratio (OR) for AD in individuals with the I allele of the ACE D/I polymorphism compared with those with the DD genotype was 1.27 (95% CI, 1.10 to 1.47; p 0.001). Heterogeneity between studies was significant (p 0.001) but not in strata defined by race and age (p > or = 0.10). The risk of AD associated with the I allele appeared to be higher among Asians (OR 2.44; 95% CI, 1.68 to 3.53) when compared with the risk among Caucasians (OR 1.18; 95% CI, 1.02 to 1.37) (p for comparison 0.001), and in younger cases (mean age 65 to 74 years) (OR 1.54; 95% CI, 1.23 to 1.93) when compared with the risk in older cases (OR 1.13; 95% CI, 0.95 to 1.35) (p for comparison = 0.03).

CONCLUSIONS

The I allele of the ACE D/I polymorphism is associated with an increased risk of late-onset AD. Further study of the pathogenetic characteristics of this allele and independent confirmation of the association in larger studies are warranted.

BACKGROUND

X-linked dominant hypophosphatemic rickets (XLHR) is a hereditary metabolic bone syndrome that is only beginning to be understood and is rarely associated with progression to irreversible tertiary hyperparathyroidism. We report our surgical experience with 6 patients with XLHR who underwent parathyroidectomy for associated autonomous parathyroid hyperfunction.

HYPOTHESIS

Parathyroidectomy can successfully treat tertiary hyperparathyroidism in the setting of XLHR, although an understanding of expected operative findings and postoperative complications is essential.

DESIGN

The study group comprised 6 patients with XLHR identified from our endocrine surgery database. Presentation, surgical procedure, parathyroid pathologic findings, and subsequent outcome are outlined.

RESULTS

There were 4 women and 2 men. All were exposed to long-term vitamin D and phosphate supplementation therapy. All had persistently elevated preoperative levels of parathyroid hormone and serum calcium. The patients were treated as follows: 3 had total parathyroidectomy, 2 had 3 parathyroid glands identified and resected, and 1 had 2 abnormal parathyroid glands resected with 2 normal-appearing parathyroid glands left in situ. One patient subsequently required completion parathyroidectomy for recurrent disease. Pathologic examination results revealed hyperplasia of all resected parathyroid glands in 4 of 6 patients. One patient had a single adenoma with 3-gland hyperplasia, and 1 patient had a double adenoma. The principal complication of this procedure was profound symptomatic hypocalcemia requiring intravenous calcium infusion. Hungry bone syndrome was also observed in most subjects. Long-term, all patients achieved normocalcemia.

CONCLUSION

Tertiary hyperparathyroidism is a rare but recognized complication of XLHR. Parathyroidectomy effectively treats this complication caused by autonomous parathyroid hyperfunction, but profound postoperative hypocalcemia necessitates careful management.

BACKGROUND

Idiopathic pulmonary fibrosis is a progressive, fatal disease with no known efficacious therapy.

METHODS

In a double-blind, multinational trial, we randomly assigned 330 patients with idiopathic pulmonary fibrosis that was unresponsive to corticosteroid therapy to receive subcutaneous interferon gamma-1b or placebo.

RESULTS

Over a median of 58 weeks, interferon gamma-1b therapy did not significantly affect the primary end point of progression-free survival, defined as the time to disease progression or death, and no significant treatment effect was observed on measures of lung function, gas exchange, or the quality of life. Ten percent of patients in the interferon gamma-1b group died, as compared with 17 percent of patients in the placebo group (P=0.08). Treatment with interferon gamma-1b was associated with more frequent constitutional symptoms. However, the rates of treatment adherence and premature discontinuation of treatment were similar in the two groups. More pneumonias were reported among patients in the interferon gamma-1b group, but the incidence of severe or life-threatening respiratory tract infections was similar in the two groups.

CONCLUSIONS

In a well-defined population of patients with idiopathic pulmonary fibrosis, interferon gamma-1b did not affect progression-free survival, pulmonary function, or the quality of life. Owing to the size and duration of the trial, a clinically significant survival benefit could not be ruled out.

We previously reported that mice with a deletion of the preprotachykinin-A (pptA) gene, from which substance P (SP) and neurokinin A (NKA) are derived, exhibit reduced behavioral responses to intense stimuli, but that behavioral hypersensitivity after injury is unaltered. To understand the contribution of SP and NKA to nociceptive transmission in the spinal cord, we recorded single-unit activity from wide dynamic range neurons in the lamina V region of the lumbar dorsal horn of urethane-anesthetized wild-type and ppt-A null mutant (-/-) mice. We found that intensity coding to thermal stimuli was largely preserved in the ppt-A -/- mice. Neither the peak stimulus-evoked firing nor the neuronal activity during the initial phase (0-4 s) of the 41-49 degrees C thermal stimuli differed between the genotypes. However, electrophysiological responses during the late phase of the stimulus (5-10 s) and poststimulus (11-25 s) were significantly reduced in ppt-A -/- mice. To activate C-fibers and to sensitize the dorsal horn neurons we applied mustard oil (MO) topically to the hindpaw. We found that neither total MO-evoked activity nor sensitization to subsequent stimuli differed between the wild-type and ppt-A -/- mice. However, the time course of the sensitization and the magnitude of the poststimulus discharges were reduced in ppt-A -/- mice. We conclude that SP and/or NKA are not required for intensity coding or sensitization of nociresponsive neurons in the spinal cord, but that these peptides prolong thermal stimulus-evoked responses. Thus whereas behavioral hypersensitivity after injury is preserved in ppt-A -/- mice, our results suggest that the magnitude and duration of these behavioral responses would be reduced in the absence of SP and/or NKA.

We have created a bioimpedance probe designed to detect subtle changes in human cervical tissue composition in vivo, and thereby detect the onset of cervical remodeling in a noninvasive manner sooner than existing clinical methods allow. Our cervical bioimpedance measurement device, which can be used during a routine pelvic examination, is composed of a contoured probe with disposable tip and, within the probe's handle, a bioimpedance sensor equipped with an integrated chip capable of generating sinusoidal voltage of varying frequencies. A constant force spring assures consistent measurements through a range of contact forces applied. An activation switch allows the operator to control the application of current. The sensor can be synchronized with a computer data storage and analysis system, which interfaces with the device. With the probe placed in contact with a collagen gels of varying concentration, the relationship between measured bioimpedance and collagen concentration is verified to be positive exponential (R/sup 2/=0.94) and repeatability in saline solution showed that measurements varied by less than +/-10% over 20 trials. Finally, a variety of user-applied forces showed that impedance values plateau when forces exceed 1N.

OBJECTIVE

Two potential barriers to use of oral contraceptives (OCPs) are out-of-pocket expenditures and the inconvenience of monthly pharmacy visits. This study used nationally representative data to examine the out-of-pocket costs of OCPs and whether women obtain more than 1 pack per purchase.

METHODS

We used data from the 1996 Medical Expenditure Panel Survey. Dependent variables were out-of-pocket expenditures per pack and the number of packs obtained per purchase. Chi2 tests were used to examine the bivariate relationships between the dependent variables and covariates. Regression analyses were used to examine the predictors of OCP expenditures and the number of packs obtained per purchase.

RESULTS

Women paid an average of 14 dollars per pack of OCPs, and 73% obtained only 1 pack per purchase. On average, privately insured women paid 60% of the total expenditures for OCPs. Women who had no prescription drug coverage, who were uninsured, or who were privately insured but not in managed care plans had higher out-of-pocket expenditures. Women who were without prescription drug coverage or who were in managed care plans were more likely to obtain only 1 pack per purchase.

CONCLUSION

Out-of-pocket costs and dispensing restrictions may be barriers to consistent use of OCPs. Women's health care providers should consider options to overcome these barriers, such as the use of mail order prescription services.

Several theories of opioid tolerance predict that the magnitude of micro opioid receptor (MOR) internalization in response to ligand changes in the setting of morphine tolerance. Here we show that in rats rendered tolerant to the analgesic action of morphine, cross-tolerance to the analgesic action of intrathecally administered [d-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) can be produced without changes in the magnitude of DAMGO-induced internalization of the MOR in lamina II neurons of the rat spinal cord. These results suggest that opioid tolerance-related changes in signaling are located downstream from or in parallel with receptor activation and internalization and support the idea that key features of opioid signaling are maintained, rather than reduced, in the setting of morphine tolerance.

Increases in neuronal activity in response to tissue or nerve injury can lead to prolonged functional changes in the spinal cord resulting in an enhancement/sensitization of nociceptive processing. To assess the contribution of alpha-calcium-calmodulin kinase II (alpha-CaMKII) to injury-induced inflammation and pain, we evaluated nociceptive responses in mice that carry a point mutation in the alpha-CaMKII gene at position 286 (threonine to alanine). The mutated protein is unable to autophosphorylate and thus cannot function independently of calcium and calmodulin. Responses to acute noxious stimuli did not differ between alpha-CaMKII T286A mutant and wild type mice. However, the ongoing pain produced by formalin injury was significantly reduced in the mutant mice, as was formalin-evoked spinal Fos-immunoreactivity. In contrast, the decreased mechanical and thermal thresholds associated with nerve injury, Complete Freund's Adjuvant-induced inflammation or formalin-evoked tissue injury were manifest equally in wild-type and mutant mice. Double-labeling immunofluorescence studies revealed that in the mouse alpha-CaMKII is expressed in the superficial dorsal horn as well as in a population of small diameter primary afferent neurons. In summary, our results suggest that alpha-CaMKII, perhaps secondary to an N-methyl-D-aspartate-mediated calcium increase in postsynaptic dorsal horn nociresponsive neurons, is a critical contributor to the spontaneous/ongoing component of tissue-injury evoked persistent pain.