Voting restrictions associated with health inequities in teenage birth rates.

OBJECTIVES: Since the Landmark Shelby V. Holder Supreme Court Ruling, the number of laws in the United States that make it difficult to vote has increased dramatically. This may lead to legislation that limits access to health care, including options for family planning services. We determine whether voting restrictions are associated with county-level teenage birth rates. STUDY DESIGN: This is an ecological study. METHODS: The Cost of Voting Index, a state-level measure of barriers to voting during US elections from 1996 to 2016, was used as a proxy for access to voting. County-level teenage birth rates were obtained from the County Health Rankings data. We used multilevel modeling to determine whether restrictive voting laws were associated with county-level teenage birth rates. We tested whether associations varied across racial and socio-economic groups. RESULTS: When confounders were included, a significant association was observed between increasing voting restrictions and teenage birth rates (ß = 1.72, 95% confidence interval: 0.54, 2.89). A Cost of Voting Index-median income interaction term was tested and was statistically significant (ß = -1.00, 95% confidence interval: -1.36, -0.64), indicating that the observed relationship was particularly strong among lower-income counties. The number of reproductive health clinics per capita within each state is a potential mediator. CONCLUSION: Restrictive voting laws were associated with higher teenage birth rates, particularly for low-income counties. Future work should use methods in which a causal relation can be identified.

The pharmacokinetic and pharmacodynamic characteristics of a long-acting growth hormone (GH) preparation (nutropin depot) in GH-deficient adults.

A pharmacokinetic-pharmacodynamic study of a long-acting GH [Nutropin Depot; somatropin (rDNA origin) for injectable suspension] was performed in 25 patients with adult GH deficiency. Single doses of 0.25 mg/kg and 0.5 mg/kg, based on ideal body weight, were administered sc. After either dose, serum GH concentrations rose rapidly in both sexes. In men, the lower dose maintained serum IGF-I levels within 1 SD of the mean for age and sex for 14-17 d; the higher dose raised IGF-I levels 2 SD above the mean. In most women, all of whom were receiving oral estrogen, the lower dose did not normalize IGF-I levels; the higher dose maintained IGF-I near the mean for approximately 14 d. Increases in IGF binding protein-3 and acid-labile subunit levels were observed in both sexes; however, a sex-related difference was not obvious. Fasting glucose and insulin concentrations were transiently elevated in men receiving the higher dose. Patients tolerated the injections well. We concluded that a single injection of Nutropin Depot at these doses in patients with adult GH deficiency increased serum IGF-I to within normal limits for 14-17 d. Estrogen-treated women required approximately twice the dose needed in men to produce comparable IGF-I concentrations.

Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.

BACKGROUND: Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. METHODS: Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. FINDINGS: Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353). INTERPRETATION: Pegvisomant is an effective medical treatment for acromegaly.

Anomalous left adrenal venous drainage directly into the inferior vena cava.

Primary hyperaldosteronism is a potential cause of hypertension. Unilateral adrenal adenoma and bilateral adrenal cortical hyperplasia are the most common causes of primary hyperaldosteronism. Adrenal venous sampling is employed as the gold standard test to differentiate between these two different causes when the results of other studies in the work-up protocol are non-diagnostic or ambiguous. Adrenal venous sampling can be a challenging procedure, especially in the presence of anomalous venous drainage patterns. Knowledge of normal adrenal venous anatomy, as well as possible variants, is therefore important to ensure a successful procedure. The authors describe an unusual variant of left adrenal venous drainage directly into the IVC.

Experience with the advanced breast biopsy instrumentation system.

OBJECTIVES: To report early experience with the advanced breast biopsy instrumentation (ABBI) system and to compare the results with those of other published studies. DESIGN: A nonrandomized case series. SETTING: An outpatient breast diagnostic centre at a large urban community hospital. PATIENTS: Thirty-four women; 27 had suspicious calcifications, 2 had a nonpalpable mass and 5 had both. INTERVENTION: The ABBI procedure to excise a breast lesion or obtain a representative sample for histologic examination. MAIN OUTCOME MEASURES: Success of the procedure with respect to diagnosis, sample quality, technical problems, margins of tumour free tissue and patient satisfaction. RESULTS: Malignant tissue was diagnosed in 7 women (21%) and atypical ductal hyperplasia in 2 (6%). In all cancers, the obtained samples had malignant cells present at the margins or less than 1 mm away. Technical problems were encountered in 32% of cases. Manual extraction of the specimen was required in 21% of cases. CONCLUSIONS: The preliminary data correlate well with those of other published results. Although it is possible that a small number of cases and a relatively high proportion of technical difficulties may represent a normal learning curve, there is a definite need for improvement of some ABBI components. ABBI does not appear to provide adequate margins of uninvolved tissue in patients with cancer and thus should not be used with curative intent. ABBI provides excellent quality samples for pathological study and good patient satisfaction. There are not yet enough data for meaningful comparison of ABBI with stereotactic core biopsy and excisional biopsy with needle localization.

Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.

BACKGROUND: Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone. METHODS: We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly. RESULTS: The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups. CONCLUSIONS: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

TraG from RP4 and TraG and VirD4 from Ti plasmids confer relaxosome specificity to the conjugal transfer system of pTiC58.

Plasmid conjugation systems are composed of two components, the DNA transfer and replication system, or Dtr, and the mating pair formation system, or Mpf. During conjugal transfer an essential factor, called the coupling protein, is thought to interface the Dtr, in the form of the relaxosome, with the Mpf, in the form of the mating bridge. These proteins, such as TraG from the IncP1 plasmid RP4 (TraG(RP4)) and TraG and VirD4 from the conjugal transfer and T-DNA transfer systems of Ti plasmids, are believed to dictate specificity of the interactions that can occur between different Dtr and Mpf components. The Ti plasmids of Agrobacterium tumefaciens do not mobilize vectors containing the oriT of RP4, but these IncP1 plasmid derivatives lack the trans-acting Dtr functions and TraG(RP4). A. tumefaciens donors transferred a chimeric plasmid that contains the oriT and Dtr genes of RP4 and the Mpf genes of pTiC58, indicating that the Ti plasmid mating bridge can interact with the RP4 relaxosome. However, the Ti plasmid did not mobilize transfer from an IncQ relaxosome. The Ti plasmid did mobilize such plasmids if TraG(RP4) was expressed in the donors. Mutations in traG(RP4) with defined effects on the RP4 transfer system exhibited similar phenotypes for Ti plasmid-mediated mobilization of the IncQ vector. When provided with VirD4, the tra system of pTiC58 mobilized plasmids from the IncQ relaxosome. However, neither TraG(RP4) nor VirD4 restored transfer to a traG mutant of the Ti plasmid. VirD4 also failed to complement a traG(RP4) mutant for transfer from the RP4 relaxosome or for RP4-mediated mobilization from the IncQ relaxosome. TraG(RP4)-mediated mobilization of the IncQ plasmid by pTiC58 did not inhibit Ti plasmid transfer, suggesting that the relaxosomes of the two plasmids do not compete for the same mating bridge. We conclude that TraG(RP4) and VirD4 couples the IncQ but not the Ti plasmid relaxosome to the Ti plasmid mating bridge. However, VirD4 cannot couple the IncP1 or the IncQ relaxosome to the RP4 mating bridge. These results support a model in which the coupling proteins specify the interactions between Dtr and Mpf components of mating systems.

The adult growth hormone deficiency syndrome.

The diagnosis of the adult GH deficiency syndrome from a clinical and laboratory standpoint has been reviewed. Therapy guidelines and monitoring should focus on the patient's symptoms and IGF-1 concentrations from a laboratory standpoint. Successful patient/physician interaction depends on physician awareness of the symptoms of the deficiency syndrome and symptoms associated with therapy. Successful therapy with GH almost always results in an extremely satisfied patient, family, and physician.

Cortisol production rates in subjects with suspected Cushing's syndrome: assessment by stable isotope dilution methodology and comparison to other diagnostic methods.

It can be difficult to establish the diagnosis of Cushing's Syndrome (CS) in patients with mild or nonspecific clinical and biochemical findings, because available diagnostic tests have limited predictive values. We hypothesized that measurement of 24-h cortisol production rates (CPRs) might be a more sensitive indicator of CS in such patients. We measured CPRs in 28 patients with suspected CS (but equivocal biochemical findings) and in 22 healthy control subjects, by infusing tracer amounts of deuterated cortisol, with simultaneous measurements of 24-h urine free cortisol (UFC) levels; and we frequently sampled serum cortisol levels. CPRs were calculated from the ratio of isotopic enrichment to isotopic dilution of cortisol measured by gas chromatography-negative ion chemical ionization mass spectrometry. Nine of the patients proved to have CS by surgery (CS-Yes), whereas 19 patients were determined not to have CS by biochemical testing (CS-No). Mean 24-h UFCs, nocturnal serum cortisol levels, and CPRs were higher in CS-Yes, compared with CS-No and normal subjects. However, one CS-Yes patient had a normal 24-h UFC, two had normal nocturnal serum cortisol levels, and two had normal 24-h CPRs. There was extensive overlap in all of the biochemical parameters between the CS-Yes and the CS-No groups. Thus, measurement of CPR does not seem to offer any diagnostic advantage over available tests for the diagnosis of CS. Patients with proven CS can have normal UFC levels, normal CPRs, or normal nocturnal cortisol levels, whereas patients not thought to have CS may have elevated levels of any one or more these parameters.

Clinical and reimbursement issues in growth hormone use in adults.

Data published in the past decade have demonstrated that adults who are deficient in growth hormone (GH) experience deleterious clinical consequences without treatment. In 1996, the Food and Drug Administration approved the use of GH in adults who were GH deficient as a result of hypothalamic or pituitary disease. However, there are other conditions in adults for which GH treatment has also been approved (acquired immune deficiency syndrome [AIDS]-related wasting) or for which it is being considered, such as aging, catabolic states, and cardiomyopathy. Clinical issues revolve around the rationale for treatment; the diagnostic evaluation; the effects of GH therapy on body composition, bone density, lipids, and cardiac function; and appropriate dosing and follow up. Clearly, the use of GH in adults raises reimbursement issues as well. In this article, Dr. Beverly M.K. Biller provides an overview of the rationale for the treatment of adult-onset GH deficiency and reviews its etiology and clinical features as well as reimbursement and utilization issues related to treatment. Dr. Mary Lee Vance discusses various assays and criteria used in the diagnostic evaluation of the patient with adult-onset GH deficiency. Dr. David L. Kleinberg focuses on the effects of GH therapy on body composition, bone density, lipid profiles, and cardiac function, as well as on reimbursement issues regarding body composition studies. To complete the clinical portion of this session, Dr. David M. Cook addresses dosing and follow up. To address economic implications, Dr. Terry Gordon provides the payer's perspective on the diagnosis and treatment of adult-onset GH deficiency.

Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults.

We prospectively studied two groups of GH-deficient patients during GH therapy based upon exposure of the liver to elevated (oral estrogen) or not elevated (endogenous or transdermal) sources of estrogen. We wondered whether higher concentrations of estrogen at the liver level (oral estrogen) might inhibit insulin-like growth factor I (IGF-I) secretion and alter exogenous GH requirements. In this study we compared GH replacement requirements in these two groups of women as well as with GH-treated adult hypopituitary males. The final GH dose was based upon maintenance IGF-I levels in the mid- to high normal range adjusted for age and sex or symptom tolerance. Each group [women taking oral estrogen (n = 12), women not taking oral estrogen (n = 13), and men (n = 12)] was similar in age and final IGF-I concentration. Women taking oral estrogen required 10.6 +/- 0.7 microg/kg x day or 867 +/- 45 microg/day GH, women not taking oral estrogen required 5.0 +/- 0.7 microg/kg x day or 424 +/- 57 microg/day, and men required 4.1 +/- 0.6 microg/kg x day or 376 +/- 49 microg/day to achieve similar IGF-I concentrations. GH requirements in men were not different from those in women not taking oral estrogen, but the GH requirements in both groups were significantly different from GH requirements in women taking oral estrogen. These observations may be useful in anticipating appropriate starting and final doses of GH in adult hypopituitary patients.

Adult growth hormone deficiency syndrome: a personal approach to diagnosis, treatment and monitoring.

Therapy guidelines and monitoring should focus on symptoms and, from a laboratory standpoint, serum IGF-I concentrations. Successful interaction between the patient and the physician depends on awareness of the symptoms of the adult GHD syndrome and those associated with replacement therapy. Successful GH replacement therapy can lead to significant improvement in the patient's condition with great satisfaction with the treatment being expressed by the patient, their family and the physician.

Cavernous sinus sampling is highly accurate in distinguishing Cushing's disease from the ectopic adrenocorticotropin syndrome and in predicting intrapituitary tumor location.

Inferior petrosal sinus sampling (IPSS) is used to distinguish pituitary Cushing's disease from occult cases of the ectopic ACTH syndrome, but is limited in that it requires the use of ovine CRH (oCRH) and is not highly accurate at predicting the intrapituitary location of tumors. This study was designed to determine whether cavernous sinus sampling (CSS) is as safe and accurate as IPSS, whether CSS can eliminate the need for oCRH stimulation, and whether CSS can accurately predict the intrapituitary location of tumors. Ninety-three consecutive patients with ACTH-dependent Cushing's syndrome were prospectively studied with bilateral, simultaneous CSS before and after oCRH stimulation. Prediction of a pituitary or ectopic ACTH source was based on cavernous/peripheral plasma ACTH ratios. Intrapituitary tumor location was predicted based on lateralization (side to side) ACTH ratios. These predictions were compared to surgical outcome in the 70 patients who had surgically proven pituitary (n = 65) or ectopic (n = 5) disease. CSS distinguished pituitary Cushing's disease from the ectopic ACTH syndrome in 93% of patients with proven tumors before oCRH administration and in 100% of patients with proven tumors after oCRH. It was as safe and efficacious as published IPSS results. CSS accurately predicted the intrapituitary lateralization of the tumor in 83% of all patients and 89% of those patients with good catheter position and symmetric venous flow. CSS is as safe and accurate as IPSS for distinguishing patients with pituitary Cushing's disease from those with the ectopic ACTH syndrome. In addition, CSS appears to be superior to IPSS for predicting intrapituitary tumor lateralization.

Identification and characterization of PtlC, an essential component of the pertussis toxin secretion system.

PtlC is a member of a set of proteins necessary for the secretion of pertussis toxin (PT) from Bordetella pertussis. Using polyclonal antibodies specific for PtlC, we identified PtlC as a protein with an apparent molecular weight of 85,000 that localizes to the membrane fraction of bacterial cell extracts. We found that a mutant strain of B. pertussis that contains an in-frame deletion in ptlC is unable to secrete PT and that PT secretion is fully restored by expressing ptlC in trans, indicating that PtlC is essential for transport of PT across the bacterial membrane(s). PT secretion was inhibited in wild-type B. pertussis after introduction of a plasmid expressing a mutant ptlC altered in the putative nucleotide-binding region, suggesting that this region of PtlC is essential for proper function. Moreover, the observed dominant negative phenotype suggests that PtlC either functions as a multimer or interacts with some other component(s) necessary for secretion of PT.

Human chorionic gonadotropin production by the pituitary gland in a premenopausal woman.

OBJECTIVE: Our purpose was to investigate the source of human chorionic gonadotropin production in a nonpregnant, premenopausal woman. STUDY DESIGN: A case of human chorionic gonadotropin production by the pituitary gland in a premenopausal woman is described. RESULTS: Our results confirm that a biologically active human chorionic gonadotropin-like molecule was secreted in a nonpregnant woman. CONCLUSIONS: Our results indicate that the pituitary gland was the most likely source of human chorionic gonadotropin production.

Hypothalamic-pituitary-insulin-like growth factor-I axis dysfunction in patients with fibromyalgia.

OBJECTIVE: To investigate the serum levels of insulin-like growth factor-I (IGF-I) in patients with fibromyalgia (FM) compared to healthy controls and patients with other rheumatic diseases, and to explore possible etiologic mechanisms of low IGF-I levels in patients with FM. METHODS: Five hundred patients with FM and 152 controls (74 healthy blood donors, 26 myofascial pain patients and 52 patients with other rheumatic diseases) were studied. All had measurements of acid extracted serum IGF-I. A subset of 90 patients with FM were evaluated for clinical features that might explain low IGF-I levels. Twenty-five patients with FM underwent growth hormone (GH) provocation testing with l-dopa and clonidine. RESULTS: The mean serum IGF-I level in patients with FM was 138 +/- 56 ng/ml and in controls 215 +/- 86 ng/ml (p = 0.00000000001). Low levels of IGF-I were not due to depression, tricyclic medications, nonsteroidal antiinflammatory drugs, poor aerobic conditioning, obesity, or pain level. Patients with focal myofascial pain syndromes had normal IGF-I levels (236 +/- 68), as did most patients with other rheumatic disorders, unless they had concomitant FM. Patients with FM with initially normal levels often had a rapid decline of IGF-I over 1 to 2 years. Most patients with FM with low IGF-I levels failed to secrete GH after stimulation with clonidine and l-dopa. CONCLUSION: Many, but not all, patients with FM have low levels of IGF-I that cannot be explained by clinical associations. These results suggest that low IGF-I levels in patients with FM are a secondary phenomenon due to hypothalamic-pituitary-GH axis dysfunction.

Intraoperative adrenocorticotropin levels during transsphenoidal surgery for Cushing's disease do not predict cure.

Recently, intraoperative rapid immunochemiluminometric assay (ICMA) ACTH measurements have been used to evaluate the completeness of resection of ectopic ACTH-secreting tumors. This study evaluates whether this method can be applied to patients undergoing transsphenoidal surgery (TSS) for Cushing's disease to predict complete pituitary tumor resection. Eighteen patients with Cushing's disease undergoing TSS had plasma ACTH concentrations measured by a standard ICMA every 10 min for 1 h immediately after pituitary tumor removal. Patients were evaluated postoperatively for cure by standard criteria. ACTH levels were evaluated for percentage decrease from baseline at each time point. Patients who were cured (n = 11) had statistically greater decreases in ACTH levels (mean decrease 54%) than patients who were not (n = 7; 26% mean decrease, P < 0.04). By Receiver-Operator Characteristic (ROC) analysis, a reduction of at least 40% best predicted which patients were cured and which were not cured. This level of reduction was observed in 82% of cured patients, and a reduction of less than 40% was observed in 71% of those not cured. The analysis misclassified 4 of the 18 patients, resulting in a diagnostic accuracy of 78%. Although the mean maximal decrease in ACTH concentrations after tumor removal was significantly different between cured and not cured patients with Cushing's disease, it was less dramatic than results in the previous ectopic ACTH study. This may relate to incomplete suppression and/or surgical manipulation of normal pituitary corticotrophs in patients with pituitary disease. In summary, in contrast to the ectopic ACTH syndrome, decline of plasma ACTH during TSS does not accurately predict complete tumor resection.