Search

Subcutaneous human parathyroid hormone (hPTH) therapy can effectively manage hypocalcemia in hypoparathyroidism, with varying effects on hypercalciuria. However, little is known about its ability to decrease the renal comorbidities of hypoparathyroidism: nephrocalcinosis (NC), nephrolithiasis (NL), and renal insufficiency. Urinary citrate (Ucit) promotes the solubility of urinary calcium (UCa); hypocitraturia is a risk factor for NC/NL. Twenty-four-hour UCa, Ucit, and UCa/Ucit were determined in 31 hypoparathyroid subjects receiving hPTH 1-34 therapy for up to 5 years. Before hPTH 1-34, the geometric least squares mean UCa was 346 mg/day (normal

Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.

Subcutaneous human parathyroid hormone (hPTH) therapy can effectively manage hypocalcemia in hypoparathyroidism, with varying effects on hypercalciuria. However, little is known about its ability to decrease the renal comorbidities of hypoparathyroidism: nephrocalcinosis (NC), nephrolithiasis (NL), and renal insufficiency. Urinary citrate (Ucit) promotes the solubility of urinary calcium (UCa); hypocitraturia is a risk factor for NC/NL. Twenty-four-hour UCa, Ucit, and UCa/Ucit were determined in 31 hypoparathyroid subjects receiving hPTH 1-34 therapy for up to 5 years. Before hPTH 1-34, the geometric least squares mean UCa was 346 mg/day (normal250) and Ucit was 500 mg/day (normal 250-1190); UCa/Ucit was 0.67 mg/mg. After 6 months of hPTH 1-34, UCa decreased (238, p 0.001), but with a greater decrease in Ucit (268, p 0.001), increasing UCa/Ucit, which became significant over time (p 0.001). After stopping hPTH 1-34 and resuming conventional therapy (follow-up; FU), compared to the last measures on hPTH 1-34, Ucit rose to 626 (p 0.001), reducing UCa/Ucit to 0.44, (p 0.05); UCa also rose (273), but was still lower than baseline (p 0.05). Daily hPTH 1-34 dose did not correlate with UCa, but was inversely related to Ucit, and directly related to UCa/Ucit (p 0.01). Mean blood bicarbonate decreased significantly on hPTH 1-34 and remained lower than baseline at FU (p 0.01). Mean eGFR increased on hPTH 1-34 (86 to 96 mL/min/1.73 m

Nephrocalcinosis is a complication of hypoparathyroidism and other metabolic disorders. Imaging modalities include ultrasonography (US) and computed tomography (CT). Few studies have compared these modalities, and standard clinical practice is not defined.The objective of the study was to determine the preferred method for assessing nephrocalcinosis.The design of the study was a retrospective, blinded analysis.The study was conducted at a clinical research center.Twenty-two hypoparathyroid subjects and 7 controls participated in the study.Contemporaneous renal US and CT images were reviewed in triplicate by 4 blinded radiologists. Nephrocalcinosis was classified using a 0-3 scale with 0 meaning no nephrocalcinosis and 3 meaning severe nephrocalcinosis.Intraobserver, interobserver, and interdevice agreements were measured.Intraobserver agreement was high, with an overall weighted kappa of 0.83 for CT and 0.89 for US. Interobserver agreement was similar between modalities, with kappas of 0.74 for US and 0.70 for CT. Only moderate agreement was found between US and CT scores, with an intermodality kappa of 0.47 and 60% concordance. Of discordant pairs, 81% had higher US scores and only 19% had higher CT scores. Of nephrocalcinosis seen on US and not CT, 45%, 46%, and 9% were grades 1, 2, and 3, respectively. Overall, US scores were higher than CT with a cumulative odds ratio (95% confidence interval) of 5.97 (2.60, 13.75) (P.01). In controls, 100% of US ratings were 0, and 95% of CT ratings were 0.US is superior to CT for assessment of mild to moderate nephrocalcinosis in patients with hypoparathyroidism. This finding, in combination with its low cost, lack of radiation, and portability, defines US as the preferred modality for assessment of nephrocalcinosis.

Background Stroke occurs in 5–10% of children with sickle cell anemia (SCA) and has a high (>50%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke, but their long term use is limited by serious side effects, including iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, especially one that also improves the management of iron overload.

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV ≥ 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P = .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 14% with placebo (P = .029). There was no evidence of a treatment effect on 6MWD (placebo-corrected effect −9 m; 95% confidence interval [95% CI] −56-38; P = .703), TRV (P = .503), or N-terminal pro-brain natriuretic peptide (P = .410). Sildenafil appeared to increase hospitalization rates for pain in patients with SCD. This study is registered at www.clinicaltrials.gov as NCT00492531.

Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.

Chronic transfusion reduces the risk of recurrent stroke in children with sickle cell anemia (SCA) but leads to iron loading. Management of transfusional iron overload in SCA has been reported as suboptimal [1], but studies characterizing monitoring and treatment practices for iron overload in children with SCA, particularly in recent years with the expansion of chelator options, are lacking. We investigated the degree of iron loading and treatment practices of 161 children with SCA receiving transfusions for a history of stroke who participated in the Stroke with Transfusions Changing to Hydroxyurea (SWiTCH) trial. Data obtained during screening, including past and entry liver iron concentration (LIC) measurements, ferritin values, and chelation were analyzed. The mean age at enrollment was 12.9 ± 4 years and the mean duration of transfusion was 7 ± 3.8 years. Baseline LIC (median 12.94 mg/g dw) and serum ferritin (median 3,164 ng/mL) were elevated. Chelation therapy was initiated after a mean of 2.6 years of transfusions. At study entry, 137 were receiving chelation, most of whom (90%) were receiving deferasirox. This study underscores the need for better monitoring of iron burden with timely treatment adjustments in chronically transfused children with SCA.

The transmission of another’s secret is likened to self-disclosure, and further predictions are set forth based on a relative intimacy hypothesis. This hypothesis maintains that individuals will be more likely to transmit private information gathered from a lower-level intimate to a higher-level intimate (upward transmission) rather than from a higher-level intimate to a lower-level intimate (downward transmission). This pattern of behavior also is predicted to be normatively enforced. Results of three studies support these assertions. Participants were more likely to communicate upward rather than downward in both imagined (Study 1) and actual (Study 2) instances of secret transmission. In addition, individuals in Study 3 evaluated a secret relayer more negatively when he or she passed the secret from a higher-level intimate to a lower-level intimate.

This study examined the effects of integrating mental health, substance abuse, and housing interventions for homeless persons with co-occurring severe mental illness and substance use disorder. With the use of a quasi-experimental design, integrated treatment was compared with standard treatment for 217 homeless, dually diagnosed adults over an 18-month period. The integrated treatment group had fewer institutional days and more days in stable housing, made more progress toward recovery from substance abuse, and showed greater improvement of alcohol use disorders than the standard treatment group. Abuse of drugs other than alcohol (primarily cocaine) improved similarly for both groups. Secondary outcomes, such as psychiatric symptoms, functional status, and quality of life, also improved for both groups, with minimal group differences favoring integrated treatment.

To compare the non-neurological events in children with sickle cell anemia (SCA) and previous stroke enrolled in SWiTCH. The NHLBI-sponsored Phase III multicenter randomized clinical trial stroke with transfusions changing to hydroxyurea (SWiTCH) (ClinicalTrials.gov NCT00122980) compared continuation of chronic blood transfusion/iron chelation to switching to hydroxyurea/phlebotomy for secondary stroke prevention and management of iron overload. All randomized children were included in the analysis (intention to treat). The Fisher's Exact test was used to compare the frequency of subjects who experienced at least one SCA-related adverse event (AE) or serious adverse event (SAE) in each arm and to compare event rates. One hundred and thirty three subjects, mean age 13 ± 3.9 years (range 5.2-19.0 years) and mean time of 7 years on chronic transfusion at study entry, were randomized and treated. Numbers of subjects experiencing non-neurological AEs were similar in the two treatment arms, including SCA-related events, SCA pain events, and low rates of acute chest syndrome and infection. However, fewer children continuing transfusion/chelation experienced SAEs (P = 0.012), SCA-related SAEs (P = 0.003), and SCA pain SAEs (P = 0.016) as compared to children on the hydroxyurea/phlebotomy arm. The timing of phlebotomy did not influence SAEs. Older age at baseline predicted having at least 1 SCA pain event. Patients with recurrent neurological events during SWiTCH were not more likely to experience pain. In children with SCA and prior stroke, monthly transfusions and daily iron chelation provided superior protection against acute vaso-occlusive pain SAEs when compared to hydroxyurea and monthly phlebotomy.

This study examined the effects of turnover and task complexity on group performance. Two hundred and forty subjects arranged into three-person groups performed a production-type task for six experimental periods. The design was a 2 (Turnover vs. No Turnover) × 2 (Simple vs. Complex Task) × 2 (Male vs. Female) × 6 (Periods) factorial with repeated measures on the last factor. The analysis revealed that group performance improved markedly as groups gained experience with the task. Groups which did not experience turnover (closed groups) produced significantly more products than did groups which experienced turnover (open groups). The superior performance of closed over open groups was amplified over periods. Groups produced more of the simple than of the complex product, and this difference was also amplified over periods. The gap in the performance of closed versus open groups increased over periods, and the increase in the gap was greater for the simple than for the complex task. The lesser impact of turnover on the complex task is consistent with an innovation hypothesis, according to which increases in the production of complex tasks are due more to innovation than to repetition. Supportive analyses of innovation data are reported.

The literature on behavior during dissatisfying incidents consistently demonstrates that one key to effective interaction involves the willingness to accommodate, or the tendency-when an interaction partner engages in a potentially destructive act-to inhibit impulses to respond in kind, instead reacting in a constructive manner. It has been argued that the cognitive underpinnings of accommodation involve transformation of motivation, or the tendency to pause and "take account of broader considerations" such as the long-term consequences of one′s actions for a relationship. Two experiments provided evidence relevant to this key assumption. In Experiment 1 subjects described two incidents when their romantic partners behaved badly, reporting on both the responses they considered enacting and the responses they actually enacted. Consistent with predictions, the responses subjects considered enacting were significantly more destructive than the responses they actually enacted. Experiment 2 examined cognitive processes using a manipulation of reaction time-subjects were given either limited or plentiful time to indicate how they would react to interpersonal scenarios in which interaction partners enacted either constructive or destructive behaviors. As predicted, subjects were more likely to respond destructively to another′s destructive act when given limited reaction time than when given plentiful reaction time.

Objective To assess the effects of chronic erythrocyte transfusions on prevalence of sonographic incidence of organ damage in children with sickle cell anemia (SCA). Study design Children (N = 148; mean age, 13.0 years) with SCA, receiving chronic transfusions (average, 7 years), underwent abdominal sonography at 25 institutions. After central imaging review, spleen, liver, and kidney measurements were compared with published normal values. Potential relations between ultrasound, clinical, and laboratory data were explored via analysis of variance, Student t test, and Cochran-Mantel-Haenzel tests of non-zero correlation. Results Average spleen length was similar to normal children, but over one-third had spleen volumes >300 mL, 15 had previous splenectomy for splenomegaly, and 24 had abnormal splenic echotexture. Two-thirds had hepatobiliary disease; 37 had prior cholecystectomy, 46 had gallstones, and 16 had gallbladder sludge. Gallbladder disease correlated with older age ( P = .002), longer liver length ( P P = .034), and higher total bilirubin ( P P P ≤ .005) were larger than published norms. Conclusions In children with SCA, long-term transfusion therapy may not prevent development or progression of abdominal organ dysfunction.

Abstract 1074 Non-Cardiopulmonary Factors Affecting the Six-Minute Walk Distance in Patients with Sickle Cell Disease: Results from the Walk-PHaSST Study. INTRODUCTION: The six-minute walk (6MW) test is frequently used to assess exercise capacity. Patients with sickle cell disease (SCD) can have decreased 6MW distance (6MWD) compared to controls. The 6MWD in conjunction with the TR-jet velocity (TRV) and NT-proBNP have recently been proposed to have a greater predictive value for screening SCD patients suspected of having pulmonary hypertension (PH) than TRV alone. (Parent et al, NEJM, 365; 1, 2011 365 (1):44–53). The American Thoracic Society guidelines recommend caution in controlling for sources of variability in the 6MWD (Am J Respir Crit Care Med 166. 111–117, 2002). Age and height are known confounders of the 6MWD. However, non-cardiopulmonary factors including skeletal-mechanics and pain may also impact the 6MWD. AIM: This study explores whether non-cardiopulmonary factors affect the 6MWD in SCD patients. METHODS: We analyzed data from subjects screened for the walk-PHaSST trial. Walk-PHaSST was a multi-center, placebo-controlled, double-blind, 16-week trial evaluating the safety and efficacy of oral sildenafil for the treatment of Doppler-defined PH (TRV '2.7m/s) in subjects with SCD aged >12 years. The primary endpoint in the trial was change in 6MWD. During screening, subjects were evaluated by self-reported medical history, physical examination, blood sampling, echocardiography and 6MWD. Univariate and multivariable linear regression was performed. A two sided p value RESULTS: Of the 673 subjects screened, 671 had a 6MW test. The median (inter-quartile range) of 6MWD was 438m (503 – 381m = 122 m). On univariate analysis, there was no statistically significant effect of the SCD genotype on the 6MWD (p=0.26). Further, when combining the severe genotypes (HbSS and HbSβ0 thalassemia) vs the less severe genotypes, there was no significant difference in the 6MWD (p=0.22). By multivariable linear regression (Table 1), after adjusting for age, gender and TRV, the presence of the following (self-reported by subjects) were independently associated with an estimated decrease in the 6MWD: a) chronic pain (n = 260/671, 38.9%) by 24.3m (95% CI: 9.1–39.4m, p-value DISCUSSION: In this multi-center study of patients with SCD, history of self-reported: 1) chronic pain 2) AVN of the hip and 3) osteopenia were independently associated with decreased functional capacity (as assessed by the 6MW test), after adjusting for age, gender, and TRV. While the 6MWD in patients with SCD is significantly related to cardiac function (i.e., PH and LV diastolic dysfunction), the potential effects of pain, osteonecrosis and osteopenia on 6MWD suggest that if using the 6MW test as the primary endpoint in future trials, one should consider documentation of the presence of these factors and use a stratified randomization based on a composite of these non-cardiopulmonary variables. Disclosures: Hassell: NIH:. Gladwin:Patents filed related to treating hemolysis.: Patents & Royalties.

The benefits of humor in reducing anxiety were investigated in a laboratory study, in which subjects were falsely led to believe they would receive a shock in 12 min. Participants were 53 undergraduate students with either high or low sense of humor as measured by the Situational Humor Response Questionnaire of Martin and Lefcourt (1984). During the anticipatory period, subjects listened to either a humorous tape, a nonhumorous tape, or no tape. Dependent variables were repeated measures of self-reported anxiety, heart rate, and zygomatic facial activity. Anxiety increased over the anticipatory period, as predicted. A significant interaction between condition and time indicated that subjects from the humor condition consistently rated themselves as less anxious and reported less increase in stress as the shock approached. A three-way interaction concentrating on the final 3 min. indicated a tendency for subjects with low sense of humor to have higher heart rates in the no-tape condition than in the humorous or nonhumorous tape conditions. Analysis for zygomatic activity indicated more smiling by subjects with high sense of humor and by subjects in the humor condition. Also, the humorous tape elicited more smiling by subjects with high sense of humor.

Abstract 571 Background: Pulmonary hypertension (PH) is associated with increased mortality in patients with sickle cell disease (SCD). Methods: Walk-PHaSST (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) is a multi-center (10 United States and United Kingdom Centers), placebo-controlled, double-blind 16-week trial evaluating the safety and efficacy of oral sildenafil for the treatment of Doppler-defined PH (tricuspid regurgitant jet velocity [TRV] ≥2.7m/s) in adults and children (aged >12 years) with SCD. The primary endpoint was the six-minute walk distance (6MWD). The study was designed with a planned screening of approximately 1000 subjects, to enroll 132 subjects for inclusion in the nested Main Interventional Trial (MIT). In the screening trial, subjects were evaluated by history and physical examination, laboratory screening, transthoracic Doppler echocardiography and 6MWD. Randomized subjects were stratified by TRV (2.7-2.9 m/s and ≥3.0 m/s), and those in upper strata underwent a right heart catheterization (RHC). Preliminary Results: Of the 722 screened subjects, 150 (26%) had both a TRV ≥2.7 m/s AND 6MWD of 150-500 meters (m), qualifying for MIT enrollment. A total of 74 subjects (13%) were randomized into the MIT. The study was prematurely stopped due to a statistically significant increase in serious adverse events (SAEs) in the sildenafil arm after 33 subjects had completed the 16 week assessments and 74 subjects (37 sildenafil: 23 female, 47 ± 12 years, TRV 3.0 ± 0.4 m/s, 6MWD 378 ± 93 m; 37 placebo: 23 female, 44 ± 14 years, TRV 2.9 ± 0.3 m/s, 6MWD 381 ± 75 m) had been randomized in the MIT. To evaluate safety and efficacy, all 74 subjects were evaluated, with pre-defined primary and secondary endpoint analysis and imputation rules for missing data. Baseline gender, hemoglobin phenotype, TRV and 6MWD were similar between sildenafil and placebo (all p>0.05). There was a significant increase in SAEs in the sildenafil arm (46% vs. 22% of randomized subjects; p=0.048) but no significant difference in adverse events (AEs; 76% vs. 68%; p=0.607). Sickle cell anemia with crisis (hospitalization defining the SAE) accounted for the significant difference in SAEs (35% vs. 11%; p=0.025). In reference to AEs, patients on sildenafil tended to have more headache (27% vs. 14%; p=0.247) and more blurred vision (11% vs. 3%; p=0.358). No other SAEs or AEs by organ system or preferred term were significantly different (all p > 0.43). There were no AEs classified as life-threatening and there was one death in the placebo arm. To assess potential efficacy, all 33 subjects with TRV of ≥3.0 m/s underwent RHC and received a single test dose of 60 mg of sildenafil; data are currently availabel for 22 of those subjects. Although this dose of sildenafil acutely decreased mean pulmonary arterial pressure (p=0.01), and mean systemic arterial pressure (p Preliminary Conclusions: In conclusion, sildenafil significantly increased rates of VOCs requiring hospitalization vs. placebo. The premature study termination for safety concerns limited the sample size for efficacy assessments; however, further investigation may be warranted in a more select group of patients with optimized hydroxyurea and transfusion therapy. Based on the completed analyses, no relationship has been established between experiencing pain (via serious VOC) and 6MWD. Additional analyses will focus on determining whether pain (as measured by BPI) is correlated with change in 6MWD. Finally, these data suggest a potential role for the cyclic cGMP axis in the pathobiology of VOC and sickle cell disease related pain. Disclosures: Barst: Pfizer: Consultancy, Research Funding. Gibbs:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Girgis:Pfizer: Research Funding. Badesch:Pfizer: Consultancy, Research Funding.

Two studies used a thought-listing technique to examine perceived superiority, or the inclination to regard one's own relationship as better than (and not as bad as) others' relationships. Consistent with the claim that this is a motivated phenomenon-and motivated in part by strong commitment-Study 1 revealed that (a) tendencies toward perceived superiority and (b) the commitment-superiority link are both strongest given psychologically threatening instructions and weakest given accuracy instructions (control instructions are intermediate). Consistent with the claim that this phenomenon serves a functional purpose, Study 2 revealed that earlier perceived superiority predicts later relationship status (persisted vs. ended) and increases over time in dyadic adjustment. Also, commitment accounts for unique variance in perceived superiority beyond self-esteem.