Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients

Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre–formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%–97%) and 6250 (5000–10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14–0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037.     

Distal rectus femoris surgery in children with cerebral palsy: results of a Delphi consensus project

PurposeThe purpose of this study was for an international panel of experts to establish consensus indications for distal rectus femoris surgery in children with cerebral palsy (CP) using a modified Delphi method.MethodsThe panel used a five-level Likert scale to record agreement or disagreement with 33 statements regarding distal rectus femoris surgery. The panel responded to statements regarding general characteristics, clinical indications, computerized gait data, intraoperative techniques and outcome measures. Consensus was defined as at least 80% of responses being in the highest or lowest two of the five Likert ratings, and general agreement as 60% to 79% falling into the highest or lowest two ratings. There was no agreement if neither threshold was reached.ResultsConsensus or general agreement was reached for 17 of 33 statements (52%). There was general consensus that distal rectus femoris surgery is better for stiff knee gait than is proximal rectus femoris release. There was no consensus about whether the results of distal rectus femoris release were comparable to those following distal rectus femoris transfer. Gross Motor Function Classification System (GMFCS) level was an important factor for the panel, with the best outcomes expected in children functioning at GMFCS levels I and II. The panel also reached consensus that they do distal rectus femoris surgery less frequently than earlier in their careers, in large part reflecting the narrowing of indications for this surgery over the last decade.ConclusionThis study can help paediatric orthopaedic surgeons optimize decision-making for, and outcomes of, distal rectus femoris surgery in children with CP.Level of evidenceV     

The Effects of Race,Socioeconomic Status,and Household Structure on Injury Mortality in Children and Young Adults

Objectives: Injuries are the leading killer of young persons in the United States, yet significant gaps in our understanding of this cause of death remain. By examining the independent influences of race, education, income, household structure, and residential location on injury mortality in young persons, this study addresses these gaps. Method: Using data from the National Longitudinal Mortality Study, survival analysis is used to examine the injury mortality risk faced by 0 to 17 year olds over a nine-year follow-up period. Separate models are estimated for homicide, suicide, unintentional injury deaths, and all injury deaths. Results: Household head's education has an independent effect on youth homicide and unintentional injury mortality risk. By contrast, family income and household structure do not have independent effects on any of the injury outcomes. Finally, much of the excess homicide risk faced by young African-Americans is explained by underlying racial differentials in socioeco-nomic status, household structure, and residential location. Conclusions: By finding an independent effect of household head's education on youth mortality risk from homicide and unintentional injuries, this study adds to the large body of evidence linking socioeconomic differentials to inequality in life chances.     

Testicular Trauma: Potential Impact on Reproductive Function

Purpose

The long-term effects of testicular trauma on reproductive function are unknown. In an effort to define the relationship between testicular injury and fertility in humans, we identified patients with a history of testicular trauma and assessed parameters commonly associated with fertility.

Materials and Methods

We reviewed 15 patients 23 to 59 years old who underwent immediate exploration after testicular trauma between 1972 and 1991. Of the patients 11 were contacted and 8 returned for prospective followup. Reproductive and sexual histories, physical examination, measurements of serum hormones and antisperm antibodies, semen analysis and scrotal ultrasound were done.

Results

Of the 8 patients 1 (13 percent) achieved and 7 (87 percent) did not attempt conception. Hormonal status was normal in all 8 patients. Six men had objective evidence of subfertility by semen analysis only, although none had severe oligospermia or asthenospermia and only 1 had severe teratospermia. Five of 9 traumatized testes were atrophic. Interestingly, only 1 patient had antisperm antibodies, the levels of which were probably low enough to be clinically insignificant.

Conclusions

There was definite evidence of subfertility as assessed by abnormal semen analyses and atrophic testes following testicular trauma. However, the subfertility did not appear to be immune mediated nor did the patients present with infertility. Since only 1 patient had severely compromised fertility according to semen analysis we conclude that early repair can help preserve hormonal function as well as fertility.     

Barriers to follow‐up of abnormal screening mammograms among low‐income minority women

Objective. To describe factors related to compliance diagnostic follow‐up among minority women of low socioeconomic status with abnormal screening mammograms.

Methods. A retrospective cross‐sectional survey using a structured telephone interview. Three cancer screening clinics at an urban inner‐city public hospital. All women with abnormal screening mammograms between September 1990 and January 1992 were eligible; women were interviewed in August 1992. Abnormal mammograms were those requiring specific, non‐routine clinical follow‐up; non‐compliance was defined as delayed follow‐up (four to six months after the date of the mammogram), or no follow‐up at the time of interview (more than 6 months after abnormal).

Results. Sixty‐two of 442 screened women had abnormal results; the overall rate of non‐compliance with follow‐up was 50%. Among the 42 (68%) women who agreed to be interviewed, non‐compliers were less likely to state that they had been told to receive follow‐up than compilers (65% versus 100%; p = 0.008). Non‐compliant women were less likely to have suspicious mammography interpretations (p = 0.05), and more likely to report barriers to follow‐up, such as cost of lost wages and medical care, system barriers, or fears, than compliant women (61.9% versus 9%, p = 0.01). There were no differences between the two groups for age, education, insurance, source of care, family history, knowledge or attitudes.

Conclusions. These preliminary results suggest that follow‐up of low income, minority women with abnormal screening mammograms could be enhanced by improved communication of results. Future studies should extend these findings with larger samples and in other settings and populations.     

Contaminated sediments from tributaries of the Great Lakes: Chemical characterization and carcinogenic effects in medaka (Oryzias latipes)

Sediments from four inshore industrial sites and a reference site in the Great Lakes were extracted with organic solvents to produce a crude extract, which was separated on alumina into two fractions: predominantly polycyclic aromatic hydrocarbons; and predominantly nitrogencontaining polycyclic aromatic compounds. Crude extracts were redissolved in acetone and analyzed by gas chromatography and gas chromatography-mass spectrometry. The acetone-redissolved crude extracts from the four industrialized sites contained 5.6–313.3 g total polycyclic aromatic compounds/g sediment and 3.0–36.4 g other compounds/g sediment. In addition to the typical EPA priority pollutants, a substantial amount (228.7 g/g sediment) of alkyl-polycyclic-aromatic compounds was detected in sediments from one of the industrialized sites. Extracts from the reference site contained 1.55 g total polycyclic aromatic compounds/ g sediment. Medaka (Oryzias latipes) were exposed to multiple pulse doses of acetone-redissolved extracts and fractions. Medaka were also exposed to a known carcinogen, methylazoxymethanol acetate, to verify that chemicals produced tumors in the test fish. Acetone-redissolved extracts and fractions from contaminated sediments were toxic to medaka. Fin erosion and non-neoplastic liver abnormalities were more prevalent in medaka after exposure to acetoneredissolved extracts and fractions from contaminated sediments. Neoplasms previously associated with chemical exposure in wild fishes were induced in medaka exposed to acetone-redissolved extracts and fractions from two of the contaminated sites, but not from the reference site or controls. These findings further support the hypothesis that chemical contaminants in sediments are involved in epizootics of neoplasms in wild fishes at contaminated sites.     

Physiological responses to high radiant heat exposure

The physiological responses to four levels of radiant heat (R) in combination with two work loads and three ambient humidity levels were studied on seven clothed young men. The globe temperature (t_g) ranged from 40 to 74°C; metabolic work load (M) was either 20 or 50% of maximal aerobic capacity (V?₀₂ max); ambient vapor pressure was either 13 or 23 mm Hg; and dry-bulb temperature (t_db) was 38 or 49°C. The criteria for heat strain were the changes in rectal temperature (T_re), mean skin temperature (T_sk), heart rate (HR), and sweating (Sw). Stress was defined by the calculated heat load requiring dissipation (M + R + C = E_req), the ambient evaporative capacity (E_max), and the skin wettedness (w), defined as the ratio of E_req/E_max. The progressive increase in R resulted in a concomitant rise of T_re and HR reflecting the physiological strain. Similarly the increase in either M or in the humidity resulted in higher T_re and HR. The changes in R or E_max were best defined by the w, thus w and the physiological responses were highly correlated. For practical application a multiple regression of the increments of HR(ΔHR) on t_db above neutral (25°C) and on t_g above t_db was derived as follows:

$\text{△HR}{}_{\mathrm{<mtext>bpm</mtext>}}\text{= 0.96(t}{}_{\mathrm{<mtext>db</mtext>}}\text{? 25°}\text{C}\text{) + 0.81(t}{}_{\mathrm{g}}\text{? t}{}_{\mathrm{db}}\text{) ? 1}$

It was concluded that the calculated skin wettedness is most suitable in the evaluation of heat stress.     

Role of neutrophils in the synergistic liver injury from monocrotaline and bacterial lipopolysaccharide exposure.

Synergistic liver injury develops in Sprague-Dawley rats from administration of a small, noninjurious dose (7.4 x 10(6) EU/kg) of bacterial lipopolysaccharide (LPS) given 4 h after a nontoxic dose (100 mg/kg) of the pyrrolizidine alkaloid, monocrotaline (MCT). Previous studies demonstrated that liver injury is mediated through inflammatory factors, such as Kupffer cells and tumor necrosis factor alpha (TNF-alpha), rather than through simple interaction between MCT and LPS. In the present study, the hypothesis that neutrophils (polymorphonuclear leukocytes or PMNs) are causally involved in this injury model is tested, and the interdependence between PMNs and other inflammatory components is explored. Hepatic PMN accumulation and the appearance of cytokine-induced neutrophil chemoattractant-1 in plasma preceded the onset of liver injury, suggesting that PMNs contribute to toxicity. Hepatic PMN accumulation was partially dependent on TNF-alpha. Prior depletion of PMNs in MCT/LPS-cotreated animals resulted in attenuation of both hepatic parenchymal cell (HPC) and sinusoidal endothelial cell (SEC) injury at 18 h. PMN depletion did not, however, protect against early SEC injury that occurred before the onset of HPC injury at 6 h. This observation suggests that SEC injury is not entirely dependent on PMNs in this model. In vitro, MCT caused PMNs to degranulate in a concentration-dependent manner. These results provide evidence that PMNs are critical to the HPC injury caused by MCT/LPS cotreatment and contribute to the progression of SEC injury.