Correlated neurocardiologic and fitness changes in athletes interrupting training

PURPOSE: We studied nine male Dutch top marathon skaters during a 1-month interruption of their training schedules after their last contest in the winter to investigate a possible decline in baroreflex sensitivity. METHODS: Before and after this period, a maximal exercise test was done, and at days 0, 4, 7, 14, and 28 neurocardiologic measurement sessions--heart rate and noninvasive baroreflex sensitivity, recumbent and tilt--were performed. RESULTS: Interruption of training resulted in a significant and relevant decrease in the maximal oxygen uptake (from 65.7 +/- 5.8 to 61.6 +/- 4.7 mL O2 x kg(-1) x min(-1); P = 0.03), most likely associated with decreased competitive possibilities. Resting heart rate modestly increased (from 54.6 +/- 7.2 to 58.8 +/- 7.5 bpm), however, not significantly. Heart rate during 60 degrees tilt increased considerably (from 70.1 +/- 6.1 to 80.1 +/- 9.1 bpm; P = 0.01), possibly due to a decrease in blood volume and an increase in cardiopulmonary baroreflex gain. Arterial baroreflex sensitivity decreased significantly in the recumbent (from 13.3 +/- 5.4 to 9.8 +/- 3.8 ms x mm Hg(-1), P = 0.04), but not in the 60 degrees tilt position (from 6.7 +/- 2.0 to 6.0 +/- 2.5 ms x mm Hg(-1)). The relative decrease in baroreflex sensitivity and maximal oxygen uptake correlated significantly (r = 0.71, P = 0.02). CONCLUSIONS: In summary, our data show that correlated detrimental changes in fitness and baroreflex sensitivity are measurable in these athletes after a month of interruption of training.     

Effectiveness of quetiapine in rapid cycling bipolar disorder: a preliminary study

OBJECTIVE: The authors examined long-term effectiveness and study retention during open-label quetiapine treatment for rapid cycling bipolar disorder. METHODS: An open-label, nonrandomized trial was conducted in 41 patients with rapid-cycling bipolar disorder (type I=33, type II=7, NOS=1) who received flexibly dosed quetiapine monotherapy (n=19) or add-on therapy (n=22) for up to one year. Linear growth curves were calculated to assess longitudinal changes in depression and mania. RESULTS: Linear growth curves demonstrated highly significant reductions in manic (p<.0001) and depressive (p<.0001) symptoms. Effect sizes were large against manic symptoms (add-on therapy: Cohen's d=0.66; monotherapy: Cohen's d=0.75) but small-to-moderate against depression (monotherapy: d=0.29; add-on therapy: d=0.40). Most patients (68%) prematurely terminated the protocol (mean duration: 18.0+/-16.9 weeks, mean dose: 195.6+/-196.1 mg/day), most often because of the need for additional psychotropic treatments. LIMITATIONS: The study protocol involved an open label design with no placebo or active comparator group. The sample size provided adequate statistical power to detect large but not medium or small within-group effects. Premature dropout during the first six months precluded inferences about longer-term treatment outcome. CONCLUSIONS: These observational findings provisionally suggest some benefit with quetiapine for both manic and depressive symptoms in rapid cycling bipolar disorder, at dosages somewhat lower than previously described either for mania or bipolar depression. The relatively high dropout rate underscores the complexity of rapid cycling bipolar disorder and likely necessity for pharmacotherapy adjustments over time.     

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

Germline mutations in checkpoint kinase 2 (CHEK2), a multiple cancer-predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially in published studies. We analyzed germline CHEK2 variants in 1,928 high-risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population-matched controls (PMCs). For a functional classification of VUS, we developed a complementation assay in human nontransformed RPE1-CHEK2-knockout cells quantifying CHK2-specific phosphorylation of endogenous protein KAP1. We identified 10 truncations in 46 (2.39%) patients and in 11 (0.33%) PMC (p = 1.1 × 10⁻¹⁴). Two types of large intragenic rearrangements (LGR) were found in 20/46 mutation carriers. Truncations significantly increased unilateral BC risk (OR = 7.94; 95%CI 3.90–17.47; p = 1.1 × 10⁻¹⁴) and were more frequent in patients with bilateral BC (4/149; 2.68%; p = 0.003), double primary BC/OC (3/79; 3.80%; p = 0.004), male BC (3/48; 6.25%; p = 8.6 × 10⁻⁴), but not with OC (3/354; 0.85%; p = 0.14). Additionally, we found 26 missense VUS in 88 (4.56%) patients and 131 (3.90%) PMC (p = 0.22). Using our functional assay, 11 variants identified in 15 (0.78%) patients and 6 (0.18%) PMC were scored deleterious (p = 0.002). Frequencies of functionally intermediate and neutral variants did not differ between patients and PMC. Functionally deleterious CHEK2 missense variants significantly increased BC risk (OR = 3.90; 95%CI 1.24–13.35; p = 0.009) and marginally OC risk (OR = 4.77; 95%CI 0.77–22.47; p = 0.047); however, carriers low frequency will require evaluation in larger studies. Our study highlights importance of LGR detection for CHEK2 analysis, careful consideration of ethnicity in both cases and controls for risk estimates, and demonstrates promising potential of newly developed human nontransformed cell line assay for functional CHEK2 VUS classification.     

Amiodarone-associated Optic Neuropathy—A Clinical Criteria–based Diagnosis?

Amiodarone-associated optic neuropathy (AAON) is a controversial diagnosis with possible impact on vital cardiac therapy decisions. This retrospective case series aims for application of distinguishing features of AAON versus non-arteritic ischaemic optic neuropathy (NAION): Bilaterality, mode of onset, degree of optic nerve dysfunction, structure of uninvolved disc (unilateral cases), and systemic toxic effects. Applying these criteria to patients with disc swelling under amiodarone, the authors identified four unilateral disc swellings, one with NAION-typical features only and three with one or more NAION-atypical features. All three sequential and six bilateral cases showed one or more NAION-atypical features. The 12 cases highlight the persisting diagnostic dilemma arising from diversity of presentation, lack of plausible pathomechanism, and controversial existence of the entity itself.     

Vaccine-induced immunity in children after orthotopic liver transplantation: a 12-yr review of the Swiss national reference center

Infections represent a significant threat in solid-organ recipients. However, a certain number of infections can be prevented by immunizing patients before their transplantation. The aim of this study is to determine the level of immunity of children undergoing liver transplantation and to assess their capacity to maintain protective levels after surgery. Charts of 44 children transplanted with deceased donation livers between 1990 and 2002 at the Children's Hospital of Geneva were reviewed. Vaccine antibody responses were established pre- and post-transplantation. Only 43% of patients were up to date for diphtheria, tetanus, acellular pertussis, and polio vaccines at the pretransplantation visit, while 44% of children older than 12 months had received their required measles-mumps-rubella vaccines. Six of 44 children had received at least one dose of hepatitis B vaccine, while only two patients had received at least one dose of hepatitis A vaccine. After immunization, and one yr after transplantation, only 14 of 44 patients had detectable anti-HBs antibodies and seven of 18 had anti-HAV antibodies. Varicella antibodies were undetectable in 15 of 19 patients immunized prior to transplantation. This study highlights the need to enforce vaccination before transplantation, follow-up on vaccine- induced immunity, and adapt vaccination schedules after liver transplantation in children, especially for non-live vaccines, which are universally recommended in this population.     

The effects of sleep loss and fatigue on resident-physicians: a multi-institutional, mixed-method study.

PURPOSE: To identify and model the effects of sleep loss and fatigue on resident-physicians' professional lives and personal well-being. METHOD: In 2001-02, 149 residents at five U.S. academic health centers and from six specialties (obstetrics-gynecology, emergency medicine, family medicine, internal medicine, pediatrics, surgery) were recruited for the study. Residents were all in good standing in their programs. In a mixed-methods design, focus groups consisted of an average of seven (range, three to 14) individuals in the same year of training and residency program, for a total of 60 interns and 89 senior residents. Trained moderators conducted focus groups using a standardized, semistructured discussion guide. Participants also completed a 30-item quantitative questionnaire assessing sleepiness and workplace sleep attitudes that included the Epworth Sleepiness Scale (ESS). RESULTS: Residents described multiple adverse effects of sleep loss and fatigue on learning and cognition; job performance, including professionalism and task performance; and personal life, including personal well-being and relationships with spouse or significant other and family. Only 16% of the sample scored within the "normal" range on the ESS; 84% scored in the range for which clinical intervention is indicated. Sleepiness was consistent across institution, specialty, years of training, age, gender, marital status, and having children. CONCLUSIONS: More residents perceived that sleep loss and fatigue had major impact on their personal lives during residency, leaving many personal and social activities and meaningful personal pleasures deferred or postponed. Sleep loss and fatigue also had major impact on residents' abilities to perform their work. This finding further substantiates the growing concern about the potential impact on professional development. These observations should be taken into account in developing new training guidelines and educational interventions for housestaff.     

Reduced length-dependent cross-bridge recruitment in skinned fiber preparations of human failing myocardium

A depressed activity of myosin ATPase has been described in human failing myocardium. Since alterations in cross-bridge kinetics may affect both systolic and diastolic cardiac function, the present study simultaneously investigated Ca²⁺-dependent tension and actomyosin ATPase activity (MYO) in triton X-skinned fiber preparations of human non-failing (donor hearts, n=8) and failing (dilated cardiomyopathy, n=11) left ventricular myocardium at increasing sarcomeric length (1.9 and 2.1 μm, α-actinin staining). The MYO/tension ratio was analyzed as a parameter characterizing myofibrillar energetics. At a sarcomere length of 1.9 μm, the Ca²⁺ sensitivity of tension was significantly increased in human failing compared to non-failing myocardium. In human non-failing myocardium, maximal Ca²⁺-activated tension [1.9 μm vs. 2.1 μm, 23.7 (1.9) vs. 28.3 (1.9) mN/mm²] and the Ca²⁺ sensitivity of tension [EC₅₀Ca²⁺ (pCa): 5.67 (0.06) vs. 7.07 (0.11)] were increased by increasing sarcomere length. This was accompanied by an enhancement in Ca²⁺-dependent MYO [+72 (11) vs. +101 (9) μM ADP/s] as well as an increase in the Ca²⁺-sensitivity of MYO [EC₅₀Ca²⁺ (pCa): 5.84 (0.08) vs. 6.86 (0.08)]. In human failing myocardium, only Ca²⁺ sensitivity of tension (but not of MYO) increased. Tension cost was increased in failing vs. non-failing tissue [1.9 μm: 4.18 (0.06) vs. 3.53 (0.06) (mN·s)/(mm²·μM ADP); 2.1 μm: 4.28 (0.13) vs. 3.52 (0.05) (mN·s)/(mm²·μM ADP)]. We concluded that, in human failing myocardium, the length-dependent force generation may be blunted due to an already increased Ca²⁺ affinity of troponin C as well as an impairment of length-dependent cross-bridge recruitment. Electronic Publication     

Unchanged sarcoplasmic reticulum Ca2+-ATPase activity, reduced Ca2+ sensitivity, and negative force-frequency relationship in transgenic rats overexpressing the mouse renin gene

Transgenic rats overexpressing the mouse Ren-2 gene [TG(mREN2)27 rats, TGR] were used to characterize alterations in force generation and relaxation following cardiac hypertrophy. Age-matched Sprague-Dawley rats were used as the control group. The β-adrenoceptor dependent increase in force of contraction was reduced in the transgenic animals but not the Ca²⁺-dependent increase in force generation. Additionally, force of contraction decreased after increasing stimulation frequencies (up to 7 Hz), but the frequency-dependent decrease in force of contraction was significantly more pronounced in the transgenic group. The Ca²⁺ sensitivity in chemically skinned fiber preparations of TGR was reduced than that in Sprague-Dawley rats while maximum effectiveness was the same. Unexpectedly, the sarcoplasmic reticulum Ca²⁺-ATPase activity measured in crude membrane preparations from TGR did not differ from that in Sprague-Dawley rats; however, the activity of the Na⁺/K⁺-ATPase was less while the Na⁺/Ca²⁺-exchanger activity was significantly greater. In the same preparations the protein expression of SERCA2 was reduced in TGR while expression of phospholamban and calsequestrin remained the same. Thus in the model of cardiac hypertrophy harboring the mouse Ren-2 gene the hypothesized correlation between SERCA2 function and force-frequency relationship was not observed. Possible reasons for the more negative force-frequency relationship in TGR included changes at the level of the myofilaments and altered intracellular Na⁺ homeostasis which may result from the reciprocal changes in the Na⁺/K⁺-ATPase and the Na⁺/Ca²⁺-exchanger activity. Received: 15 September 1997 / Accepted: 7 April 1998     

Mesenchymal stem cells induce endothelial activation via paracine mechanisms.

Mesenchymal stem cells (MSCs) are bone marrow-derived, pluripotent cells that possess the ability to transdifferentiate into various mesenchymal tissues such as bone, endothelium, and (heart) muscle. Therefore, these cells may provide a therapeutic tool, especially for the treatment of myocardial infarction. The interaction of the MSCs with the endothelial barrier and their ability to ultimately leave blood vessels after application are crucial in this context. In this study, the authors focused on the soluble factors produced by MSCs and their effect on the intracellular signal transduction of endothelial cells. The authors performed immunohistochemical measurements on human umbilical vein endothelial cells (HUVECs) treated with conditioned stem cell medium and took measurements of the intracellular nitric oxide (NO) levels and calcium changes. After application of conditioned stem cell medium, the authors detected an increase in endothelial NO synthase (eNOS) activity by translocation (Ca(2+)) and by phosphorylation (increase of pAKT and peNOS1177). Additionally, the authors observed an upregulation of pERK within the same time. The phosphorylated eNOS forms are linked to these findings and the increase of intracellular NO in the DAF measurements. Moreover, conditioned medium also increased intracellular calcium levels in endothelial cells. Concluding, the authors postulate that MSCs emit soluble factors that alter the NO and calcium levels of endothelial cells and may be important for facilitate crossing the endothelial barrier.     

Live vaccines after pediatric solid organ transplant: Proceedings of a consensus meeting, 2018

Growing evidence suggests receipt of live‐attenuated viral vaccines after solid organ transplant (SOT) has occurred and is safe and needed due to lapses in herd immunity. A 2‐day consortium of experts in infectious diseases, transplantation, vaccinology, and immunology was held with the objective to review evidence and create expert recommendations for clinicians when considering live viral vaccines post‐SOT. For consideration of VV and MMR post‐transplant, evidence exists only for kidney and liver transplant recipients. For MMR vaccine post‐SOT, consider vaccination during outbreak or travel to endemic risk areas. Patients who have received antiproliferative agents (eg. mycophenolate mofetil), T cell–depleting agents, or rituximab; or have persistently elevated EBV viral loads, or are in a state of functional tolerance, should be vaccinated with caution and have a more in‐depth evaluation to define benefit of vaccination and net state of immune suppression prior to considering vaccination. MMR and/or VV (not combined MMRV) is considered to be safe in patients who are clinically well, are greater than 1 year after liver or kidney transplant and 2 months after acute rejection episode, can be closely monitored, and meet specific criteria of “low‐level” immune suppression as defined in the document.