Recombinant human erythropoietin attenuates weight loss in a murine cancer cachexia model

Background Within hypoxic tumor regions anaerobic dissimilation of glucose is the sole source of energy generation. It yields only 5% of the ATP that is normally gained by means of oxidative glucose catabolism. The increased need for glucose may aggravate cancer cachexia. We investigated the impact of recombinant human erythropoietin (RhEPO) and increased inspiratory oxygen concentrations on weight loss in tumor-bearing mice.Methods Fragments of the murine C26-B adenocarcinoma were implanted in 60 BALB/c-mice. The mice were divided into four groups and assigned to: (A) no treatment; (B) RhEPO- administration (25 IU daily from day 1–11, three times per week from day 12); (C) RhEPO and 25% oxygen; and (D) RhEPO and 35% oxygen. Three control groups of four healthy mice each received the same treatment as groups A, B, and D, respectively. Hematocrit and hemoglobin levels, tumor volume, and body weight were monitored. At day 17 the experiment was terminated and the serum lactate concentration was measured. The tumors were excised and weighed and, for each mouse, the percentage weight loss was calculated. The impact of tumor weight and the treatments on lactate concentration and weight loss was evaluated.Results Significant positive correlations were found between tumor weight and lactate concentration and between tumor weight and percentage weight loss. In the mice with the largest tumors, RhEPO displayed a significant weight loss-reducing effect, and a significant negative correlation was found between hemoglobin concentration and weight loss. An oxygen-rich environment did not appear to influence weight loss.Conclusion Anaerobic glycolysis in a growing C26-B tumor is related to weight loss. RhEPO administration results in a reduction of the percentage weight loss; this effect is probably mediated by an increased hemoglobin concentration.This study was financially supported by a grant from Ortho Biotech, a division of Janssen Cilag, Tilburg, the Netherlands     

Successful treatment of COVID-19 infection with convalescent plasma in B-cell-depleted patients may promote cellular immunity

Treatment with convalescent plasma has been shown to be safe in coronavirus disease in 2019 (COVID-19) infection, although efficacy reported in immunocompetent patients varies. Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody-producing B cells, such as those treated with rituximab (anti-CD20) for hematological malignancies, lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analyzed clinical course and inflammation markers of three B-cell-depleted patients suffering from COVID-19 who were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA-DR-positive T-cells ex vivo and CD137-positive T-cells after in vitro stimulation with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137-positive T-cells after stimulation with SARS-CoV-2 peptides showed an increase in peptide-specific T-cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B-cell-depleted patients and present data that suggest that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T-cell responses.     

Survival, but not maturation, is affected in neutrophil progenitors from GSD-1b patients

Glycogen storage disease type 1b (GSD 1b) is caused by mutations in the Glucose-6-phosphate transporter and is characterized by impaired glucose homeostasis. In addition, GSD-1b is associated with chronic neutropenia resulting in recurrent infections and inflammatory bowel disease. It is unclear whether the neutropenia is solely due to enhanced apoptosis of mature neutrophils or whether aberrant neutrophil development may also contribute. Here we demonstrate that hematopoietic progenitors from GSD-1b patients are not impaired in their capacity to develop into mature neutrophils. However, optimal survival of neutrophil progenitors from GSD-1b patients requires high glucose levels (> 200 mg dl⁻¹), suggesting that even under normoglycemic conditions these cells are more prone to apoptosis. Furthermore, analysis of cytokine levels in peripheral blood suggests an inflammatory state with an inverse correlation between the level of inflammation and the number of neutrophils. Finally, in some patients, with low numbers of peripheral blood neutrophils, high numbers of neutrophils were observed in the intestine. Together, these results suggest that the neutropenia observed in GSD-1b patients is not caused by impaired maturation, but may be caused by both increased levels of apoptosis and egress of neutrophils from the blood to the inflamed tissues.     

Long-term outcome of kidney transplantation in patients with a urinary conduit: a case–control study

Purpose

To study the short- and long-term outcomes of kidney transplantation in patients with a bladder augmentation or urinary diversion compared to patients with a kidney transplantation in a normal functional bladder.

Patients and methods

Between January 2000 and March 2011, 13 patients received 16 grafts into a reconstructed urinary tract. We performed a retrospective case–control study and matched each patient to 4 controls for donor and recipient gender and year of transplantation.

Results

Short- and long-term complications of kidney transplantation occurred in 12 patients, varying from urinary tract infections to medical hospitalization with or without surgical or radiological intervention. In 5 patients, a percutaneous nephrostomy (PCN) was placed followed by surgical re-intervention. In three patients, the grafts failed as a result of chronic rejection and were re-transplanted. There was no graft loss as a result of surgical complications or the reconstructed urinary tract. One-year patient and graft survival was 100 %. After five years, all patients were alive and seven of nine grafts (77.8 %) were functioning. Mean follow-up time was 4.3 years. Among the controls, 55 grafts were transplanted in 52 patients. Ten patients received a PCN. Five patients needed surgical re-intervention. In three patients, transplantectomy was performed for ongoing rejection. Three patients were re-transplanted. One patient had a failing graft 7.5 years post-transplantation and became dialysis dependent.

Conclusion

Kidney transplantation in patients with a reconstructed urinary tract has an increased complication rate. Nevertheless, the long-term results are comparable to patients with a normal urinary bladder.     

Self‐regulatory skills: Are they helpful in the prevention of overuse injuries in talented tennis players?

Talented athletes use metacognitive skills to improve their performance. Also, it is known that these skills are important for managing one's health. The goal of this study was to identify the relationship between metacognitive skills and overuse injuries in talented tennis players. Metacognitive skills were measured in 73 talented tennis players (45 boys and 28 girls, age 11‐14) at the start of the season, using the Self‐Regulation of Learning Self‐Report Scale. Overuse injuries were monitored for one season using the Oslo Sports Trauma Research Centre Questionnaire on Health Problems. Ordinal regression indicated that moderate or low selfmonitoring skills (compared to high selfmonitoring) (OR 4.555, CI 1.096‐18.927, P = 0.037) and exposure time (OR 1.380, CI 1.106‐1.721, P = 0.004) were associated with more time loss overuse injuries. A second analysis showed that this was the case in girls (OR 10.757, CI 1.845‐62.714, P = 0.008), but not in boys. Linear regression revealed that higher reflection scores and exposure time predicted overuse severity (F(5,58) = 2.921, P = 0.020, R² = 0.201). Possibly, selfmonitoring can help players to prevent themselves from time loss overuse injuries. Coaches should be aware that players can differ in selfmonitoring ability and thus in the ability to prevent overuse injuries. The role of reflection needs more research.     

Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized,Double-Blind Primary Endpoint

ObjectivePublished reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease.Materials and MethodsParticipants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life.ResultsThe study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs 21.2% (41/193) who preferred the omnidirectional period.ConclusionDirectional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.     

A diagnostic study in patients with sciatica establishing the importance of localization of worsening of pain during coughing,sneezing and straining to assess nerve root compression on MRI

Purpose

To test whether the localization of worsening of pain during coughing, sneezing and straining matters in the assessment of lumbosacral nerve root compression or disc herniation on MRI.

Methods

Recently the diagnostic accuracy of history items to assess disc herniation or nerve root compression on magnetic resonance imaging (MRI) was investigated. A total of 395 adult patients with severe sciatica of 6–12 weeks duration were included in this study. The question regarding the influence of coughing, sneezing and straining on the intensity of pain could be answered on a 4 point scale: no worsening of pain, worsening of back pain, worsening of leg pain, worsening of back and leg pain. Diagnostic odds ratio’s (DORs) were calculated for the various dichotomization options.

Results

The DOR changed into significant values when the answer option was more narrowed to worsening of leg pain. The highest DOR was observed for the answer option ‘worsening of leg pain’ with a DOR of 2.28 (95 % CI 1.28–4.04) for the presence of nerve root compression and a DOR of 2.50 (95 % CI 1.27–4.90) for the presence of a herniated disc on MRI.

Conclusions

Worsening of leg pain during coughing, sneezing or straining has a significant diagnostic value for the presence of nerve root compression and disc herniation on MRI in patients with sciatica. This study also highlights the importance of the formulation of answer options in history taking.