Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO‐incompatible pancreas and kidney transplantation

Summary We describe the presumably first intentional ABO‐incompatible deceased‐donor kidney and pancreas transplantation with a severe antibody‐mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement‐related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.     

Management of degenerative disk disease and chronic low back pain

Degenerative disk disease is a strong etiologic risk factor of chronic low back pain (LBP). A multidisciplinary approach to treatment is often warranted. Patient education, medication, and cognitive behavioral therapies are essential in the treatment of chronic LBP sufferers. Surgical intervention with a rehabilitation regime is sometimes advocated. Prognostic factors related to the outcome of different treatments include maladaptive pain coping and genetics. The identification of pain genes may assist in determining individuals susceptible to pain and in patient selection for appropriate therapy. Biologic therapies show promise, but clinical trials are needed before advocating their use in humans.     

Transplanted L1 expressing radial glia and astrocytes enhance recovery after spinal cord injury

A major obstacle for the transplantation of neural stem cells (NSCs) into the lesioned spinal cord is their predominant astrocytic differentiation after transplantation. We took advantage of this predominant astrocytic differentiation of NSCs and expressed the paradigmatic beneficial neural cell adhesion molecule L1 in radial glial cells and reactive and nonreactive astrocytes as novel cellular vehicles to express L1 under the control of the promoter for the human glial fibrillary acidic protein (GFAP-L1 NSCs). Behavioral analysis and electrophysiological H-reflex recordings revealed that mice transplanted with GFAP-L1 NSCs showed enhanced locomotor recovery in comparison to mice injected with wild type (WT) NSCs or control mice injected with phosphate-buffered saline (PBS). This functional recovery was further accelerated in mice transplanted with L1-expressing radial glial cells that had been immunoisolated from GFAP-L1 NSCs (GFAP-L1-i cells). Morphological analysis revealed that mice grafted with GFAP-L1 NSCs exhibited increased neuronal differentiation and migration of transplanted cells, as well as increased soma size and cholinergic synaptic coverage of host motoneurons and increased numbers of endogenous catecholaminergic nerve fibers caudal to the lesion site. These findings show that L1-expressing astrocytes and radial glial cells isolated from GFAP-L1 NSC cultures represent a novel strategy for improving functional recovery after spinal cord injury, encouraging the use of the human GFAP promoter to target beneficial transgene expression in transplanted stem cells.     

Defecation disturbances after cystectomy for urinary bladder cancer

Study Type – Preference (prospective cohort) Level of Evidence 4 What’s known on the subject? and What does the study add? Functional gastrointestinal symptoms and problems are common after radical cystectomy with urinary diversion. This study adds new important epidemiological data on this group of symptoms.

OBJECTIVE

• ? To describe and compare long‐term defecation disturbances in patients who had undergone a cystectomy due to urinary bladder cancer with non‐continent urostomies, continent reservoirs and orthotopic neobladder urinary diversions.

PATIENTS AND METHODS

• ? During their follow‐up we attempted to contact all men and women aged 30–80 years who had undergone cystectomy and urinary diversion at seven Swedish hospitals.
• ? During a qualitative phase we identified defecation disturbances as a distressful symptom and included this item in a study‐specific questionnaire together with free‐hand comments. The patients completed the questionnaire at home.
• ? Outcome variables were dichotomized and the results are presented as relative risks with 95% confidence interval.

RESULTS

• ? The questionnaire was returned from 452 (92%) of 491 identified patients. Up to 30% reported problems with the physiological emptying process of stool (bowel movement, sensory rectal function, awareness of need for defecation, motoric rectal and anal function, straining ability).
• ? A sense of decreased straining capacity was reported by 20% of the men and women with non‐continent urostomy and 14% and 8% of those with continent reservoirs and orthotopic neobladders, respectively.

CONCLUSIONS

• ? Of the cystectomized individuals 30% reported problems with the physiological emptying process of stool (bowel movement, sensory rectal function, awareness of need for defecation, motoric rectal and anal function, straining ability).
• ? Those wanting to improve the situation for bladder cancer survivors may consider communicating before surgery the possibility of stool‐emptying problems, and asking about them after surgery.

     

Evaluation of cystine transport in cultured human kidney cells and establishment of cystinuria type I phenotype by antisense technology

Cystinuria is a rare hereditary disease resulting in recurrent stone formation and the need for repeated invasive interventions. So far, two responsible genes have been identified which encode the two transporters, rBAT and b^0,+AT forming a heterodimer to transport cystine in proximal tubular cells (PTC) and whose defect results in increased excretion of cystine. A human cell line mimicing the phenotype of cystinuria in vitro is yet to be developed. Human kidney (HK)-2 is a PTC line derived from normal HK. After determining the presence of rBAT gene by RT-PCR and Western blot analysis, radioactively labeled cystine (S³⁵) was used to evaluate the functional presence of the amino acid transport in HK-2 cells when cultured in vitro. To achieve a cystinuria type I phenotype in HK-2 cells, the rBAT gene was silenced using antisense oligonucleotides complimentary to human rBAT mRNA. The reduced transport activity of cystine was then determined by radiolabeled cystine uptake measurements. RT-PCR and Western blot confirmed the expression of the rBAT gene in HK-2 cells. Considerable transport of the radio labeled cystine was observed in HK-2 cells and was linearly dependent on the incubation time with the amino acid. The cystine transport in rBAT knockdown cells after incubation with antisense oligonucleotides was significantly lower compared to control (0.76 vs. 0.98%; P = 0.0008), proving a transient knock-down of the rBAT gene. This study demonstrates the presence of the b^0,+ amino acid transport system in human proximal tubular HK-2 cells when cultured in vitro. Inhibition of this transport system is possible by using antisense technology. A permanent inhibition of the cystine transport, based on our model, would be useful for the development and evaluation gene therapeutic approaches. Gunnar Wendt-Nordahl, Sreedhar Sagi contributed equally to this work.     

Pulmonary hemodynamics as predictors of mortality in patients awaiting lung transplantation.

Lung transplantation (LTx) is a therapeutic option for patients with end-stage lung disease. However, the mortality rate of patients on the waiting list is high. The purpose of this study was to examine the prognostic value of cardio-pulmonary hemodynamics for death in patients awaiting LTx. Retrospectively, 177 patients with advanced lung disease accepted for LTx at Sahlgrenska University Hospital from January 1990 through December 2003 were studied. Patient demographics, pulmonary function tests, gas exchange and hemodynamic variables were included in the analysis. Death while awaiting LTx was the primary endpoint for all analyses. Mean age was 49 +/- 9 years. Main diagnoses were alpha 1 antitrypsin deficiency (n = 56), chronic obstructive pulmonary disease (n = 61), cystic fibrosis (n = 14) and interstitial lung disease (n = 46). Thirty patients died (17%). LTx was performed in 143 cases. By univariate analyses, forced vital capacity (FVC) % of predicted, pulmonary vascular resistance (PVR) and diagnosis were associated with risk for death. In multivariate analysis PVR (HR, 1.22; 95% CI, 1.06-1.41; P = 0.006) and FVC% of predicted (HR, 0.97; 95% CI, 0.94-0.99; P = 0.01) were independently associated with death. Patients with increased PVR and a lower FVC % of predicted awaiting LTx should be considered for a higher organ allocation priority. Assessment of pulmonary hemodynamics needs to be considered during evaluation for LTx.     

Characteristics of children with hip displacement in cerebral palsy

Background  

Hip dislocation in children with cerebral palsy (CP) is a common and severe problem. The dislocation can be avoided, by screening and preventive treatment of children with hips at risk. The aim of this study was to analyse the characteristics of children with CP who develop hip displacement, in order to optimise a hip surveillance programme.     

Gene polymorphism association studies in dialysis: vascular access

Complications of the vascular access site for hemodialysis are a major cause of morbidity, suboptimal dialysis, and hospitalization. Vascular access for dialysis that is achieved by central venous catheters is associated with complications such as infection and thrombosis. Arteriovenous fistulas and grafts are also at risk for infectious complications. Further, proliferation of the venous wall with secondary thrombosis is a common pathophysiological process that leads to vascular access dysfunction. Genetic polymorphisms that contribute to vascular access failure are found among factors of the coagulation cascade, and host mediators that induce endothelial dysfunction as well as vessel wall proliferation. The two most common mutations of coagulation factors seem to influence the risk of central venous catheter and fistula thrombosis. Indeed, both the single nucleotide polymorphism of the factor V gene at amino acid position 506 (factor V Leiden mutation) and the prothrombin 20210 polymorphism have been associated with thrombotic complications of the vascular access. Among the endothelium-directed factors, a polymorphism of the methylene tetrahydrofolate reductase gene coding for an enzyme that degrades the endothelium toxic product homocysteine, has been associated with fistula failure. While the angiotensin converting enzyme polymorphism does not seem to be associated with vascular access complications, polymorphisms of the profibrogenic cytokine transforming growth factor-beta1 are associated with the prognosis of native arteriovenous fistulae. The role of pro- and anti-inflammatory cytokine gene polymorphisms as prognostic factors for vascular access is yet to be clearly defined.