Clinical significance of isolated v lesions in paediatric renal transplant biopsies: muscular arteries required to refute the diagnosis of acute rejection

Intimal vascular lesions are considered features of acute T‐cell‐mediated rejection yet can occur in the absence of tubulointerstitial inflammation, termed isolated ‘v’ lesions. The clinical significance of these lesions is unclear. The diagnosis requires a biopsy with the presence of arteries. The frequency of adequate biopsies was analysed in 89 renal transplant biopsies from 57 paediatric renal allograft recipients, and the incidence of isolated endarteritis was determined. 60 (67%) biopsies contained an artery and of these, isolated ‘v’ lesions occurred in 6 (10%). 5 (83%) biopsies with isolated ‘v’ lesions were associated with positive DSA, suggesting that these lesions may represent acute antibody‐mediated rejection. Patients with vessel‐negative biopsies had an increased decline in eGFR (median ?20.5, IQR ?24.4 to 1.2 ml/min/1.73 m² vs. ?9.6, IQR ?78.7 to ?6.8 ml/min/1.73 m²; P = 0.01). Patients with vessel‐negative biopsies were more likely to have repeat biopsy for ongoing allograft dysfunction, (25.0% vs. 2.4%; P < 0.01). The data suggest that isolated ‘v’ lesions are more common than previously thought. A significant proportion of biopsies classified as ‘normal’ or ‘borderline change’ in the absence of a large vessel may represent undiagnosed acute rejection. This may result in suboptimal therapy with possible adverse effects on renal outcome.     

Is intermittent androgen‐deprivation therapy beneficial for patients with advanced prostate cancer?

Use of intermittent androgen‐deprivation therapy (IADT) in patients with prostate cancer has been evaluated in several studies, in an attempt to delay the development of castration resistance and reduce side‐effects associated with ADT. However it is still not clear whether survival is adversely affected in patients treated with IADT. In this review, we explore the available data in an attempt to identify the most suitable candidate patients for IADT, and discuss factors that may inform appropriate patient stratification. ADT is first‐line treatment for advanced/metastatic prostate cancer and is also recommended for use with definitive radiotherapy for high‐risk localised prostate cancer. The changes in hormone levels induced by ADT can lead to short‐ and long‐term side‐effects which, although treatable in most cases, can significantly reduce the tolerability of ADT treatment. IADT has been investigated in several phase II and phase III studies in patients with locally advanced or metastatic prostate cancer, in an attempt to delay time to tumour progression and reduce the side‐effect burden of ADT. In selected patient groups IADT is no less effective than continuous ADT, ameliorating the impact of ADT‐related side‐effects, and, to a degree, their impact on patient health‐related quality of life (HRQL). Further comparative study is required, particularly in relation to HRQL and long‐term complications associated with ADT.     

Atypical Femoral Fractures,Bisphosphonates, and Mechanical Stress

Atypical fractures are stress fractures occurring in the femoral shaft and closely related to bisphosphonate use. We here discuss their radiographic definition and different putative etiologies, apart from mechanical stress. Long time reduction of skeletal remodeling because of bisphosphonate use is thought to allow time for the bone to deteriorate mechanically, resulting in reduced toughness. However, the risk of atypical fracture diminishes rapidly after cessation of treatment, which suggests more acute effects of bisphosphonate use. Microdamage normally accumulates at areas of high stress. Possibly, ongoing bisphosphonate use reduces the ability to resorb and replace areas of microdamage by targeted remodeling. This could lead to crack propagation beyond a point of no return, ending in macroscopic stress fracture.     

The sooty moulds

Sooty moulds are a remarkable, but poorly understood group of fungi. They coat fruits and leaves superficially with black mycelia, which reduces photosynthesis rates of host plants. Few researchers have, however, tried to quantify their economic importance. Sooty moulds have been well-studied at the morphological level, but they are poorly represented in a natural classification based on phylogeny. Representatives are presently known in Antennulariellaceae, Capnodiaceae, Chaetothyriaceae, Coccodiniaceae, Euantennariaceae, Metacapnodiaceae and Trichomeriaceae and several miscellaneous genera. However, molecular data is available for only five families. Most sooty mould colonies comprise numerous species and thus it is hard to confirm relationships between genera or sexual and asexual states. Future studies need to obtain single spore isolates of species to test their phylogenetic affinities and linkages between morphs. Next generation sequencing has shown sooty mould colonies to contain many more fungal species than expected, but it is not clear which species are dominant or active in the communities. They are more common in tropical, subtropical and warm temperate regions and thus their prevalence in temperate regions is likely to increase with global warming. Sooty moulds are rarely parasitized by fungicolous taxa and these may have biocontrol potential. They apparently grow in extreme environments and may be xerophilic. This needs testing as xerophilic taxa may be of interest for industrial applications. Sooty moulds grow on sugars and appear to out-compete typical “weed” fungi and bacteria. They may produce antibiotics for this purpose and their biochemical potential for obtaining novel bioactive compounds for medical application is underexplored.     

Echocardiographic assessment at rest and during stress in patients with intermittent claudication

Objective. Skeletal muscle perfusion during walking relies on complex interactions between cardiac activity and vascular control mechanisms, why cardiac dysfunction may contribute to intermittent claudication (IC) symptoms. The study aims were to describe cardiac function at rest and during stress in consecutive IC patients, to explore the relations between cardiac function parameters and treadmill performance, and to test the hypothesis that clinically silent myocardial ischemia during stress may contribute to IC limb symptomatology. Design. Patients with mild to severe IC (n?=?111, mean age 67 y, 52% females, mean treadmill distance 195 m) underwent standard echocardiography, dobutamine stress echocardiography (SE) and treadmill testing. The patient cohort was separated in two groups based on treadmill performance (HIGH and LOW performance). Results. Ten patients (9%) had regional wall motion abnormalities of which three had left ventricular ejection fraction <50% at standard echocardiography. A majority had lower than expected systolic- and diastolic ventricular volumes. LOW performers had smaller diastolic left ventricular volumes and lower global peak systolic velocity during dobutamine stress. No patient demonstrated significant cardiac dysfunction during dobutamine provocation that was not also evident at standard echocardiography. Conclusions. Most IC patients were without signs of ischemic heart disease or cardiac failure. The majority had small left ventricular volumes. The hypothesis that clinically silent myocardial ischemia impairing left ventricular function during stress may contribute to IC limb symptomatology was not supported.

Trial registration: ClinicalTrials.gov identifier: NCT01219842.     

Time-dependent sensory nerve ingrowth into a bone conduction chamber

We studied time-dependent ingrowth of sensory nerve fibers into a bone defect in a rat bone conduction chamber model. In 10 male Sprague Dawley rats, a titanium chamber was implanted bilaterally in the proximal tibiae, representing an experimental bone defect. To mimic a clinical situation, the chambers were filled with a fresh blood clot. After 1, 2, 4, 6 and 8 weeks, 2 rats were fixed in vivo at each time before removal of specimens, and histological and immunohistochemical analyses. We used antisera against protein gene product 9.5, neural growth-associated protein 43/B-50, calcitonin gene-related peptide, and substance P, to locate regenerating sensory nerve fibers in the chamber. During bone defect healing, hematoxylin/eosin sections showed that new bone grew in through the ingrowth openings in the chamber, gradually filling it and replacing the blood clot. At 1 and 2 weeks after implantation, no nerve fibers could be detected. At 4, 6 and 8 weeks, however, small numbers of nerve fibers were seen in 8 of 11 specimens. The nerve fibers were located mainly in the dense fibrous tissue in close proximity to the new bone, and in some cases within the new forming bone. In this chamber model, the periosteum is not in contact with the bone ingrowth openings, and all ingrowing nerve fibers thus originated from the cortical bone, endosteum or bone marrow. We speculated that these late ingrowing sensory nerve fibers may actively participate in bone repair.     

Unstable versus stable uncemented femoral stems: a radiological study of periprosthetic bone changes in two types of uncemented stems with different concepts of fixation

Introduction Uncemented stems in total hip arthroplasty (THA) are used increasingly often because they are believed to offer a reliable long-term fixation. However, periprosthetic bone remodelling has been a worrying issue. A proximal demineralization has been noted in femurs with well-fixed stems, and it has been explained as by-passing of mechanical forces along the fixed implant (stress-shielding). Aseptic loosening has been a major problem in several uncemented series with earlier designs. The objective for this study was to investigate how the host bone adapts to a loose stem compared with a well-fixed stem after a long time.Materials and methods An investigation with dual-energy X-ray absorptiometry (DEXA), scintimetry and radiological assessment was carried out in 20 patients 8 years after a THA for arthrosis with two different uncemented stems. Ten patients received a stem coated with polytetrafluoroethylene (Anaform); all prostheses showed migration and were considered unstable. Ten patients received a hydroxyapatite-coated stem (Bi-Metric); no prosthesis migrated.Results Different remodelling patterns were seen. In the unstable group, the periprosthetic bone mineral density (BMD) was significantly reduced along the entire stem, while in the stable group only proximal bone loss was seen. The scintigraphic uptake was increased under the stem tip in both groups, and among unstable stems uptake was also increased in the calcar region.Conclusion The assessment of periprosthetic bone remodelling after uncemented THA with long-term observation shows a different host-bone response in stable versus unstable femoral implants. Prior to a femoral revision, measurement of the BMD could be beneficial; it may guide the surgeon when deciding which surgical technique to use.     

Alcohol Withdrawal: Effects of Clonidine Treatment on Sympathetic Activity, the Renin-Aldosterone System, and Clinical Symptoms

Twenty male alcoholics with alcohol withdrawal syndrome were randomized to receive either oral clonidine (3-600 micrograms, six hourly) or oral chlormethiazole (500-1000 mg, six hourly) for 4 days. All subjects were also given oral carbamazepine (200 mg, 12 hourly) throughout the study. Nine subjects given clonidine and eight given chlormethiazole completed the study. Clonidine was as effective as chlormethiazole in suppressing the symptoms and signs of alcohol withdrawal. However, plasma catecholamines, blood pressure, and pulse rate fell more rapidly and to a greater extent during clonidine than following chlormethiazole, findings which could have therapeutic implications. It is suggested that activation of brain noradrenergic neurons constitutes a common denominator in the pathophysiology of several withdrawal syndromes.     

Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder: A randomised,placebo-controlled,blinded trial

Objectives. We assessed if prolonged-release melatonin can facilitate withdrawal of long-term benzodiazepine usage in patients with schizophrenia or bipolar disorder. Methods. Randomised, placebo-controlled, blinded, parallel superiority trial of 24 weeks duration. Participants were randomised to prolonged-release melatonin 2 mg daily versus matching placebo and were continuously guided to gradually reduce their usual benzodiazepine dosage. The primary outcome was mean benzodiazepine daily dosage at 24 weeks. Secondary outcomes included pattern of benzodiazepine dosage over time, benzodiazepine cessation proportion, and benzodiazepine withdrawal symptoms. Results. In total, 86 patients (21–74 years) were enrolled: 42 were randomised to melatonin versus 44 to placebo. We found no significant effect of melatonin on mean benzodiazepine dosage at 24 weeks (melatonin group 8.01 mg versus placebo group 5.72 mg diazepam equivalents; difference between means –2.29; 95% CI –5.78 to 1.21; P = 0.20). Benzodiazepine cessation proportion was 38.1% (16/42) in the melatonin group versus 47.7% (21/44) in the placebo group (OR 0.64; 95% CI 0.26 to 1.56; P = 0.32). Prolonged-release melatonin had no effect on benzodiazepine withdrawal symptoms. Conclusions. Benzodiazepine dosage was comparably low between the groups after 24 weeks of guided gradual dose reduction. In this context, prolonged-release melatonin did not seem to further facilitate benzodiazepine discontinuation.