Apoptosis driven infection

Professional phagocytes like polymorphonuclear neutrophil granulocytes (PMN) and macrophages (MF) kill pathogens as the first line of defense. These cells possess numerous effector mechanisms to eliminate a threat at first contact. However, several microorganisms still manage to evade phagocytic killing, survive and retain infectivity. Some pathogens have developed strategies to silently infect their preferred host phagocytes. The best example of an immune silencing phagocytosis process is the uptake of apoptotic cells. Immune responses are suppressed by the recognition of phosphatidylserine (PS) on the outer leaflet of their plasma membrane. Taking Leishmania major as a prototypic intracellular pathogen, we showed that these organisms can use the apoptotic “eat me” signal PS to silently enter PMN. PS-positive and apoptotic parasites, in an altruistic way, enable the intracellular survival of the viable parasites. Subsequently these pathogens again use PS exposition, now on infected PMN, to silently invade their definitive host cells, the MF. In this review, we will focus on L. major evasion strategies and discuss other pathogens and their use of the apoptotic “eat me” signal PS to establish infection.     

Surgical treatment of achilles tendon rupture: examination of strength of 3 types of suture techniques in a cadaver model

BACKGROUND: The mechanical properties of present-day percutaneous repairs of Achilles tendon ruptures are not known. MATERIAL AND METHODS: Artificially-created ruptures in 24 human cadaveric Achilles tendons were repaired with an open Bunnell repair, a percutaneous calcaneal tunnel or a percutaneous bone-anchor repair. In the open technique no.1 PDS-II absorbable suture material was used, and in the percutaneous techniques either no.1 PDS-II or no.1 Panacryl absorbable suture material was used. The specimens were tested in a materials testing machine until failure occurred. RESULTS: The common mode of failure was suture breakage in non-anchor repairs, and anchor pullout in anchor repairs. The average strength of the repairs varied from 166 N (SD 60) to 211 N (SD 30), with no differences between the techniques (p = 0.5). INTERPRETATION: Taking costs into account, the percutaneous calcaneal tunnel technique and the open technique are the methods of choice.     

Physical training and fatigue, fitness, and quality of life in Guillain-Barré syndrome and CIDP

Many patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) experience excessive fatigue, which may persist for years and reduce quality of life. The authors performed a 12-week study of bicycle exercise training in 20 patients with severe fatigue, 16 with relatively good recovery from GBS, and 4 with stable CIDP. Training seemed well tolerated, and self-reported fatigue scores decreased 20% (p = 0.001). Physical fitness, functional outcome, and quality of life were improved.     

Characterization of zebrafish primordial germ cells: morphology and early distribution of vasa RNA.

Research into germ line development is of conceptual and biotechnologic importance. In this study, we used morphology at the level of light and electron microscope to characterize the primordial germ cells (PGCs) of the zebrafish throughout embryonic and larval development. The study was complemented by the detailed analysis of mRNA expression of a putative germ line marker vasa. By morphology alone PGCs were identified at the earliest at the 5-somite stage in the peripheral endoderm in contact with the yolk syncytial layer. Subsequently, they move from lateral to medial positions into the median mesoderm and from there by means of the dorsal mesentery into the gonadal anlage at day 5 postfertilization (pf), to establish gonads with mesenchymal cells by day 9 pf. Ultrastructural analysis of the 4-day-old zebrafish larvae demonstrates the presence of the germ line-specific structures, nuage, and annulate lamellae. vasa RNA-positive cells can be followed during zebrafish embryogenesis from the 32-cell stage onward (Yoon et al., 1997). Upon completion of gastrulation, the RNA is exclusively present in the cells of the hypoblast, which as a consequence of convergence and extension movements first arrange themselves in a V-shaped string-like conformation to end up, by late somitogenesis, as a string of cells on each side of the midline. We show that the localization of maternal vasa RNA in the ovary changes from cytoplasmic, in the previtellogenic oocytes, to cortical in the vitellogenic oocytes, to concentrate at the boundary of the yolk and cytoplasm in the one cell stage zygote. These results demonstrate that the cortical vasa RNA localization precedes its cleavage furrow-associated localization in the embryos and is presumably cytoskeleton dependent. vasa RNA localization changes from asymmetric subcellular at the sphere stage, to become entirely cytoplasmic at the dome stage. These data suggest a close resemblance in modes of segregation of the germ plasma in the frog and vasa mRNA in the fish during cleavage stages. Based on the significantly larger size and the stereotype and similar position of morphologically distinct cells, presumed to be PGCs, and their vasa RNA-positive counterparts, we conclude that vasa RNA-positive cells are the PGCs and vasa RNA represents a definitive germ line marker in the fish. Dev Dyn 1999;216:153-167.     

Severe withdrawal symptoms with fever during paroxetine tapering off]

A 30-year-old man with depression who was treated with paroxetine (Seroxat) developed severe withdrawal symptoms when the medication was gradually diminished and stopped: agitation, irritability, vertigo, lightheadedness and fever up to 40 degrees C. The symptoms disappeared after the medication was reintroduced but recurred after rediscontinuation. When the dosage was diminished very gradually the symptoms were mild. The depression did not recur. Such withdrawal symptoms are most prevalent after discontinuation of paroxetine but can occur after use of all selective serotonin reuptake inhibitors. The withdrawal syndrome includes both physical and psychiatric symptoms and needs to be distinguished from a relapse of the psychiatric disorder. Good information and gradual discontinuation of the antidepressant after long-term use are adequate measures to prevent severe withdrawal symptoms.     

Systematic review of prediction of poor outcome in anoxic-ischaemic coma with biochemical markers of brain damage

OBJECTIVE: To investigate whether accurate prognostic rules can be derived from the combined results of studies concerning prediction of poor prognosis in anoxic-ischaemic coma with biochemical markers of brain damage in cerebrospinal fluid (CSF) or serum. DESIGN: A meta-analysis of prognostic studies in anoxic-ischaemic coma, selected from Medline and EMBASE databases, according to predefined criteria. SUBJECTS: Twenty-eight studies, with a total of 802 unselected, consecutive patients, in which tests, sampling time and outcome measures were described unequivocally and results were described using clear cut-off values or raw data. MAIN OUTCOME MEASURES: Poor outcome, defined as death or vegetative state, versus good outcome, defined as any other outcome state. ANALYSES: The overall prognostic accuracy of these variables was expressed as the 95% CIs of the pooled false-positive test rate and the pooled positive-likelihood ratios. RESULTS: Only markers in CSF (creatine kinase isoenzyme (CKBB) >204 U/l, neuron specific enolase (NSE) >33 ng/ml, lactate dehydrogenase (LDH) >82 U/l and glutamate oxaloacetate (GOT) >62 U/l) reached a 0% false-positive rate. However, due to small sample sizes, the confidence limits were wide. The accuracy of prediction of poor outcome seemed acceptably high for CSF-CKBB (pooled false-positive rate 0% [95% CI 0-2.3%]; pooled positive-likelihood ratio 33.2 [95% CI 4.8-230.2]), but this result was based on two retrospective studies without blinding of the treating physicians for the test result. CONCLUSIONS: Because of small numbers of patients studied and methodological limitations the combined results are not sufficiently accurate to provide a solid basis for non-treatment decisions.     

High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa

Clinical trials have demonstrated beneficial effects of enzyme replacement therapy (ERT) with alglucosidase alfa in infants, children and adults with Pompe disease. Recent studies have shown that high antibody titers can occur in patients receiving ERT and counteract the effect of treatment. This particularly occurs in those patients with classic-infantile Pompe disease that do not produce any endogenous acid α-glucosidase (CRIM-negative). It is still unclear to what extent antibody formation affects the outcome of ERT in adults with residual enzyme activity.We present the case of a patient with adult-onset Pompe disease. He was diagnosed at the age of 39 years by enzymatic testing (10.7% residual activity in fibroblasts) and DNA analysis (genotype: c.-32-13T>G/p.Trp516X). Infusion-associated reactions occurred during ERT and the patient's disease progressed. Concurrently, the antibody titer rose to a similarly high level as reported for some CRIM-negative patients with classic-infantile Pompe disease.Using newly developed immunologic-assays we could calculate that approximately 40% of the administered alglucosidase alfa was captured by circulating antibodies. Further, we could demonstrate that uptake of alglucosidase alfa by cultured fibroblasts was inhibited by admixture of the patient's serum.This case demonstrates that also patients with an appreciable amount of properly folded and catalytically active endogenous acid α-glucosidase can develop antibodies against alglucosidase alfa that affect the response to ERT.     

Low bone mass in Pompe disease: Muscular strength as a predictor of bone mineral density

Pompe disease is an inherited metabolic myopathy caused by deficiency of acid alpha-glucosidase. The introduction of enzyme replacement therapy as treatment for the disease may change prospects for patients and may require that more attention be paid to co-morbidities such as osteoporosis.MethodsBone mineral status was assessed in children and adults with Pompe disease and compared with reference values by means of dual energy X-ray absorptiometry (DXA) technology (GE Lunar DPX, GE Health Care). Bone mineral density (BMD) of the total body and the lumbar spine (L2–L4) was measured in adults and children; BMD of the femoral neck was measured in adults only. Exclusion criteria were: age < 4 years, severe contractures, and inability to transfer the patient.Results46 patients were enrolled in the study; 36 adults and 10 children. The BMD was significantly lower in Pompe patients than in healthy individuals. Sixty-seven percent of patients had a BMD Z-score below ?1, 26% were classified as osteoporosis/low bone mass for chronological age (T-score < ?2.5 in adults or Z-score < ?2 in children), 66% had a BMD Z-score below ?1 of the femoral neck, and 34% had a BMD Z-score below ?1 for the lumbar spine. Osteoporosis/low bone mass for chronological age was more frequent in patients who were wheelchair-bound, but was also observed in ambulant patients. We found a significant correlation between proximal muscle strength and total body BMD. Of the 10 children, 8 (all four patients with the classic infantile form) had a low BMD.ConclusionLow BMD is a frequent finding in patients with Pompe disease and may be causally related to decreased proximal muscle strength. BMD should be monitored at regular intervals. Children deserve specific attention.     

Apoptosis driven infection

Professional phagocytes like polymorphonuclear neutrophil granulocytes (PMN) and macrophages (MF) kill pathogens as the first line of defense. These cells possess numerous effector mechanisms to eliminate a threat at first contact. However, several microorganisms still manage to evade phagocytic killing, survive and retain infectivity. Some pathogens have developed strategies to silently infect their preferred host phagocytes. The best example of an immune silencing phagocytosis process is the uptake of apoptotic cells. Immune responses are suppressed by the recognition of phosphatidylserine (PS) on the outer leaflet of their plasma membrane. Taking Leishmania major as a prototypic intracellular pathogen, we showed that these organisms can use the apoptotic "eat me" signal PS to silently enter PMN. PS-positive and apoptotic parasites, in an altruistic way, enable the intracellular survival of the viable parasites. Subsequently these pathogens again use PS exposition, now on infected PMN, to silently invade their definitive host cells, the MF. In this review, we will focus on L. major evasion strategies and discuss other pathogens and their use of the apoptotic "eat me" signal PS to establish infection.