On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.

METHODS

We administered

intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently CH5424802 administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.

RESULTS

A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response LY3039478 solubility dmso rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence

of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for >= 24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.

CONCLUSIONS

Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients.”
“P-glycoprotein (P-gp), traditionally

linked to cancer poor prognosis and multidrug resistance, is undetectable in normal gastric mucosa and overexpressed in gastric cancer (GC). We propose that P-gp may be involved in Helicobacter pylori (Hp)-related gastric carcinogenesis by inhibiting apoptosis. Immune system Aim of the study was to evaluate the expression of P-gp in fetal stomach and in Hp-related gastric carcinogenesis, the epigenetic control of the multi-drug resistance-1 (MDR1) gene, the localization and interaction between P-gp and BcI-x(L) and the effect of the selective silencing of P-gp on cell survival. P-gp and Bcl-xl expression was evaluated by immunohistochemistry on 28 spontaneously abortive human fetuses, 66 Hp-negative subjects, 138 Hp-positive chronic gastritis (CG) of whom 28 with intestinal metaplasia (IM) and 45 intestinal type GCs.

c-FLIP over expression in stromal cells stimulated the growth and invasion of prostate cancer, including LNCaP and PC3 cells in vitro.

Conclusions: These results indicate the over expression of stromal c-FLIP and its function for promoting prostate

cancer growth and invasion.”
“The purpose of this study is to reveal characteristics of (64)Cu-labeled diacetyl-bis(N(4)-methylthiosemicarbazone) ([(64)Cu]Cu-ATSM) during cell proliferation and hypoxia by autoradiography imaging and immunohistochemical staining.

Methods: The intratumoral distribution of [(64)Cu]Cu-ATSM and [(18)F]-2-fluoro-2-deoxy-D-gloucose ([(18)F]FDG) in mice implanted with Lewis lung carcinoma (LLC1) tumor cells according to dual autoradiography were compared with the immunohistochemica staining patterns of proliferating markers [Ki-67 and 5-bromo-2'-deoxyuridine Ruxolitinib (BrdU)] and a hypoxic marker (pimonidazole). A clonogenic assay was performed using the cells of LLC1 tumor-implanted mice, and it was compared with the distribution of [(64)CL]Cu-ATSM.

Results:

[(64)Cu]Cu-ATSM mainly accumulated at the edge of rumors, whereas [(18)F]FDG was distributed inside the tumor and inside the [(64)Cu] Cu-ATSM accumulation. The number of Ki-67-positive cells/area tended to increase with [(18)F]FDG accumulation and decrease with [(64)Cu] Cu-ATSM accumulation. Selleck JNK-IN-8 On the other hand, the number of BrdU-positive cells/area was negatively correlated with [(18)F]FDG With [(64)Cu]Cu-ATSM accumulation. High [(64)Cu]Cu-ATSM accumulation was found outside the high-[(18)F]FDG-accumulation and pimonidazole-positive regions. Colony formation ability was significantly higher in the tumor cells obtained from high-[(64)Cu]Cu-ATSM-accumulation regions than the cells from the intermediate- and the

low-accumulation regions.

Conclusion: [(64)Cu]Cu-ATSM accumulation regions in tumor cells indicate quiescent but clonogenic tumor cells under mild hypoxia. [(64)Cu] Cu-ATSM could play an important role in planning appropriate tumor radiotherapy. (C) 2009 Elsevier Inc. All rights reserved.”
“Purpose: Microdialysis is a technique for monitoring the concentration of molecules in the interstitial fluid of living tissue. We these report the effects of ischemia on human renal interstitial fluid molecules.

Materials and Methods: Ten patients with a renal mass or upper tract transitional cell carcinoma who elected laparoscopic nephrectomy or nephroureterectomy were studied with in situ renal microdialysis. Microdialysate was continuously collected into separate vials every 10 minutes before and after the renal artery was stapled. Samples, were analyzed for the glucose, pyruvate, lactate and glycerol concentration.

Results: The concentration of all 4 molecules was stable throughout the pre-ischemia baseline period. Glucose and pyruvate concentrations decreased to almost zero during the first 60 minutes of ischemia.

The results showed that extracellular glutamate concentration in the CM was decreased following administration of morphine in non-sensitized rats. However, morphine-induced behavioral sensitization significantly increased the extracellular glutamate concentration in this area. The enhancement of glutamate in morphine sensitized rats was prevented by administration of naloxone 30 min before each Oligomycin A supplier of

three daily doses of morphine. These results suggest an adaptation of the glutamatergic neuronal transmission in the hippocampus after morphine sensitization and it is postulated that opioid receptors may play an important role in this effect. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Pigs are capable of generating reassortant influenza viruses of pandemic potential, as both the avian and mammalian influenza viruses can infect pig epithelial cells in the respiratory tract. The source of the current influenza pandemic is H1N1 influenza A virus, possibly of swine

origin. This study was conducted to understand better the pathogenesis of H1N1 influenza virus and associated host PLX-4720 mouse mucosal immune responses during acute infection in humans. Therefore, we chose a H1N1 swine influenza virus, Sw/OH/24366/07 (SwIV), which has a history of transmission to humans. Clinically, inoculated pigs had nasal discharge and fever and shed virus through nasal secretions. Like pandemic H1N1, SwIV also replicated extensively in both the upper and lower respiratory tracts, and lung lesions were typical of H1N1 infection. We detected innate, proinflammatory, Th1, Th2, and Th3 cytokines, as well as SwIV-specific IgA antibody in lungs of the virus-inoculated

pigs. Production of IFN-gamma by lymphocytes of the tracheobronchial lymph nodes was also detected. Higher frequencies of cytotoxic T this website lymphocytes, gamma delta T cells, dendritic cells, activated T cells, and CD4(+) and CD8(+) T cells were detected in SwIV-infected pig lungs. Concomitantly, higher frequencies of the immunosuppressive T regulatory cells were also detected in the virus-infected pig lungs. The findings of this study have relevance to pathogenesis of the pandemic H1N1 influenza virus in humans; thus, pigs may serve as a useful animal model to design and test effective mucosal vaccines and therapeutics against influenza virus.”
“Periodic transmeningeal administration of muscimol into the neocortical epileptogenic zone via a subdurally implanted device has been proposed for the treatment of intractable focal neocortical epilepsy. It is unknown whether such muscimol applications induce tolerance. The purpose of this study was to determine whether daily transmeningeal (epidural) muscimol applications into the rat parietal cortex induce tolerance to the antiepileptic effect of this drug. Rats were chronically implanted with an epidural cup and adjacent epidural EEG electrodes over the right parietal cortex. After recovery 1.

In this review we address the emerging concept of complex links between these factors. We also discuss the role of the mitochondrial genome and mutations associated with diabetes, the effect of oxidative

stress and reactive oxygen species, the sensitivity of mitochondria to lipotoxicity, and the adaptive dynamics of mitochondrial morphology. Better comprehension of the molecular Selleck Sepantronium mechanisms contributing to mitochondrial dysfunction will help drive the development of effective therapeutic approaches.”
“Patients with schizophrenia exhibit a decrease or loss of normal anatomical brain asymmetry that also extends to functional levels. We applied functional magnetic resonance imaging (fMRI) to investigate language lateralization in patients with schizophrenia during their first episode of illness, thus excluding effects of chronic illness and treatment. Brain regions activated during language tasks of verb generation and passive music listening were explored in 12 first-episode patients with schizophrenia and 17 healthy controls. Regions of interest corresponded to Broca’s area in the inferior frontal gyrus (IFG) and Wernicke’s area in the superior temporal sulcus (STS). Patients with schizophrenia had significantly smaller lateralization indices in language-related regions than controls. A similar effect was observed in their IFG and STS regions. There was no difference between the groups

in the auditory cortex for the music task. Patients with schizophrenia demonstrated greater activation than the controls in temporal regions: the difference was larger in patients with more severe positive symptom subscores. In conclusion, patients with schizophrenia Ilomastat concentration demonstrated loss of normal functional brain

asymmetry, as reflected in diminished lateralization of language-related activation in frontal and temporal regions. This phenomenon was already present during their first episode of psychosis, possibly reflecting developmental brain abnormalities of the illness. (c) 2008 Elsevier Ireland Ltd. All tights reserved.”
“Aims: To evaluate the effect of oral administration of Lactobacillus fermentum CRL1446 on the intestinal feruloyl esterase (FE) activity and oxidative status of mice.

Methods and Results: Adult Swiss albino mice received Lact fc,inentum CRI,1446 at the doses 107 and 109 cells per day per mouse for 2, 5, 7 and 10 Tolmetin days. Intestinal FE activity, intestinal microbiota counts, plasmatic thiobarbituric acid reactive substances (TBARS) percentage and glutathione reductase (GR) activity were determined. Mice that received Lact,.fermentnrn CR1 1446 at the dose 107 cells per day for 7 days showed a twofold increase in total intestinal FE activity, compared to the nontreated group. In large intestine content, FE activity increased up to 6.4 times. Ni) major quantitative changes in colonic microbiota were observed in treated animals. Administration of this strain produced an approx.

In some cases, an RNA segment is replaced by a rearranged RNA segment, which is derived from its standard counterpart by partial sequence duplication. We report here a reverse genetics system for RV based on the preferential packaging of rearranged RNA segments. Using this system, wild-type or in vitro-engineered forms of rearranged segment 7 from

a human rotavirus (encoding the NSP3 protein), derived from cloned cDNAs and selleck compound transcribed in the cytoplasm of COS-7 cells with the help of T7 RNA polymerase, replaced the wild-type segment 7 of a bovine helper virus (strain RF). Recombinant RF viruses (i.e., engineered monoreassortant RF viruses) containing an exogenous rearranged RNA were recovered by propagating the viral progeny in MA-104 cells, with no need for additional selective pressure. Our findings offer the possibility to extend RV reverse genetics

to segments encoding nonstructural or structural proteins for which no potent selective tools, such as neutralizing antibodies, are available. In addition, the system described here is the first to enable the introduction of a mutated gene expressing a modified nonstructural protein into an infectious RV. This reverse genetics system offers new perspectives for investigating RV Cell Cycle inhibitor protein functions and developing recombinant live RV vaccines containing specific changes targeted for attenuation.”
“Excitatory amino acid transporters (EAAT) uptake Orotic acid extracellular glutamate, the major excitatory neurotransmitter in the brain. EAAT type 3 (EAAT3), the main neuronal EAAT, is expressed widely in the CNS. We have shown that the volatile

anesthetic isoflurane increases EAAT3 activity and trafficking to the plasma membrane. Thus, we hypothesize that EAAT3 mediates isoflurane-induced anesthesia. To test this hypothesis, the potency of isoflurane to induce immobility and hypnosis, two major components of general anesthesia, was compared in the CD-1 wild-type mice and EAAT knockout mice that had a CD-1 strain gene background. Hypnosis was assessed by loss of righting reflex in this study. The expression of EAAT1 and EAAT2, two widely expressed EAATs in the CNS, in the cerebral cortex and spinal cord was not different between the EAAT3 knockout mice and wild-type mice. The concentration required for isoflurane to cause immobility to painful stimuli, a response involving primarily reflex loops in the spinal cord, was not changed by EAAT3 knockout. However, the EAAT3 knockout mice were more sensitive to isoflurane-induced hypnotic effects, which may be mediated by hypothalamic sleep neural circuits. Interestingly, the EAAT3 knockout mice did not have an altered sensitivity to the hypnotic effects caused by ketamine, an i.v. anesthetic that is a glutamate receptor antagonist and does not affect EAAT3 activity. These results suggest that EAAT3 modulates the sensitivity of neural circuits to isoflurane.

During recent years, interest has increased, and promising results have been published concerning both Parkinson’s disease and nonparkinsonian tremor.

We reviewed the literature to investigate the development of surgery in the posterior subthalamic area from the lesional era to the present.”
“The human health risk associated with the consumption of molluscan shellfish grown in sewage-contaminated waters is well established. Noroviruses are the principal agent of shellfish-related illness. This study describes the evaluation of two silica-based viral RNA extraction protocols find more as well as two real time RT-PCR assays for norovirus detection in shellfish and plankton. Using a GII RNA transcript, the Qiagen RNeasy method was able to recover 80%, 1.85%, and 0.14% of the RNA copies in seeded oyster, small

plankton (63-200 mu m), and large plankton (> 200 mu m) samples, respectively, whereas a silica-bead based method was able to recover only 0.175%, 0.0044%, and 0.0006% in the same seeded samples. The detection limit of two published TaqMan RT-PCR assays (A and B) evaluated with RNA run-off transcripts established RT-PCR assay A was more sensitive for detecting low copies of GI.3 RNA whereas RT-PCR assay B was more sensitive for detecting GI.4 and GII.4; however, only assay A was able to detect GI and GII in naturally contaminated shellfish whereas only assay B was able to detect GI and GII in this website naturally contaminated plankton. The combination of a rapid RNA extraction method followed by both TaqMan RT-PCR assays offers significant advantages for development of routine assays for norovirus detection in bivalve shellfish and shows promise for detection in other high inhibitor environmental sources, such as plankton. (c) 2008 Elsevier B.V. All rights reserved.”
“OBJECTIVE: High rates of restenosis after stenting to treat vertebral artery (VA) origin

disease have revitalized interest in microsurgical revascularization for this condition. This study analyzes the outcomes of microsurgical revascularization used to treat proximal VA occlusive 5-FU disease.

METHODS: Between 1986 and 2007, 29 patients (19 men, 10 women; age range, 35-93 years) underwent microsurgical revascularization for proximal VA disease. Their medical records were reviewed retrospectively for presenting symptoms, presence of comorbidities, target lesion characteristics, contralateral VA findings, procedure-related morbidity, and clinical and radiographic outcomes.

RESULTS: Thirteen, 7, and 6 patients underwent VA-to-carotid artery transposition, endarterectomy, or both, respectively. Two patients underwent subclavian endarterectomy plus vertebral endarterectomy, and 1 patient underwent carotid endarterectomy associated with VA transposition. There were no cases of periprocedural stroke or death. Permanent procedure-related neurological complications included I case of Horner’s syndrome and I case of hoarseness.

8 mm. The auditory radiations and the claustro-opercular and insulo-opercular fibers of the external and extreme capsules pass through the temporal stem above the IFOF, whereas the optic radiations pass below.

CONCLUSION: In the transsylvian approach to the mesiotemporal structures in the left dominant hemisphere, an incision within the posterior 8 mm from the limen insulae is less likely to damage the IFOF than more posterior incisions along the inferior limiting sulcus. In the temporal transopercular approach to left temporo-insular gliomas, the IFOF constitutes the deep functional INCB28060 limit of the resection within the temporal stem.”
“Purpose: Polyorchidism is an uncommon congenital

anomaly. We systematically analyzed the literature due to the contradictory data regarding this condition.

Materials and Methods: We conducted a database search and evaluated relevant articles for the appearance, comorbidities and complications of supernumerary testes. Only cases of polyorchidism confirmed by histological examination were included in the study.

Results: We found 140 cases of polyorchidism. Triorchidism was the most common type, and 6 cases of 4 testes (4.3%) were reported. Most supernumerary testes (64%, chi-square

p <0.001) were drained by SCH727965 a vas deferens. Median patient age at detection was 17 years. Left side demonstrated predominance (64.5%, chi-square p <0.001). Most cases were found during surgery for other symptoms including inguinal hernia, undescended testicle, testicular torsion and scrotal pain. Only 16%

of patients complained of an accessory mass without any symptoms. Neoplasms were found in 9 cases 4��8C (6.4%), of which 8 were malignant and 1 was benign. Data available for 7 malignomas (88%) revealed that all were in cryptorchid supernumerary testes.

Conclusions: Polyorchidism is rare and is generally found during evaluation for other conditions such as inguinal hernia, undescended testis and testicular torsion. Cryptorchidism appears to be the most important risk factor for malignancy in patients with supernumerary testes. Thus, patients with nonscrotal supernumerary testes require appropriate counseling. The supernumerary testis is frequently drained by a vas deferens, implying a probable reproductive function. Decision for surgery, biopsy or orchiectomy should be based on concomitant symptoms, cryptorchidism or suspected malignancy. We provide a guideline for management based on a functional classification of polyorchidism.”
“BACKGROUND: Intermuscular approaches can expose the lumbar spine and minimize muscular trauma and injury. The segmental anatomy of the posterior lumbar musculature allows surgical access through separation of muscle groups and fascicles and provides one to develop intermuscular working channels while preserving the integrity of the muscles and their function. In addition, preservation of the accompanying neurovascular bundles minimizes blood loss, tissue atrophy, and pain.

“
“Chronic lymphocytic leukemia (CLL) is uniquely characterized by the existence of subsets of cases with quasi-identical, ‘stereotyped’ B-cell receptors (BCRs). Herein we investigate this stereotypy in 2662 patients with CLL, the largest series yet, using purpose-built bioinformatics methods based on sequence pattern discovery. selleck Besides improving the identification of ‘stereotyped’ cases, we demonstrate that CLL actually consists of two

different categories, based on the BCR repertoire, with important biological and ontogenetic differences. The first (similar to 30% of cases) shows a very restricted repertoire and is characterized by BCR stereotypy (clustered cases), whereas the second includes cases with heterogeneous BCRs (nonclustered

cases). Eleven major CLL clusters were identified with antigen-binding sites defined by just a few critically positioned residues, regardless of the actual immunoglobulin (IG) variable gene used. This situation is closely reminiscent of the receptors expressed by cells participating in innate immune responses. On these grounds, we argue that whereas CLL cases with heterogeneous BCRs likely derive from the conventional B-cell pool, cases with stereotyped BCRs could derive from progenitor cells evolutionarily adapted to particular antigenic challenges, perhaps intermediate between a true innate immune click here system and the conventional adaptive B-cell immune system, functionally similar to what has been suggested previously for mouse B1 cells. Leukemia (2010) 24, 125-132; doi:10.1038/leu.2009.186; published online 17 September

2009″
“In the CNS, lipocalin-type prostaglandin D synthase (L-PGDS) is predominantly a non-neuronal enzyme responsible for the production of PGD(2), an endogenous sleep promoting substance. We have previously demonstrated that estradiol differentially regulates L-PGDS transcript levels in the rodent brain. In hypothalamic nuclei, estradiol increases L-PGDS transcript expression, whereas in the ventrolateral preoptic area L-PGDS gene expression is reduced after estradiol treatment. In the present study, we Phospholipase D1 have used an immortalized glioma cell line transfected with a L-PGDS reporter construct and estrogen receptor (ER) alpha and EB beta expression plasmids to further elucidate the mechanisms underlying estradiol regulation of L-PGDS gene expression. We found that physiologically relevant concentrations of estradiol evoked an inverted U response in cells expressing ER alpha. The most effective concentration of estradiol (10(-11) M) increased the promoter activity 3-fold over baseline. Expression of ER beta did not increase activity over control and when ER beta was co-expressed with ER alpha there was a significant attenuation of the promoter activity. While ER alpha significantly increased L-PGDS promoter activity, our previous in vivo studies demonstrate a greater magnitude of change in L-PGDS gene expression in the presences of estradiol.

Furthermore, male gender was an independent Lonafarnib datasheet predictor of late (but not early or overall) mortality.

Conclusions: The independent predictors of mortality after aortic valve replacement for aortic stenosis differed between

the male and female patients. Male gender increased the risk of late mortality, and a valve size of <= 21 mm increased the risk of early and overall mortality among the male patients only. These differences need to be taken into consideration preoperatively and require consideration during operative management. (J Thorac Cardiovasc Surg 2011;142:595-601)”
“Drawing on converging behavioral, electrophysiological, and imaging evidence, we advance an hypothesis for a cognitive phenotype of a SNP in the CHRNA4 gene encoding the alpha(4) subunit of alpha(4)beta(2) nicotinic receptors. First, we review evidence that visuospatial attention can be decomposed into several component processes. Secondly, we consider evidence that one component, redirection selleck chemicals of attention, is modulated by the nicotinic cholinergic system. Third, we review evidence that nicotinic stimulation exerts effects at the network level. Fourth, we consider evidence

that normal variation in this SNP exerts nicotine-like modulatory effects on visuospatial attention. Fifth, we hypothesize that the cognitive phenotype of the CHRNA4 rs1044396 SNP is characterized by greater ability of T allele carriers to preferentially process events in the attentional focus compared to events outside the attentional focus. Finally, CYTH4 we consider effects of the CHNRA4 rs1044396 SNP on brain activity and cognition in light of our hypothesized cognitive phenotype. This hypothesis makes an important contribution to the development of cognitive phenomics by arguing for

a cognitive phenotype of CHRNA4. (C) 2012 Elsevier Ltd. All rights reserved.”
“Rationale Preclinical data indicates that threat stimuli elicit two classes of defensive behaviors, those that are associated with imminent danger and are characterized by flight or fight (fear), and those that are associated with temporally uncertain danger and are characterized by sustained apprehension and hypervigilance (anxiety).

Objective The objectives of the study are to (1) review evidence for a distinction between fear and anxiety in animal and human experimental models using the startle reflex as an operational measure of aversive states, (2) describe experimental models of anxiety, as opposed to fear, in humans, (3) examine the relevance of these models to clinical anxiety.

In addition, bisindolylmaleimide II, a broad-spectrum inhibitor of PKC, reversed the regulatory action of histamine on GS expression. These results indicate that histamine can effectively protect against OGD-induced cell damage in astrocytes

through H-1 and H-2 receptors, and its regulatory effect on astrocytic GS expression may be due to the activation of H-1 receptor and PKC pathway. Histamine may be an endogenous protective factor and calls for its further study as a regulator of astrocyte function during ischemic stroke. (C) 2013 Elsevier Ireland Ltd. All rights reserved.”
“Lysophosphatidic AZD5153 in vitro acid (LPA; 1- or 2-acyl-sn-glycerol-3-phosphate) is a phospholipid that is involved in numerous normal physiological and pathological processes such as brain development, blood vessel formation, embryo implantation, hair growth, neuropathic pain, lung fibrosis and colon cancer. Most of these functions are mediated by G protein-coupled receptors (GPCRs) specific to LPA. So far, six GPCRs for LPA have been identified: LPA(1)/Edg2, LPA(2)/Edg4, LPA(3)/Edg7, LPA(4)/GPR23/P2Y9, LPA(5)/GPR92 and LPA(6)/P2Y5. An intracellular target of LPA has also been proposed. Among the LPA receptors, LPA(3) is unique in that it is activated significantly by a specific form of LPA (2-acyl LPA with unsaturated fatty acids) and is expressed in a limited number of tissues such as the reproductive organs. Recent studies have shown

that LPA3-mediated LPA signaling is essential for proper embryo implantation and have revealed an unexpected check details genetic linkage between LPA and prostaglandin signaling. Here we review recent advances in the study of LPA3, especially studies using LPA3-deficient mice. In addition, we focus on the agonists and antagonists that are specific to each LPA receptor as important tools for the functional study of LPA signaling. (C) 2010 Elsevier Ltd. All rights reserved.”
“We study the

stochastic dynamics of evolutionary games, and focus on. the so-called ‘stochastic slowdown’ effect, previously observed in Altrock et al. (2010) for simple evolutionary dynamics. Slowdown here refers to the fact that a beneficial mutation may take longer to fixate than a neutral one. Florfenicol More precisely, the fixation time conditioned on the mutant taking over can show a maximum at intermediate selection strength. We show that this phenomenon is present in the Prisoner’s Dilemma, and also discuss counterintuitive slowdown and speedup in coexistence games. In order to establish the microscopic origins of these phenomena, we calculate the average sojourn times. This allows us to identify the transient states which contribute most to the slowdown effect, and enables us to provide an understanding of slowdown in the takeover of a small group of cooperators by defectors in the Prisoner’s Dilemma: Defection spreads fast initially, but the final steps to takeover can be delayed substantially.