Anticoagulation in simultaneous pancreas kidney transplantation - On what basis?

BACKGROUND: Despite technical refinements, early pancreas graft loss due to thrombosis continues to occur. Conventional coagulation tests (CCT) do not detect hypercoagulability and hence the hypercoagulable state due to diabetes is left untreated. Thromboelastogram (TEG) is an in-vitro diagnostic test which is used in liver transplantation, and in various intensive care settings to guide anticoagulation. TEG is better than CCT because it is dynamic and provides a global hemostatic profile including fibrinolysis. AIM: To compare the outcomes between TEG and CCT (prothrombin time, activated partial thromboplastin time and international normalized ratio) directed anticoagulation in simultaneous pancreas and kidney (SPK) transplant recipients. METHODS: A single center retrospective analysis comparing the outcomes between TEG and CCT-directed anticoagulation in SPK recipients, who were matched for donor age and graft type (donors after brainstem death and donors after circulatory death). Anticoagulation consisted of intravenous (IV) heparin titrated up to a maximum of 500 IU/h based on CCT in conjunction with various clinical parameters or directed by TEG results. Graft loss due to thrombosis, anticoagulation related bleeding, radiological incidence of partial thrombi in the pancreas graft, thrombus resolution rate after anticoagulation dose escalation, length of the hospital stays and, 1-year pancreas and kidney graft survival between the two groups were compared. RESULTS: Seventeen patients who received TEG-directed anticoagulation were compared against 51 contemporaneous SPK recipients (ratio of 1: 3) who were anticoagulated based on CCT. No graft losses occurred in the TEG group, whereas 11 grafts (7 pancreases and 4 kidneys) were lost due to thrombosis in the CCT group (P = 0.06, Fisher's exact test). The overall incidence of anticoagulation related bleeding (hematoma/ gastrointestinal bleeding/ hematuria/ nose bleeding/ re-exploration for bleeding/ post-operative blood transfusion) was 17.65% in the TEG group and 45.10% in the CCT group (P = 0.05, Fisher's exact test). The incidence of radiologically confirmed partial thrombus in pancreas allograft was 41.18% in the TEG and 25.50% in the CCT group (P = 0.23, Fisher's exact test). All recipients with partial thrombi detected in computed tomography (CT) scan had an anticoagulation dose escalation. The thrombus resolution rates in subsequent scan were 85.71% and 63.64% in the TEG group vs the CCT group (P = 0.59, Fisher's exact test). The TEG group had reduced blood product usage {10 packed red blood cell (PRBC) and 2 fresh frozen plasma (FFP)} compared to the CCT group (71 PRBC/ 10 FFP/ 2 cryoprecipitate and 2 platelets). The proportion of patients requiring transfusion in the TEG group was 17.65% vs 39.25% in the CCT group (P = 0.14, Fisher's exact test). The median length of hospital stay was 18 days in the TEG group vs 31 days in the CCT group (P = 0.03, Mann Whitney test). The 1-year pancreas graft survival was 100% in the TEG group vs 82.35% in the CCT group (P = 0.07, log rank test) and, the 1-year kidney graft survival was 100% in the TEG group vs 92.15% in the CCT group (P = 0.23, log tank test). CONCLUSION: TEG is a promising tool in guiding judicious use of anticoagulation with concomitant prevention of graft loss due to thrombosis, and reduces the length of hospital stay

A Cross-Sectional Study of People with Epilepsy and Neurocysticercosis in Tanzania: Clinical Characteristics and Diagnostic Approaches.

Neurocysticercosis (NCC) is a major cause of epilepsy in regions where pigs are free-ranging and hygiene is poor. Pork production is expected to increase in the next decade in sub-Saharan Africa, hence NCC will likely become more prevalent. In this study, people with epilepsy (PWE, n=212) were followed up 28.6 months after diagnosis of epilepsy. CT scans were performed, and serum and cerebrospinal fluid (CSF) of selected PWE were analysed. We compared the demographic data, clinical characteristics, and associated risk factors of PWE with and without NCC. PWE with NCC (n=35) were more likely to be older at first seizure (24.3 vs. 16.3 years, p=0.097), consumed more pork (97.1% vs. 73.6%, p=0.001), and were more often a member of the Iraqw tribe (94.3% vs. 67.8%, p=0.005) than PWE without NCC (n=177). PWE and NCC who were compliant with anti-epileptic medications had a significantly higher reduction of seizures (98.6% vs. 89.2%, p=0.046). Other characteristics such as gender, seizure frequency, compliance, past medical history, close contact with pigs, use of latrines and family history of seizures did not differ significantly between the two groups. The number of NCC lesions and active NCC lesions were significantly associated with a positive antibody result. The electroimmunotransfer blot, developed by the Centers for Disease Control and Prevention, was more sensitive than a commercial western blot, especially in PWE and cerebral calcifications. This is the first study to systematically compare the clinical characteristics of PWE due to NCC or other causes and to explore the utility of two different antibody tests for diagnosis of NCC in sub-Saharan Africa

Marburg virus survivor immune responses are Th1 skewed with limited neutralizing antibody responses.

Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized. We report that immune responses in MARV survivors share characteristics with EBOV and SUDV infections but have some distinct differences. MARV survivors developed multivariate CD4(+) T cell responses but limited CD8(+) T cell responses, more in keeping with SUDV survivors than EBOV survivors. In stark contrast to SUDV survivors, rare neutralizing antibody responses in MARV survivors diminished rapidly after the outbreak. These results warrant serious consideration for any vaccine or therapeutic that seeks to be broadly protective, as different filoviruses may require different immune responses to achieve immunity

Mutation rate dynamics reflect ecological change in an emerging zoonotic pathogen.

Funder: Raymond and Beverly Sackler FoundationFunder: Isaac Newton TrustFunder: Newnham College, University of CambridgeFunder: Medical Research CouncilMutation rates vary both within and between bacterial species, and understanding what drives this variation is essential for understanding the evolutionary dynamics of bacterial populations. In this study, we investigate two factors that are predicted to influence the mutation rate: ecology and genome size. We conducted mutation accumulation experiments on eight strains of the emerging zoonotic pathogen Streptococcus suis. Natural variation within this species allows us to compare tonsil carriage and invasive disease isolates, from both more and less pathogenic populations, with a wide range of genome sizes. We find that invasive disease isolates have repeatedly evolved mutation rates that are higher than those of closely related carriage isolates, regardless of variation in genome size. Independent of this variation in overall rate, we also observe a stronger bias towards G/C to A/T mutations in isolates from more pathogenic populations, whose genomes tend to be smaller and more AT-rich. Our results suggest that ecology is a stronger correlate of mutation rate than genome size over these timescales, and that transitions to invasive disease are consistently accompanied by rapid increases in mutation rate. These results shed light on the impact that ecology can have on the adaptive potential of bacterial pathogens

Constitutive cytoplasmic localization of p21Waf1/Cip1 affects the apoptotic process in monocytic leukaemia

In the present study, we analysed the expression and localization of p21Waf1/Cip1 in normal and malignant haematopoietic cells. We demonstrate that in normal monocytic cells, protein kinase C (PKC)-induced p21 gene activation, which is nuclear factor-κB (NF-κB) independent, results in predominantly cytoplasmic localized p21 protein. In acute monocytic leukaemia (M4, M5), monocytic blasts (N=12) show constitutive cytoplasmic p21 expression in 75% of the cases, while in myeloid leukaemic blasts (N=10), low nuclear and cytoplasmic localization of p21 could be detected, which is also PKC dependent. Constitutive p21 expression in monocytic leukaemia might have important antiapoptotic functions. This is supported by the finding that in U937 cells overexpressing p21, VP16-induced apoptosis is significantly reduced (20.0±0.9 vs 55.8±3.8%, P<0.01, N=5), reflected by a reduced phosphorylation of p38 and JNK. Similarly, AML blasts with high cytoplasmic p21 were less sensitive to VP16-induced apoptosis as compared to AML cases with low or undetectable p21 expression (42.25 vs 12.3%, P<0.01). Moreover, complex formation between p21 and ASK1 could be demonstrated in AML cells, by means of coimmunoprecipitation. In summary, these results indicate that p21 has an antiapoptotic role in monocytic leukaemia, and that p21 expression is regulated in a PKC-dependent and NF-κB independent manner.

Predicting the Distribution of Spiral Waves from Cell Properties in a Developmental-Path Model of Dictyostelium Pattern Formation

The slime mold Dictyostelium discoideum is one of the model systems of biological pattern formation. One of the most successful answers to the challenge of establishing a spiral wave pattern in a colony of homogeneously distributed D. discoideum cells has been the suggestion of a developmental path the cells follow (Lauzeral and coworkers). This is a well-defined change in properties each cell undergoes on a longer time scale than the typical dynamics of the cell. Here we show that this concept leads to an inhomogeneous and systematic spatial distribution of spiral waves, which can be predicted from the distribution of cells on the developmental path. We propose specific experiments for checking whether such systematics are also found in data and thus, indirectly, provide evidence of a developmental path

Frequent burning promotes invasions of alien plants into a mesic African savanna

Fire is both inevitable and necessary for maintaining the structure and functioning of mesic savannas. Without disturbances such as fire and herbivory, tree cover can increase at the expense of grass cover and over time dominate mesic savannas. Consequently, repeated burning is widely used to suppress tree recruitment and control bush encroachment. However, the effect of regular burning on invasion by alien plant species is little understood. Here, vegetation data from a long-term fire experiment, which began in 1953 in a mesic Zimbabwean savanna, were used to test whether the frequency of burning promoted alien plant invasion. The fire treatments consisted of late season fires, lit at 1-, 2-, 3-, and 4-year intervals, and these regularly burnt plots were compared with unburnt plots. Results show that over half a century of frequent burning promoted the invasion by alien plants relative to areas where fire was excluded. More alien plant species became established in plots that had a higher frequency of burning. The proportion of alien species in the species assemblage was highest in the annually burnt plots followed by plots burnt biennially. Alien plant invasion was lowest in plots protected from fire but did not differ significantly between plots burnt triennially and quadrennially. Further, the abundance of five alien forbs increased significantly as the interval (in years) between fires became shorter. On average, the density of these alien forbs in annually burnt plots was at least ten times as high as the density of unburnt plots. Plant diversity was also altered by long-term burning. Total plant species richness was significantly lower in the unburnt plots compared to regularly burnt plots. These findings suggest that frequent burning of mesic savannas enhances invasion by alien plants, with short intervals between fires favouring alien forbs. Therefore, reducing the frequency of burning may be a key to minimising the risk of alien plant spread into mesic savannas, which is important because invasive plants pose a threat to native biodiversity and may alter savanna functioning

Telomerase and breast cancer

Current therapies for breast cancer include treatments that are toxic and often result in drug resistance. Telomerase, a cellular reverse transcriptase that maintains the ends of chromosomes (telomeres), is activated in the vast majority of breast cancers (over 90% of breast carcinomas) but not in normal adjacent tissues. Telomerase is thus an attractive target for both diagnosis and therapy because of its distinct pattern of expression. We address the use of telomerase in the diagnostics of breast pathology, as well as the use of telomerase inhibitors in the treatment and prevention of breast cancer

The presence of the proteolysis-inducing factor in urine does not predict the malignancy of a pancreatic tumour

BACKGROUND: The proteolysis-inducing factor (PIF) was identified as a tumour product in various gastrointestinal cancers. A previous study in pancreatic cancer patients suggested PIF expression as a tumour marker, which is not related to tumour size. We hypothesized that PIF could be a useful marker to exclude benign pancreatic tumors, as chronic pancreatitis with a pancreatic mass. METHODS: Urine of patients with a pancreatic mass of uncertain malignancy was investigated for PIF expression by Western blot. Sufficient urine protein for analysis was available in 59 patients. The diagnosis was established by histology in 54 patients and by follow up in five patients with chronic pancreatitis. In addition, serum CA19-9 was measured. RESULTS: The sensitivity (specifity) for the detection of a malignant pancreatic tumour was 90% (75%) and 54% (71%) for CA19-9 and PIF, respectively. The sensitivity (specifity) for the distinction of pancreatic cancer from chronic pancreatitis was 89% (80%) and 57% (63%) for CA19-9 and PIF, respectively. CONCLUSION: Evaluation of PIF in urine is of no diagnostic value in patients with a pancreatic mass of unknown malignancy