Sunlight exposure, hat use, and squamous cell skin cancer on the head and neck

TF (tissue factor) is a physiological inhibitor of blood coagulation in normal hemostasis and is a major initiator of clotting in thrombotic disease. TF functions as a protein cofactor for FVIIa. Coagulation at a site of injury is initiated by exposure of blood to cell-surface formation of TF/VIIa complex. The TF/VIIa complex then activates both factors IX and X leading to thrombin generation and fibrin formation. TFPI (tissue factor pathway inhibitor) appears to play a primary role in regulating TF-induced coagulation. Abnormal coagulation may contribute to the pathogenesis of many serious illnesses. In particular, induced expression of TF and TF-mediated coagulation occurs in atherosclerotic plaques, sepsis, malignancy, ARDS and glomerulonephritis. Several observations support the need for exogenous TFPI administration to effectively turn off the TF/VIIa complex in several clinical conditions with TF-induced coagulopathy. There are some reports about successful administration of rTFPI for antithrombotic therapy in humans.     

Evaluation of intracranial cysts by intraoperative MR

Eleven patients with intracranial cystic collections were evaluated in the open-bore intraoperative MR system. In each case, the cystic collection or the surrounding cerebrospinal fluid (CSF) space was injected with .02 to .5 cc of .5 mol/l gadopentetate dimeglumine. Serial imaging was performed using T1-weighted imaging. In seven patients, free communication was demonstrated between the cystic collection and the surrounding CSF spaces. In four cases, the cyst did not communicate with the CSF; two of these were drained in the intraoperative MR system with reduction in symptoms. One patient developed an aseptic meningitis 10 days after the study, which was successfully treated with steroids; no other complications were noted. We conclude that the communication of intracranial cystic collections with the cisterns and ventricles can be safely and effectively elucidated with gadolinium injection in the intraoperative MR system.     

Patients with isolated trisomy 8 in acute myeloid leukemia are not cured with cytarabine-based chemotherapy: results from Cancer and Leukemia Group B 8461

To date, neither the clinical significance of isolated trisomy 8, the most frequent trisomy in acute myeloid leukemia (AML), nor the effect of age within a single cytogenetic group has been examined. We report a large cohort of adult trisomy 8 patients and examine whether increasing age within a homogeneous cytogenetic group alters clinical outcome. Characteristics and outcome of patients with isolated trisomy 8 enrolled in the prospective Cancer and Leukemia Group B (CALGB) cytogenetic study CALGB 8461 are described. Isolated trisomy 8 was identified in 42 (3.03%) of 1387 patients enrolled in five CALGB treatment protocols. These patients had a median age of 64 (range, 16-79) years, 50% female proportion, and a low frequency of hepatomegaly (10%) or splenomegaly (10%). Laboratory features included a median white blood count of 7.3 x 10(9)/L, nonspecific French-American-British distribution, with 36% of patients having Auer rods. Treatment outcome was unsatisfactory with a complete remission (CR) rate of 59%, median CR duration of 13.6 months, and median survival of 13.1 months. Older age adversely affected outcome; trisomy 8 patients > or =60 years had both an inferior CR rate (40% versus 88%; P = 0.004) and overall survival (median, 4.8 versus 17.5 months; P = 0.01), as compared with those <60 years of age. Of the patients <60 years of age, only four remain alive, and all received noncytarabine-based intensive chemotherapy, followed in three cases by autologous (n = 2) or allogeneic (n = 1) stem cell transplant in CR1. Adults with AML and isolated trisomy 8 have a poor outcome that is accentuated by increasing age and is rarely cured with cytarabine-based therapy. Alternative investigational treatments should be considered for individuals with this AML subset.     

DNA fragmentation in human substantia nigra: apoptosis or perimortem effect?

DNA fragmentation was examined in situ in flash-frozen human postmortem midbrain as a marker for programmed cell death. A large series of cases comprising 16 pathologically confirmed idiopathic Parkinson's disease (IPD) cases, 14 control cases without brain pathology, and a group of 6 patients with other parkinsonian movement disorders were examined using TdT-mediated dUTP-biotin 3' end-labeling histology. Labeling of neurons and glia was seen in the substantia nigra of control and IPD cases and in other movement disorder cases. Labeled nuclei were seen in melanized nigral neurons; apoptotic bodies were also found but were more commonly associated with nigral glia. In the control group, labeling of neurons and glia was strongly associated with poor agonal status, assessed by tissue pH, a marker for antemortem hypoxia. The mean tissue pH of the control group with neuronal labeling was 6.28 (SEM .057), which was significantly different from that of the unlabeled group 6.55 (SEM .055). Mean tissue pH for all cases was 6.38. There was no association of nigral neuronal labeling with poor agonal status in the IPD cases, which showed labeling throughout the range of pH values. However, extranigral labeling, seen in the mesencephalon, red nucleus, superior colliculus, rostral pons, and periaqueductal gray matter, in all three subject groups was associated with tissue pH values of less than 6.3. These findings suggest that DNA fragmentation is influenced by antemortem hypoxia and that apoptosis-like changes seen in the postmortem nigra may parallel those seen in experimental ischemia in the animal brain. The likely influence of perimortem factors on these changes indicates that results from postmortem studies of apoptotic cell death in neurodegenerative disease should be treated with caution and underlines the importance of determining postmortem markers for agonal status in human brain.     

20q gain associates with immortalization: 20q13.2 amplification correlates with genome instability in human papillomavirus 16 E7 transformed human uroepithelial cells

Pisatin is the major phytoalexin produced by pea upon microbial infection. The enzyme that catalyzes the terminal step in the pisatin biosynthetic pathway is (+)6a-hydroxymaackiain 3-O-methyltransferase (HMM). We report here the isolation and characterization of two HMM cDNA clones (pHMM1 and pHMM2) made from RNA obtained from Nectria haematococca-infected pea tissue. The two clones were confirmed to encode HMM activity by heterologous expression in Escherichia coli. The substrate specificity of the methyltransferases in E. coli was similar to the activity detected in CuCl2-treated pea tissue. Nucleotide sequence analysis of Hmm1 and Hmm2 revealed an open reading frame of 1080 bp and 360 amino acid residues which would encode 40.36 kda and 40.41 kDa polypeptides, respectively. The deduced amino acid sequence of HMM1 has 95.8% identity to HMM2, 40.6% identity to Zrp4, a putative O-methyltransferase (OMT) in maize root, and 39.1% to pBH72-F1, a putative OMT induced in barley by fungal pathogens or UV light. Comparison of the deduced amino acid sequences of the cDNA clones to OMTs from other higher plants identified the binding sites of S-adenosylmethionine (AdoMet). Southern blot analysis showed two closely linked genes with strong homology to Hmm in the pea genome.     

Family support services for stroke patients

Provision of long-term support and rehabilitation after stroke varies in the UK. Patients and their carers are not always aware of services available. Family support service organisers can help increase awareness of risk factors and minimise recurrence of stroke.     

In-situ forces in the human posterior cruciate ligament in response to posterior tibial loading

The presence of human cytomegalovirus (HCMV) DNA in liver, spleen, and kidney samples of HCMV-seropositive trauma victims during latency was demonstrated by polymerase chain reaction (PCR), using primers reactive with the major immediate early gene exon 4 and the structural gene pp150. Sequence analysis of the PCR amplificates showed more than 95% homology with the reference HCMV strain AD169. The few mutations observed were mostly distributed randomly. In one subject two types of the MIE-4 gene were detected, and in another subject two types of the pp150 gene were found, suggesting that different strains of HCMV can be found in organs of the same patient during latency.     

Effects of Ara-C on neutral sphingomyelinase and mitogen- and stress-activated protein kinases in T-lymphocyte cell lines

Neutral sphingomyelinase (SMase) can be activated by extracellular signals to produce ceramide, which may affect mitogen-activated protein kinase (MAPK) activities. Neutral SMase activity was assessed in membranes from Jurkat, a human T-cell line, and EL4, a murine T-cell line. Ara-C activated SMase with 10 minutes in both Jurkat and EL4 cells, while phorbol ester (PMA) had no effect. PMA, but not Ara-C or ceramides, activated ERK MAPKS, in Jurkat and EL4. PMA acted synergistically with ionomycin to activate JNK MAPKs in Jurkat and EL4 within 10 minutes. Ara-C activated JNKs only after prolonged incubation (90-120 minutes). Thus, ceramide is not a positive signal for ERK activation in T-cell lines. The effects of Ara-C on JNK activity may be mediated through secondary response pathways.     

Effects of chicken anemia virus on macrophage function in chickens

One-day-old chicks were inoculated intramuscularly with chicken anemia virus (CAV). Four birds were killed at 7, 14, 21, 28, and 42 days postinoculation (PI), and macrophages were recovered from spleen and bone-marrow suspensions. These were tested for interleukin-1 (IL-1) production, Fc receptor expression, phagocytosis, and bactericidal activity. Macrophages recovered from uninoculated chickens at the same sample times, and exposed to CAV in vitro, were also tested. IL-1 production, Fc receptor expression, phagocytosis, and bactericidal activity were significantly lower in all macrophage cultures from CAV-inoculated chickens, and in cultures exposed to the virus in vitro, than in uninfected controls.     

Failure of a single cycle of high dose cyclophosphamide followed by intensive myeloablative therapy and autologous stem cell transplantation to improve outcome in relapsed disease

BACKGROUND: This study attempted to determine the use of a single cycle of high dose cyclophosphamide (60 mg/kg/day x 2) with (N = 16) and without granulocyte macrophage colony stimulating factor (GM-CSF) (N = 12) followed by intensive treatment and autologous stem cell transplantation (ASCT) in patients with relapsed disease. METHODS: Ten patients with multiple myeloma, eight with non-Hodgkin's lymphoma, three with Hodgkin's disease, six with breast cancer, and one with ovarian cancer were studied. Eighteen patients were in resistant relapse (RR) and 10 had sensitive relapses (SRs). All patients had marrow involvement with tumor and had received extensive prior therapy. RESULTS: When responses were assessed just before undergoing ASCT, none of the patients achieved a complete response (CR). Overall, 17 of 28 patients (61%) achieved a partial response (PR). Seven of 18 patients with RR achieved PR (39%). All 10 patients with SR achieved a PR. There were three early deaths. Sixteen patients underwent peripheral blood stem cell (PBSC) collection. Ten of 16 patients received cyclophosphamide plus GM-CSF, and 6 received cyclophosphamide alone. In patients treated with cyclophosphamide plus GM-CSF and cyclophosphamide alone, a median of 5.52 x 10(6) CD34+ cells/kg (range, 0.26-30.49) and 5.72 x 10(6) (range, 1.25-15.66) were collected, respectively. There was no apparent improvement in collection efficiency with GM-CSF. Twenty-two of 28 patients proceeded to ASCT irrespective of response, a median of 45 days (range, 21-203 days) after cyclophosphamide administration. After transplantation, 11 achieved a CR (50%) and 6 a PR (27%). To date, eight patients are alive (median, 679 days; range, 215-1190 days) and five remain in CR more than 6 months (median, 321 days; range, 215-1190 days). All eight surviving patients achieved a PR after high dose cyclophosphamide. CONCLUSIONS: High dose cyclophosphamide reduced the tumor burden by at least 50% in all patients with sensitive disease and in 39% of patients with refractory disease. However, only 5 of 22 patients (23%) remained in CR after ASCT, and all had sensitive disease before the administration of cyclophosphamide. These data suggest that high dose cyclophosphamide followed by intensive treatment and ABMT does not improve the fraction of long term disease free survivors in patients with refractory disease. Future trials would probably be required to demonstrate the utility of intensive treatment in patients with responsive relapse.