Natural resistance to worms exacerbates bovine tuberculosis severity independently of worm coinfection

Pathogen interactions arising during coinfection can exacerbate disease severity, for example when the immune response mounted against one pathogen negatively affects defense of another. It is also possible that host immune responses to a pathogen, shaped by historical evolutionary interactions between host and pathogen, may modify host immune defenses in ways that have repercussions for other pathogens. In this case, negative interactions between two pathogens could emerge even in the absence of concurrent infection. Parasitic worms and tuberculosis (TB) are involved in one of the most geographically extensive of pathogen interactions, and during coinfection worms can exacerbate TB disease outcomes. Here, we show that in a wild mammal natural resistance to worms affects bovine tuberculosis (BTB) severity independently of active worm infection. We found that worm-resistant individuals were more likely to die of BTB than were nonresistant individuals, and their disease progressed more quickly. Anthelmintic treatment moderated, but did not eliminate, the resistance effect, and the effects of resistance and treatment were opposite and additive, with untreated, resistant individuals experiencing the highest mortality. Furthermore, resistance and anthelmintic treatment had nonoverlapping effects on BTB pathology. The effects of resistance manifested in the lungs (the primary site of BTB infection), while the effects of treatment manifested almost entirely in the lymph nodes (the site of disseminated disease), suggesting that resistance and active worm infection affect BTB progression via distinct mechanisms. Our findings reveal that interactions between pathogens can occur as a consequence of processes arising on very different timescales.

Interactions between pathogens cooccurring within a single host can have profound effects on infection outcomes, ranging from the severity of clinical disease in individual hosts to the rate of disease spread across populations (1–3). Because most hosts are commonly infected by more than one type of pathogen at a time (4), understanding the consequences of pathogen interactions during concurrent infection (or coinfection) is essential for effective disease management and control. While many studies focus on pathogen interactions that are the result of one pathogen responding to the simultaneous presence of another (5), two pathogens need not overlap in time to interact with one another. For example, heterologous immunity, where prior exposure or infection with one pathogen modifies the immune response to another, can drive both positive and negative interactions between pathogens (6). This phenomenon highlights how modifications of the host immune system by one pathogen that occur during the lifetime of a host (i.e., in ecological time) can shape future responses to secondary pathogens. Likewise, strong selection pressure imposed by pathogens on hosts, particularly on immune function (7), can result in modifications of the host immune system that occur over generations (i.e., in evolutionary time), a process which should also affect responses to secondary infections. In this case, a historical population-level response to selection by one pathogen may generate heritable differences among individuals in contemporary responses to another. Crucially, ecological- vs. evolutionary-scale interactions between pathogens may operate for different reasons, so distinguishing between the two is integral to understanding both the mechanistic basis and consequences of these interactions.Helminths, or parasitic worms, and tuberculosis (TB) are involved in one of the most geographically extensive of pathogen interactions (2, 8). Both pathogens affect approximately one-third of the world’s human population and are widespread in domestic and wild animals (9–11). Caused by bacteria in the Mycobacterium tuberculosis complex, including M. tuberculosis (Mtb), the causative agent of human TB, and Mycobacterium bovis (Mb), the causative agent of bovine TB, TB is responsible for 2 million human deaths (12) and 25% of all disease-related cattle deaths (13) annually. In humans, about 10% of individuals infected with Mtb progress to active pulmonary disease, but the mechanisms underlying progression to active TB are poorly defined (14). Accumulating evidence suggests that coinfection with worms may be a factor in TB disease progression (2, 15), although some studies do not support this link, highlighting the complex nature of worm–TB interactions (16). Interestingly, research in laboratory animals suggests that enhanced immunity (i.e., resistance) to worms can compromise a host’s ability to control TB even in the absence of active worm infection (17–20), implying that evolved defenses against worms may independently affect the response to TB. Considered in light of widespread worm resistance in human and animal populations (21, 22) and the broad geographic coincidence of worms and TB, worm–TB interactions may represent an illustrative case where variation in evolved resistance to one pathogen (worms) contributes to variable responses to another (TB).In this study, we tested the hypothesis that resistance to worms modifies the host response to TB. To do this, we monitored gastrointestinal (GI) worm (specifically strongyle nematode) and Mb infections in a cohort of wild African buffalo (Syncerus caffer) to assess the effects of natural variation in worm resistance on the incidence, severity, and progression of bovine TB (BTB). In previous work, we demonstrated the presence of an ecological interaction between worms and BTB in buffalo by showing that clearance of active worm infection via anthelmintic treatment reduces BTB-associated mortality (23). Thus, we took advantage of the fact that half of our study animals were subject to long-term deworming to compare the relative effects of worm coinfection vs. natural worm resistance on BTB outcomes. We found evidence of a genetic basis to worm resistance in buffalo and that buffalo with resistance to worms were more severely affected by BTB in terms of both mortality risk and disease progression. However, the mechanisms by which natural variation in the host response to worms was associated with BTB progression appeared to be distinct from the effects of anthelmintic treatment. Our results suggest that negative effects of worms on BTB outcomes occur as a result of both concurrent worm infection and genetically based differences in host responsiveness to worms. This discovery fundamentally alters our understanding of the timescales over which worms and TB interact in real-world populations.     

Activity of lower limb muscles during treadmill running at different velocities

[Purpose] The present study aimed to determine changes in muscle activity while moving on a treadmill at various speeds. [Subjects] The activities of the left vastus lateralis, vastus medialis, hip adductors, lateral head of gastrocnemius, medial head gastrocnemius, soleus, and tibialis anterior of 10 healthy male university students were analyzed. [Methods] University students walked, jogged, and ran for 10 minutes each in random order, and then myogenic potentials were measured 10 minutes later for 30 seconds. The flexion angle of the lower limb upon initial contact, mid stance, and toe off were measured. [Results] The average walking, jogging, and running speeds were 3.6 ± 0.4, 6.7 ± 0.6, and 10.4 ± 1.3 km/h, respectively. The average electromyographic activities of the vastus medial, tibialis anterior, medial head of gastrocnemius, and lateral head of gastrocnemius significantly differed. All muscles were more active during jogging and running than walking. Only the soleus was more active during running than walking, and the activities of the hip adductors and vastus lateralis did not significantly differ. [Conclusion] Velocity is faster and the angles of the lower limbs and ground reaction force (GRF) are larger during running than walking. The vastus medialis and soleus worked more easily according to the angle of the knee joint, whereas the tibialis anterior worked more easily at faster velocities and the medial and lateral heads of the gastrocnemius worked more easily with an increased GRF.Key words: Walking, Running, Skeletal muscle     

Worldwide Distribution of Four SNPs in X‐Ray and Repair and Cross‐Complementing Group 1 (XRCC1)

Purpose

X‐ray repair cross‐complementing group 1 (XRCC1) repairs single‐strand breaks in DNA. Several reports have shown the association of single nucleotide polymorphisms (SNPs) (Arg194Trp, Pro206Pro, Arg280His, Arg399Gln) in XRCC1 to diseases. Limited population data are available regarding SNPs in XRCC1, especially in African populations. In this study, genotype distributions of four SNPs in worldwide populations were examined and compared with those reported previously.

Materials and Methods

Four SNPs (Arg194Trp, Pro206Pro, Arg280His, Arg399Gln) in XRCC1 from genomic DNA samples of 10 populations were evaluated by using polymerase chain reaction followed by restriction fragment length polymorphism analysis.

Results

The frequency of the minor allele corresponding to the Trp allele of XRCC1Arg194Trp was higher in Asian populations than in African and Caucasian populations. As for XRCC1Pro206Pro, Africans showed higher minor allele frequencies than did Asian populations, except for Tamils and Sinhalese. XRCC1 Arg280His frequencies were similar among Africans and Caucasians but differed among Asian populations. Similarly, lower mutant XRCC1 Arg399Gln frequencies were observed in Africans.

Conclusions

This study is the first to show the existence of a certain genetic heterogeneity in the worldwide distribution of four SNPs in XRCC1.     

Granulocyte-colony stimulating factor-producing myeloma with clinical manifestations mimicking chronic neutrophilic leukemia

A 68-year-old man was diagnosed as having bronchial asthma in November 1996. He presented with leukocytosis in June 2002. The WBC count was 29,900/microliter with 82% mature neutrophils showing toxic granules. The neutrophil alkaline phosphatase score and serum level of vitamin B12 were elevated. Bone marrow demonstrated myeloid hyperplasia and plasmacytosis. Cytogenetic and molecular analyses were negative for Philadelphia chromosome and BCR/ABL fusion gene. Lambda-type Bence-Jones protein was detected on the serum and urinary immunoelectrophoresis. The coexistence of chronic neutrophilic leukemia and myeloma was suspected based on the clinical features. The serum level of granulocyte-colony stimulating factor (G-CSF) was elevated. Immunohistochemically, atypical plasma cells were positive for anti G-CSF antibody. Finally, we diagnosed this patient as having a G-CSF-producing myeloma. Treatment with melphalan and prednisolone was initiated without beneficial response. He was then admitted to our hospital for ROAD therapy (ranimustine, vincristine, melphalan, and dexamethasone). The neutrophil count decreased in parallel with the serum G-CSF level. These observations indicated that the neutrophilia in this case was probably caused by a reactive response to G-CSF secreted from the myeloma cells.     

Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones

To increase our understanding of the effect of thiazolidinediones, a new class of antidiabetic drugs, on liver function as well as glycemic control, we investigated liver function before, during, and after treatment with troglitazone and pioglitazone. A total of 32 patients with type 2 diabetes were studied. Glycemic control and liver function were measured before, during, and after 4 to 12 weeks of treatment with troglitazone or pioglitazone. Glycemic control was assessed by fasting levels of plasma glucose, hemoglobin A 1c , and serum insulin, and liver function was assessed by asparatate aminotransferase (AST), alanine aminotransferase (ALT), and gamma -glutamyl transpeptidase ( gamma-GTP). Homeostasis model assessment for insulin resistance was used as an index of insulin resistance. During treatment with troglitazone, fasting plasma glucose and hemoglobin A 1c levels and homeostasis model assessment for insulin resistance were significantly decreased. Serum AST, ALT, and gamma-GTP levels were significantly decreased during treatment (AST, -17.4%; ALT, -27.2%; gamma-GTP, -47.9%) and returned to pretreatment levels after 4 weeks of withdrawal of the drug. A similar tendency was observed during treatment with pioglitazone (AST, -4.7%; ALT, -16.4%; gamma-GTP, -30.8%). These data suggest that, in contrast to the deterioration of liver function reported in a small subset of patients treated with troglitazone, treatment with thiazolidinediones was associated with a decrease in serum transaminases in most patients. The improvement in liver function parameters known to be associated with fatty liver in the present study, together with an improvement in fatty liver reported for another class of insulin sensitizers, biguanides, suggests that thiazolidinediones may have a beneficial effect on fatty liver.     

Modifiable factors for the length of life with disability before death: mortality retrospective study in Japan

BACKGROUND: Past studies have measured and described the length of life with disability before death, but there has been no study of the relationship between modifiable lifestyle factors and duration of disability. OBJECTIVE: To examine whether there are modifiable factors influencing the length of life with disability before death. METHODS: The study was designed as a retrospective observation of the deceased who had earlier been enrolled in a prospective cohort study.During the follow-up period (1996-1999), we documented 781 deaths among those who were 70-79 years of age at the baseline survey in 1994 (n=10,216). In 2000, we interviewed family members of the deceased about the duration of the subjects' disability before death (n=655). RESULTS: The median duration of disability before death was approximately 6 months. Both higher Body Mass Index (BMI) and shorter time spent walking were significantly associated with an increased risk of long-term disability (more than 6 months). The odds ratios of long-term disability were 1.3 in those with BMI 20-25 and 2.1 in those with BMI>25, compared with BMI<20. The odds ratios of long-term disability were 1.3 in those walking for 0.5-0.9 h/day and 1.7 in those walking for <0.5 h/day, compared with those walking for >1.0 h/day. These relationships were unchanged after stratification for causes of death. CONCLUSION: Weight control and walking in later life may shorten the length of life with disability before death.     

Healthy HTLV-I carriers in Japan: the haematological and immunological characteristics

The haematological and immunological characteristics of 34 healthy anti-HTLV-I antibody-positive individuals (HTLV-I carriers) in southwestern Japan were examined. No significant difference was noted between carriers and the controls in counts of RBC, WBC and the absolute number of lymphocytes. The serum IgG in the carriers was higher than that of the controls. The percentages of OKT4, OKT8, OKIa1 and B1-positive cells were found to be normal in the peripheral blood of the carriers, whereas the percentages of OKT11 and anti-Tac-positive cells were significantly higher in the carriers than in the controls. A correlation was observed between the percentages of anti-Tac-positive cells and the titres of anti-HTLV-I antibody in the carriers. After a 72 h incubation of peripheral blood lymphocytes with medium alone, the percentage of anti-Tac-positive cells tended to decrease in the controls, but to increase in carriers, with the appearance of large blastoid cells resembling blastic transformed lymphocytes cultured with mitogen. Tac and Ia antigens were markedly expressed on these large blastoid cells.     

An XXX female with essential thrombocythemia

We describe an XXX female patient accompanied with essential thrombocythemia. To our knowledge this is the first case ever to have been reported. The patient was asymptomatic, but her platelet count had increased to 111.2 x 10(4)/microliter, and she was diagnosed as having essential thrombocythemia based on the diagnostic criteria of the Polycythemia Vera Study Group. At the same time, chromosome analysis of bone marrow cells revealed that she was an XXX female. The patient remained asymptomatic throughout the course of treatment.