Functionally weighted airway sparing (FWAS): a functional avoidance method for preserving post-treatment ventilation in lung radiotherapy.

Recent changes to the guidelines for screening and early diagnosis of lung cancer have increased the interest in preserving post-radiotherapy lung function. Current investigational approaches are based on spatially mapping functional regions and generating regional avoidance plans that preferentially spare highly ventilated/perfused lung. A potentially critical, yet overlooked, aspect of functional avoidance is radiation injury to peripheral airways, which serve as gas conduits to and from functional lung regions. Dose redistribution based solely on regional function may cause irreparable damage to the 'supply chain'. To address this deficiency, we propose the functionally weighted airway sparing (FWAS) method. FWAS (i) maps the bronchial pathways to each functional sub-lobar lung volume; (ii) assigns a weighting factor to each airway based on the relative contribution of the sub-volume to overall lung function; and (iii) creates a treatment plan that aims to preserve these functional pathways. To evaluate it, we used four cases from a retrospective cohort of SAbR patients treated for lung cancer. Each patient's airways were auto-segmented from a diagnostic-quality breath-hold CT using a research virtual bronchoscopy software. A ventilation map was generated from the planning 4DCT to map regional lung function. For each terminal airway, as resolved by the segmentation software, the total ventilation within the sub-lobar volume supported by that airway was estimated and used as a function-based weighting factor. Upstream airways were weighted based on the cumulative volumetric ventilation supported by corresponding downstream airways. Using a previously developed model for airway radiosensitivity, dose constraints were determined for each airway corresponding to a <5% probability of airway collapse. Airway dose constraints, ventilation scores, and clinical dose constraints were input to a swarm optimization-based inverse planning engine to create a 3D conformal SAbR plan (CRT). The FWAS plans were compared to the patients' prescribed CRT clinical plans and the inverse-optimized clinical plans. Depending on the size and location of the tumour, the FWAS plan showed superior preservation of ventilation due to airflow preservation through open pathways (i.e. cumulative ventilation score from the sub-lobar volumes of open pathways). Improvements ranged between 3% and 23%, when comparing to the prescribed clinical plans, and between 3% and 35%, when comparing to the inverse-optimized clinical plans. The three plans satisfied clinical requirements for PTV coverage and OAR dose constraints. These initial results suggest that by sparing pathways to high-functioning lung subregions it is possible to reduce post-SAbR loss of respiratory function.

Lactobacillus plantarum IS-10506 supplementation increases faecal sIgA and immune response in children younger than two years.

The immature intestinal immune system in young children develops as it comes into contact with dietary and microbial antigens in the gut. Intestinal microbiota plays a significant role in host defence mechanisms as shown by inflammatory responses towards potential pathogens. We investigated the probiotic function of Lactobacillus plantarum IS-10506 of 'dadih' origin in modulating immune response in young children. We aimed to assess its effect on their immune response by assessing transforming growth factor-ß1 (TGF-ß1) and tumour necrosis factor-α (TNF-α) responses and faecal secretory immunoglobulin A (sIgA) titre in a randomised, double-blinded placebo-controlled trial in 12-24-month-old children (n=38). We used four treatment groups for a 90-day supplementation period: placebo (n=11), probiotic (n=9), zinc (n=8) and probiotic and zinc (n=10). Faecal sIgA, plasma TGF-ß1 and TNF-α titre were evaluated using the enzyme-linked immunosorbent assay standard technique. Statistical analysis divided the results (pre/post treatment) into high (>1) and low (<1) ratios. The results showed that faecal sIgA titre increased in all treatment groups compared with the control (placebo) and significantly increased in the probiotic group (P=0.05). In addition, the TGF-ß1 ratio in the zinc group was significantly higher (P=0.05) than that in the placebo group. We observed a significant positive correlation between TGF-ß1/TNF-α and faecal sIgA (r=0.27, P=0.04). Post hoc test results revealed that zinc supplementation has a significant effect on body-weight gain. Taken together, probiotic L. plantarum IS-10506 supplementation stimulates TGF-ß1, which in turn increases the production of sIgA, in line with the significant correlation between TGF-ß1/TNF-α and faecal sIgA.

Maternal and child cytokine relationship in early life is not altered by cytokine gene polymorphisms.

The development of immune responses is influenced by the interaction between environmental and genetic factors. Our previous study showed a close association between maternal and young infant's cytokine responses. The question is how this association evolves over time and the contribution of genetic polymorphisms to this association. Five cytokines in mitogen-stimulated whole blood culture were measured from pregnant mothers and their children aged 2, 5, 12, 24 and 48 months. Cytokine gene polymorphisms were determined in both mothers and children. High production of maternal interleukin (IL)-10, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) was significantly associated with higher levels of the corresponding cytokines in their children at 2 months (T2), but the association decreased over time. Maternal single-nucleotide polymorphism (SNP) in IFN-γ gene, rs3181032, was found to be associated with child's IFN-γ levels at T2 only, whereas maternal IL-10 rs4579758 and child's TNF-α rs13215091 were associated with child's corresponding cytokines at later ages but not at T2. In the final models including the gene polymorphisms, maternal cytokines were still the strongest determinant of child cytokines. Maternal cytokine during pregnancy, which could be a proxy for child's environmental factors, showed its highest impact at early age, with no or little influence from genetic factors.

PCR-based detection and identification of the filarial parasite Brugia timori from Alor Island, Indonesia.

Brugia timori is widely distributed on Alor Island, Indonesia, where it causes a high degree of morbidity. The HhaI tandem repeat of B. timori was found to be identical to that of B. malayi, for which sensitive PCR-based assays have already been developed. Using one of these assays, a single microfilaria (mf) of B. timori, present in a spot of dry blood on filter paper, could be detected. The assay was equally sensitive in the detection of B. timori and B. malayi. When the collected mosquitoes were pooled according to species and tested with the assay, 39 (64%) of the 61 Anopheles barbirostris pools (containing a total of 642 mosquitoes) were positive. As none of the 33 Culex pools tested (which contained 624 mosquitoes) gave a positive result, and An. barbirostris is the only Anopheles species commonly caught on human bait in Alor, An. barbirostris is assumed to be the main and perhaps only local vector. Brugia timori could be differentiated from B. malayi by restriction-endonuclease digestion of the PCR-amplified mitochondrial cytochrome oxidase subunit 2. A few distinct nucleotide exchanges were also found in the second internal transcribed ribosomal spacer of the filariae, and in the 16S rDNA and FTSZ gene of their Wolbachia endobacteria. The results show that B. timori can be effectively detected using the PCR-based assay developed for B. malayi and can then be differentiated from B. malayi by other molecular markers. PCR-based techniques targeting the HhaI repeat can therefore be employed for monitoring B. timori in the framework of the Global Programme to Eliminate Lymphatic Filariasis.

High tuberculosis notification and treatment success rates through community participation in central Sulawesi, Republic of Indonesia.

SETTING: Central Sulawesi Province, Republic of Indonesia. OBJECTIVE: To increase tuberculosis case notification and maintain high treatment success rates through community participation in a tuberculosis field programme. DESIGN: Comparison of tuberculosis case notification and treatment results in a community based tuberculosis programme (CBTP), before and after introduction of the programme and between areas where the programme was and was not introduced. RESULTS: During 1998, the CBTP was introduced in two of the four rural districts of the Central Sulawesi province, covering 224 (29%) of the 772 villages and 362,700 (33%) of the 1,109,100 population in these districts. In the CBTP villages the notification rate of new smear-positive patients per 100,000 population increased from SI in 1996 and 48 in 1997 to 166 in 1998. In the 548 non-CBTP villages the rates were 62, 60 and 70, respectively. The sputum conversion rate at the end of the first 2 months of the treatment was over 85% in both the CBTP and the non-CBTP villages. In the CBTP villages the treatment success rate (cure and treatment completion) was 90.4%, 89.5% and 93.7% in 1996, 1997, and 1998. For the non-CBTP villages these rates were respectively 85.4%, 86.8% and 85.9%. In 1998 the sputum conversion and treatment success rates were significantly higher in the CBTP villages than in the non-CBTP villages. CONCLUSION: Through community participation, the notification of new smear-smear positive patients increased substantially, while sputum conversion and treatment success rates remained high.

Detection of DNA of nocturnally periodic Brugia malayi in night and day blood samples by a polymerase chain reaction-ELISA-based method using an internal control DNA.

An internal control was used in a polymerase chain reaction (PCR)-ELISA-based technique to detect the Hha I repeat of the filarial parasite Brugia malayi. A single microfilaria added to 200 microl of blood was reliably detected. The assay was evaluated on field samples from persons living in an area endemic for Anopheles-transmitted, nocturnally periodic B. malayi in central Sulawesi, Indonesia. Examination of night blood of 138 individuals for the presence of microfilariae by filtration revealed 44 microfilaria carriers. All microfilaria carriers were also positive in the PCR-ELISA and, in addition, 14 more samples were proven to contain parasite DNA. The sensitivity of both methods was compared on night and on day blood samples collected from 113 persons. Whereas 37 microfilaria carriers were identified by filtration of night blood, no microfilariae were observed in the corresponding day blood samples. The PCR-ELISA result was positive in all 37 night blood samples of microfilaria carriers and in an additional 13 night blood samples without microfilariae. Parasite DNA was detected in 31 day blood samples of microfilaria carriers and in 3 day blood samples of amicrofilaremic persons. Assuming a sensitivity of the PCR-ELISA on night blood of 100%, the sensitivity of night blood filtration is 74% and that of the PCR-ELISA on day blood is 68%. These data suggest that the described PCR-ELISA method is capable of detecting infections with nocturnally periodic B. malayi in day blood samples. Therefore, this method may facilitate both the identification of endemic areas and the monitoring of control programs.

High cure rates in smear-positive tuberculosis patients using ambulatory treatment with once-weekly supervision during the intensive phase in Sulawesi, Republic of Indonesia.

SETTING: The four provinces of Sulawesi, Republic of Indonesia. OBJECTIVE: Treatment of smear-positive pulmonary tuberculosis patients using ambulatory treatment with supervision once weekly during the intensive phase and once fortnightly during the continuation phase. DESIGN: Pilot projects with gradual expansion of activities according to defined quantitative criteria. RESULTS: During the period January 1993-December 1997, 11,879 new smear-positive and 320 smear-positive previously treated patients, of whom 259 were relapses, were placed on short-course chemotherapy. At the end of the intensive phase, 87.5% of new patients and 80.0% of retreatment patients had become sputum smear-negative. During the period January 1993-December 1996, of 7,251 new smear-positive patients placed on treatment 85.2% were cured and an additional 7.9% had completed treatment, giving a total success rate of 93.1%. For 239 patients placed on retreatment the total success rate was 86.6%. CONCLUSION: The treatment results show that the policy introduced in Sulawesi is effective. In two provinces priority will now be given to increasing case detection, while in the other two provinces the emphasis will be on reaching full coverage. The reasons for the success of the projects are discussed, as are the prerequisites for introducing the policy in other areas.

Ivermectin and diethylcarbamazine trials in leaf monkeys (Presbytis cristatus) infected with Wuchereria kalimantani.

Clinical trials of Ivermectin in single oral doses of 200, 400, and 1,000 mg/kg body weight or in multiple doses of 200 mg/kg body weight for 5 consecutive days were performed in leaf monkeys (Presbytis cristatus) infected with Wuchereria kalimantani. Optimal microfilaricidal effect occurred at 200 mg/kg body weight. The drug was less effective than diethylcarbamazine in this animal model for human filariasis but had no adverse effects.