Intercycle Intervals Research Articles

Insect-inspired breathing interfaces: investigating robustness of coating-free gas entrapping microtextured surfaces under pressure cycles

Numerous natural and engineering scenarios necessitate the entrapment of air pockets or bubbles on submerged surfaces. Current technologies for bubble entrapment rely on perfluorocarbon coatings, limiting their sustainability. Herein, we investigated the efficacy of doubly reentrant cavity architecture towards realizing gas-entrapping microtextured surfaces under static and dynamic pressure cycling. The effects of positive (>1 atm), negative (<1 atm), and positive–negative cycles on the stability the gas entrapment inside individual doubly reentrant cavities were studied across a range of pressures, ramp rates, intercycle intervals, and water-column heights. Remarkably, the fate of the trapped air under pressure cycling fell into either of the following regimes: the bubble (i) monotonically depleted (unstable), (ii) remained indefinitely stable (stable), or (iii) started growing (bubble growth). This hitherto unrealized richness of underwater bubble dynamics should guide the development of coating-free technologies and help us understand the curious lives of air-breathing aquatic and marine insects.

The role of monoclonal antibodies in treatment of refractory multiple myeloma

Multiple myeloma (MM) is a B-cell malignant tumor; its morphological substrate – plasma cells – produces monoclonal immunoglobulin. Primarily, MM is diagnosed in elderly people and is characterized by a variety of clinical manifestations caused by plasma cells infiltration and organ damage. Despite successes in MM therapy, in the majority of cases recurrences of MM or refractory process are observed. In this case, the choice of antitumor drug is usually made depending on its tolerability, toxicity, and availability. Selection of correct treatment can be complicated by such frequent clinical manifestations of MM as osteolytic vertebral lesions leading to development of pathologic compression fractures which in some cases cause spinal cord compression and full immobility in the patients with MM.A clinical case of a 62-year-old female patient with refractory MM is presented. Pathologic compression fractures of the Th12 and L2 vertebral bodies with massive extraosseous component at the Th12 vertebra level posed a threat of spinal cord compression. At the 1st stage, percutaneous vertebroplasty was performed, then antitumor therapy with daratumumab without increased intercycle intervals which significantly increased patient’s quality of life.

Changing the time intervals between cisplatin cycles alter its ototoxic side effect

Various methods have been tested and deployed clinically to identify and minimize cisplatin ototoxicity. Upon early identification of hearing loss, one of the possible approaches to reducing future ototoxicity is to increase the gaps or breaks between cycles or doses of cisplatin. However, recent findings about the retention of cisplatin in the cochlea and the potential for its long-term ototoxic effects call into question whether such an approach is effective in reducing hearing loss. The current study was undertaken to determine whether increasing the rest intervals between cycles of cisplatin altered the resulting ototoxicity. CBA/CaJ mice were exposed to a cumulative dose of 48 mg/kg cisplatin delivered in three cycles of 16 mg/kg (4 mg/kg per day for 4 consecutive days). The cycles were separated by either 10, 17, or 87 days to determine if the inter-cycle rest intervals affected resulting ototoxicity. Ototoxicity was measured using auditory brainstem response threshold shifts and hair cell losses. Results indicated that longer intervals between cycles of cisplatin led to lower threshold shifts and outer hair cell lesions. The results support the principle that ‘slowing down’ cisplatin dosing by increasing rest intervals between doses can reduce the ototoxic side effect. Further testing is needed to optimize the timing and to determine the impact of longer inter-cycle intervals on cisplatin's anti-tumor efficacy.

Model driven optimization of antiangiogenics + cytotoxics combination: application to breast cancer mice treated with bevacizumab + paclitaxel doublet leads to reduced tumor growth and fewer metastasis.

Bevacizumab is the first-in-class antiangiogenic drug and is almost always administrated in combination with cytotoxics. Reports have shown that bevacizumab could induce a transient phase of vascular normalization, thus ensuring a better drug delivery when cytotoxics administration is adjuvant. However, determining the best sequence remains challenging. We have developed a mathematical model describing the impact of antiangiogenics on tumor vasculature. A 3.4 days gap between bevacizumab and paclitaxel was first proposed by our model. To test its relevance, 84 mice were orthotopically xenografted with human MDA-231Luc+ refractory breast cancer cells. Two sets of experiments were performed, based upon different bevacizumab dosing (10 or 20 mg/kg) and inter-cycle intervals (7 or 10 days), comprising several combinations with paclitaxel. Results showed that scheduling bevacizumab 3 days before paclitaxel improved antitumor efficacy (48% reduction in tumor size compared with concomitant dosing, p < 0.05) and reduced metastatic spreading. Additionally, bevacizumab alone could lead to more aggressive metastatic disease with shorter survival in animals. Our model was able to fit the experimental data and provided insights on the underlying dynamics of the vasculature's ability to deliver the cytotoxic agent. Final simulations suggested a new, data-informed optimal gap of 2.2 days. Our experimental data suggest that current concomitant dosing between bevacizumab and paclitaxel could be a sub-optimal strategy at bedside. In addition, this proof of concept study suggests that mathematical modelling could help to identify the optimal interval among a variety of possible alternate treatment modalities, thus refining the way experimental or clinical studies are conducted.

Perianal infection in patients with hemoblastosis: Risk factors and possibilities of prevention

to identify poor prognostic factors for perianal infection (PI) in patients with hemoblastosis and to define an effective tactic for preventive and therapeutic measures. The prospective study enrolled 72 patients (37 men and 35 women; mean age, 47 years) with hemoblastosis that was complicated by the development of one of the following forms of PI: abscess, infiltrate, multiple ulcers. Different clinical and laboratory characteristics of the patients were examined to identify risk factors for PI. The species-specific concordance of microorganisms isolated from the anus and blood in the development of PI was assessed to record the latter as a source of sepsis. Treatment policy was defined according to the clinical form of PI. Acute myeloid leukemias and lymphomas were the most common background diseases in 30 (41.7%) and 22 (30.6%) patients, respectively. During induction chemotherapy cycles, perianal tissue infection occurred twice more frequently (66%) than totally at the onset of hemoblastosis (13%) and after achievement of remission (during consolidation and maintenance therapy) (21%; Fisher's exact test; p=0.01). PI in agranulocytosis was more than twice as common as in its absence: 69.4% vs 30.6% (p=0.01) and was responsible for sepsis in 9 (18%) of 50 patients. The main source of perianal tissue infection in patients with granulocytopenia was anal fissures and fistulas and ulcers of the anal canal: 44 (88%) cases of the 50 cases. In PI as an abscess, the average white blood cell count was 5 times higher (p=0.01) than that in PI as an infiltrate (or multiple ulcers): 6.6·109/l and 1.2·109 g/l. Abscess formation was observed in 16 (22.2%) patients and an indication for surgical drain. The inflammatory infiltrate was found to develop in 48 (66.7%) patients; multiple ulcers were seen in 8 (11.1%); in this group, parenteral antimicrobial therapy proved to be effective in 36 (78%) patients. 29 patients were operated on for anal fissures and fistulas at intercycle intervals. After continuing CT, PI recurrences were observed in 4 (9.1%) patients. In the operated versus medically treated patients, the risk of complications associated with abnormalities in the perianal area during continued CT was 5 times statistically significantly lower (odds ratio=0.2; 95% confidence interval 0.1 to 0.5; p=0.04; Cochran-Mantel test). Induction CT cycles, the status of granulocytopenia, and the presence of infection sources in the anal canal as an anal fissure, skin ulcerations, or a fistula should be considered as independent statistically significant prognostic risk factors for PI. The number of granulocytes determines the form of inflammation, the course of infection, and the chance of developing sepsis. The effective prevention encompassing surgical treatment for anal canal diseases reduces the risk of septic complications and the number of paraproctitis recurrences, contributing to the implementation of a planned CT program in patients with hemoblastosis.

Stereotypic behaviours and mating success in domestic mares

Stereotypies are often associated with suboptimal environments. However, their adaptive significance remains under debate. The aim of this study was to relate the occurrence of stereotypies in breeding mares to their mating success. The overall, first and second cycle conception rates, inter-cycle interval and the number of cycles per conception were compared between stereotypic mares (n=31) and non-stereotypic mares (n=83). Mares were mated by 9 stallions which were equally balanced between the two groups. Rectal palpation and ultrasound were used to monitor the follicular state of the mares and to confirm pregnancy. The relationship between the occurrence of stereotypies and mating success was analyzed using a multivariate logistic regression. χ2 tests were used to compare independent variables’ distribution between the two groups of mares. Stereotypic mares had a significantly lower overall conception rate (55% vs. 84%, p=0.0018), first-cycle conception rate (26% vs. 54%, p=0.0214) and second cycle. This was still the case when only one type of stereotypic behaviour was considered. Thus, weaving mares (n=26) had a lower overall (58% vs. 81%, p=0.034) and first cycle (33% vs. 64%, p=0.005) conception rate well as a significantly higher number of cycles per conception (2, 0±0.9 in stereotypic vs. 1.5±0.8 in control mares, p=0.037) as compared to non stereotypic mares (n=31). There was no difference between weaving and control mares in inter-cycle intervals (26.1±7.7 in weaving mares vs. 23.9±6.6 in control mares, p=0.74). These findings suggest a lowered fitness in stereotypic mares. To our knowledge, this is the first study relating the occurrence of stereotypies to fertility in horses. The findings that fertility may be impaired in stereotypic animals have important implications and deserve further consideration to elucidate the processes involved.

Cyclic Cushing's syndrome

The cyclic Cushing's syndrome is a rare disease characterized by multiple episodes of elevated cortisol levels alternating with periods of its normal secretion. The so-called hypercorticism cycles may be either regular or episodic with intercycle intervals as long as a few days to several years. Most researchers agree that the reliable diagnosis of cyclic Cushing's syndrome should be based on laboratory detection of 3 peaks and 2 falls of plasma cortisol level. Cyclic Cushing's syndrome may be either ACTH dependent or independent. A review of 65 verified cases indicates that this condition may be caused by pituitary corticotropinoma (54%), ectopic ACTH-producing tumour (26%), and adrenal tumour (roughly 11%). The cause of the disease remains uncertain in 9% of the patients. Pathophysiological mechanisms of cyclic Cushing's syndrome are poorly known. In certain cases of bilateral macronodular adrenal hyperplasia or adrenal corticosteroma, it may be associated with the presence of ectopic receptors or anomalous expression of normally located receptors. The majority of the patients presenting with cyclic Cushing's syndrome exhibit symptoms of classical hypercorticism that manifest themselves either on a permanent or cyclic basis. In a small number of patients, clinical signs of cyclic Cushing's syndrome are virtually absent. Variations of the clinical picture and conflicting results of hormonal assays taken together make cyclic Cushing's syndrome difficult to diagnose. Therefore, physicians must be aware of this condition and actively search for it in all patients believed to have an enhanced cortisol production despite normal results of laboratory analysis. Frequent changes of urinary or salivary free cortisol levels are reliable and convenient criteria for cyclic Cushing's syndrome in patients suspected to have this condition. Results of cortisol stimulation or suppression tests are likely to lead to a false conclusion due to spontaneous falls and rises in serum cortisol levels at the time of analysis. Given laboratory confirmation of cyclic Cushing's syndrome, subsequent studies should be focused on the elucidation of its cause. The average life expectancy of patients with cyclic Cushing's syndrome remains to be determined.

Rapidly Cycled Aggressive Lymphoma-Like Therapy (HD-DTPACE) for Salvage of Patients with Advanced Multiple Myeloma (MM).

Background: High-dose melphalan (MEL)-based autotransplants (AT) have significantly improved complete response rates (CR) and survival in MM. We previously reported on DTPACE (Dexamethasone, Thalidomide, cis-Platin, Adriamycin, Cyclophosphamide, Etoposide) as a highly effective salvage regimen, although EFS and OS were short in the presence of cytogenetic abnormalities (CA) and elevated LDH. Hypothesizing that the 2–3mo recovery after MEL-AT permitted MM re-growth, we explored whether non-stem cell-toxic rapidly cycled dose-intensified DTPACE (HD-DTPACE) induced more sustained responses in AR-MM.Patients and Methods: 23 patients (median age, 58yr; range, 43–74) had high-risk features comprising CA, elevated LDH or high-risk gene expression profiles; 21 (91%) had progressed after AT(1, 4 pts; 2, 14 pts; 3, 3 pts); all had failed ≥1 line of salvage. HD-DTPACE comprised iv D 200mg/d and po T 200mg/d for 4–6d, and 4-day continuous infusions of P 15mg/m2/d, A 15mg/m2/d, C 600mg/m2/d and E 60mg/m2/d, which is an increase in D from 40mg to 200mg and 50% dose escalation of PACE.Results: 23 patients received 39 cycles of HD-DTPACE (1, 15 pts; 2, 3 pts; 3, 4 pts; 4, 1 pt); 18 (78%) responded (CR, 3; near-CR, 8, PR, 7). Focal lesions (FL) were present on PET-CT scans in 15 patients before therapy; after 1 cycle, the median FL decreased from 39 (range, 2–103) to 9 (range, 1–44); in 6 of 12 patients, extramedullary MM resolved. Thirteen patients subsequently received MEL- or BEAM-based AT; 7 received further consolidation and/or maintenance therapy. The tolerability of HD-DTPACE was underscored by its out-patient administration in 17 patients, only 3 of whom required subsequent admission. The median days to ANC> 500/ml and platelets>20.000/ml after the 1st cycle was 16 (range, 9–23) and 18 (range, 10–56). Prior to HD-DTPACE, 4 patients had compromised bone marrow reserve reflected by a platelet count <100,000/ml; however, only 1 required a PBSC boost. The median intervals between cycle 1–2, 2–3 and 3–4 were 41 days (range: 22–165), 39 days (range: 36–93), and 77 days respectively; 3 of 8 patients undergoing repeated cycles of HD-DTPACE had inter-cycle intervals of 22, 29 and 31 days, respectively, with excellent hematopoietic recovery. Consistent with the absence of hematopoietic stem cell injury, there was no evidence of cumulative thrombocytopenia. Non-hematological toxicities included colitis in 4 patients, although oral mucositis was virtually absent. Sepsis, CMV reactivation and DVT occurred in one patient each. Three patients died after HD-DTPACE (progressive disease n=2; cause unknown, n=1). While follow-up is short (median 4mo; range, 1–11), of the 33 patients, 11 remain event-free and 18 alive.Conclusion: HD-DTPACE is an effective, well-tolerated salvage regimen for AR-MM and could be cycled rapidly in heavily pre-treated patients. Rapid cycling of HD-DTPACE within 28 days will be evaluated up-front in patients with poor prognosis MM (CA, high LDH, high-risk genetics), whose 6-yr EFS and OS in our Total Therapy II trial was only 21% and 32%, respectively. Such approach has substantially advanced the outcome patients with aggressive, high-LDH lymphoma.

β-carotene supplementation in patients radically treated for stage I-II head and neck cancer: Results of a randomized trial

This study was aimed at evaluating the efficacy of beta-carotene in improving survival (S) and in disease-free survival (DFS) and reducing the incidence of second primary tumors (SPT) in patients with a radically treated stage I-II squamous head and neck tumors. Eligible patients were randomly allocated to receive beta-carotene (n=104) or no treatment (n=110). beta-carotene was administered at the dose of 75 mg/day for 3-month cycles within one month intercycle intervals for a 3-year period. The 3-year compliance to the beta-carotene was 68.7%. Only eight patients reported drug-related toxicity (7.8%). The median follow-up of all patients was 59 months. The median follow-up was 61 months (range 1-116 months) in the beta-carotene and 58 months (1-123 months) in the control group. The 10-year DFS was 75.7% for the patients in the beta-carotene and 74.3% for those in the control group (P=0.56). The 10-year S was 85.9% in the beta-carotene group and 80.9% in the control group (P=0.20). beta-carotene supplementation had no significant effect on the incidence of second primary tumors (RR=0.99; 95% C.I. 0.28-3.44). A statistically non-significant 40% reduction in the risk of death among subjects assigned to the beta-carotene compared to the controls was observed (RR=0.60; 95% C.I. 0.26-1.38). No increase in the death from cardiovascular diseases was observed among patients treated with beta-carotene. Our results might support the hypothesis that an adequate beta-carotene treatment could be potentially associated with a decreased risk of death in these patients.

73 Post-operative radiotherapy and concomitant adjuvant chemotherapy for breast carcinoma

Between May 1992 and December 1993, 72 patients operated for breast carcinoma underwent radiotherapy (RT) and concomitant adjuvant chemotherapy (CT). There were 2 T0, 23 T1, 47 T2 and 1 T4b. Lymph node status was 59 N0, 10 N1 and 4 unknown. Surgical treatment was lumpectomy (59) or mastectomy (13) and axillary dissection for all. Radiation therapy delivered 50 Gy in 5 weeks to the breast or chest wall. A 10 Gy boost was added to the tumor site after lympectomy. The internal mammary chain was irradiated in 64 patients, the subclavicular area in 53 and the axilla in I patient. The CT regimen was a combination of Mitoxantrone (12mg/m²), 5-FU (500 mg/m²) and Cyclophosphamide (500 mg/m²), 6 cycles were delivered with 21 days interval. Compliance to RT evaluated on dose and treatment length was good for 88%. On the 65 patients analysed for CT: 98% received all 6 cycles at the prescribed dose, but 69% strictly respected intercycle intervals. Mild digestive and cutaneous toxicity (grade 1 and 2) was observed in 50%. Major toxicity was neutropenia (grade 2 or 3) in 18 patients and 1 severe infection. The 3 year actuarial survival rate was 87%. No local relapse was observed Metastases occurred in 6 patients. These preliminary results show that this concomitant association is safe although compliance to chemotherapy should be improved.

Communication and synchronized molting in a colonial araneid spider,Eriophora bistriata

The colonial orb-weaving spider,Eriophora bistriata, coordinates molting cycles through communication. Colonies with differing molting cycles synchronize when combined. Intercycle intervals depend upon food availability. The possible coordination of this synchrony by chemical communication among spiders is discussed.

Altered menstrual cycles in rhesus monkeys induced by lead

Adult, female rhesus monkeys ingested lead daily for three 1-year exposures over a 5-year period followed by chronic lead intake for 3 additional, consecutive years. Lead was administered as lead acetate in the drinking water at levels producing average circulating concentrations of lead between 44 and 89 μg/100 ml and zinc protoporphyrin concentrations between 87 and 105 μg/100 ml. The monkeys were without overt signs of lead toxicity at all times; i.e., appetite, body weight, and hematocrit levels were normal. Menstrual cycles were altered by lead. During the last 2 years of exposure, the lead-treated monkeys had less frequent cycles, longer and more variable intercycle intervals, and fewer days of vaginal bleeding than controls. These differences were not due to seasonal artifacts or differences in exposure to environmental influences such as light or diet. Further, historical data indicated that cycles were normal for the treated monkeys prior to exposure to lead and that three of four cycle characteristics remained normal during the first lead exposures. Duration of vaginal bleeding was initially attenuated by lead but returned to normal when lead intake was discontinued between exposures. In contrast, the effects of lead observed during the later years of exposure remained apparent 1 year following termination of lead ingestion. These results suggest that persistent alterations of the menstrual cycle and perhaps premature menopause resulted from prolonged exposure to lead at levels which produced no obvious signs or symptoms of toxicosis.

The identity model and factors controlling the superiority of the study-test method over the anticipation method.

Short-term memory (STM) and long-term memory (LTM) components are assumed to overlap in such a way that the response reflects predominantly STM components in short retention intervals but LTM ones in long retention intervals. Based on the STM and LTM overlap hypothesis, the identity model postulates that basic processes per study, test, and intervening study and test events as well as intercycle intervals, respectively, are the same for both anticipation and study-test methods in cued (paired-associate) recall and recognition (verbal discrimination learning). A crucial difference between the two methods is the differential retention interval distribution (containing an overlap area). Amounts of STM components in the short-term store (STS), that is, critical items, seem to control the varied superiority of the study-test method over the anticipation method. This is directly linked to the learning difficulty dimension, which in turn is determined by such variables as list length, learning materials, exposure durations (presentation rates), acquisition stages, learning ability, developmental stages (ages), and others.

Quantitative Tests of the Retention Interval Model

Summary The retention interval model (Izawa, 1981), formulated to explain quantitative performance differences between anticipation and study-test item-presentation methods, was examined through three experiments, each conducted with massed practice with no intercycle intervals and with two levels of spaced practice using 30- and 100-sec intercycle intervals, respectively. In spite of the fact that an extremely restricted parameter-estimation method was used—estimating all parameters that control retention phenomena from the 30-sec intercycle interval condition only, and using the values to all the other conditions with 0- and 100-sec intercycle intervals—results turned out to be quite satisfactory. The retention interval model accounted for 95% of data based on 198 points, stemming from a total of 24,948 observations with 174 Ss, by the use of only 36 estimated parameters in three experiments (66 data points via 12 parameters per experiment). Thus, this single theory seems to account for performances with both massed and two levels of spaced practice, as well as under both anticipation and study-test item-presentation methods, which were previously considered to be quite different. Overall trends exhibited in the parameter values were also in the direction predicted from the retention interval model.

Toward a quantitative theory for performance differences between anticipation and study‐test procedures: The retention interval model

In an effort to account quantitatively for performance differences between study‐test and anticipation methods, a rudimentary theory, the retention interval model, is proposed. This model postulates three different theoretical functions for the three operationally distinguishable and qualitatively different events in the retention interval: intercycle rest, intervening‐study‐events and intervening‐test‐events intervals. The retention interval model satisfactorily accounted for 144 data points based on 35, 136 observations (164 subjects) by using only 30 estimated parameters in three experiments (48 points via 10 parameters per experiment), with massed as well as spaced practice, under both anticipation and study‐test (RT) methods. In spite of a restrictive parameter estimation mode, close agreements were achieved between the model and data. The retention interval appears to generate powerful effects in determining the absolute performance levels for both anticipation and study‐test learning procedures in the various intercycle intervals.

An inexpensive pure-tone pattern generator

A low-cost sound pattern generator that is remotely programmable has been developed to produce pure-tone auditory patterns. The device, which is compatible with relay programming equipment, can generate either of two auditory patterns in the sequence ABA or BAB. The generator features an independently settable range of ON and OFF durations (0.1 to 1.0 sec) for pure-tone bursts and a selectable range (0.2 to 2.0 sec) of intercycle intervals. The inexpensive construction cost coupled with the flexibility of the timing characteristics of the generator should make it of interest to a wide variety of auditory researchers.