A dynamical model of oncotripsy by mechanical cell fatigue: selective cancer cell ablation by low-intensity pulsed ultrasound.

The method of oncotripsy, first proposed in Heyden & Ortiz (Heyden & Ortiz 2016 J. Mech. Phys. Solids 92, 164-175 (doi:10.1016/j.jmps.2016.04.016)), exploits aberrations in the material properties and morphology of cancerous cells in order to ablate them selectively by means of tuned low-intensity pulsed ultrasound. We propose the dynamical model of oncotripsy that follows as an application of cell dynamics, statistical mechanical theory of network elasticity and 'birth-death' kinetics to describe the processes of damage and repair of the cytoskeleton. We also develop a reduced dynamical model that approximates the three-dimensional dynamics of the cell and facilitates parametric studies, including sensitivity analysis and process optimization. We show that the dynamical model predicts-and provides a conceptual basis for understanding-the oncotripsy effect and other trends in the data of Mittelstein et al. (Mittelstein et al. 2019 Appl. Phys. Lett. 116, 013701 (doi:10.1063/1.5128627)), for cells in suspension, including the dependence of cell-death curves on cell and process parameters.

Phase I study of temsirolimus in combination with cetuximab in patients with advanced solid tumours.

BACKGROUND: Preclinical studies suggest synergistic antitumour effects of mammalian target of rapamycin (mTOR) inhibitor such as temsirolimus combined with anti-EGFR monoclonal antibody such as cetuximab. METHODS: Temsirolimus (T) and cetuximab (C) were combined and escalated in cohorts of patients with advanced or metastatic solid tumours, respectively from 15 to 25 mg and 150-250 mg/m2, until the maximum tolerated dose (MTD) was determined. Effort was made in the expansion cohort to enrol patients harbouring a molecular aberration in the human epidermal growth factor receptor (EGFR) and/or phosphoinositide 3-kinase (PI3K) pathways. Paired biopsies were optional to evaluate pathway modulation. RESULTS: Among 39 patients enrolled, three experienced dose-limiting toxicities (DLTs): pulmonary embolism (C200 + T20), stomatitis (C250 + T20) and acneiform rash (C250 + T25). The weekly C 250 mg/m2 and T 25 mg dose level was selected as the MTD. The most common treatment-related adverse events were: acneiform rash (97%), oral mucositis (82%), fatigue (59%), nausea (41%) and diarrhoea (36%). The median progression-free survival (PFS) and overall survival (OS) were respectively 2.0 months [95% CI: 1.8, 3.5] and 7.5 months [95% CI: 5.5, 11.9]. Among all patients, partial responses (PRs) and stable diseases (SDs) were observed in 2 (5.1%) and 18 patients (46.2%), respectively. The objective response rate (ORR) in patients with a molecular aberration was 2/14 (14%), versus 0/24 in those without molecular aberration. CONCLUSIONS: Combination of T + C showed significant but manageable toxicities. Due to modest clinical activity, further evaluation is not recommended. Molecular selection could potentially increase the objective response rate and should be implemented during drug development.

Matched sample comparison of intramuscular versus vaginal micronized progesterone for prevention of preterm birth.

OBJECTIVES: To compare vaginal with intramuscular progesterone administration to prevent preterm labor in women with singleton pregnancies and at increased risk of preterm birth. STUDY DESIGN: Prospective comparative clinical trial. POPULATION: One hundred and sixty pregnant women at 20-24 weeks gestation at the risk of preterm labor were classified into: 80 women who received micronized progesterone tablets 200 mg vaginally daily (Group A) and 80 women who received 100 mg progesterone in the form of intramuscular every third day (Group B). METHODS: Estimation of gestational age, assessment of fetal growth and fetal biophysical profile by trans-abdominal ultrasonographic examination was done every 4 weeks till delivery. Measurement of cervical length was achieved by transvaginal ultrasonography, done every 4 weeks till delivery. MAIN OUTCOME MEASURES: Incidence of preterm delivery, mean gestational age and the incidence of adverse events of intramuscular versus vaginal route of progesterone administration. RESULTS: The incidence of preterm delivery in Group A was 20% and in Group B was 27.5%. The difference between both groups was statistically insignificant. In addition, the rate of adverse events reported in women received injectable progesterone was significantly higher than the rate of adverse events reported in women who received vaginal progesterone therapy. CONCLUSION: Vaginally administrated progesterone was nearly as equally effective as intramuscular progesterone in the prevention of preterm labor in women at risk and in the meantime has less undesirable events.

Inflammatory BCG adenitis associated with immune reconstitution following allogeneic haematopoietic stem cell transplant in infancy.

We describe four cases of a localized, granulomatous reaction to BCG including ipsilateral painful, suppurative lymphadenopathy associated with donor immune reconstitution following allogeneic haematopoietic stem cell transplant performed in infancy and preceded by uneventful, routine BCG immunisation. The management of the inflammatory disease in these cases with surgery, antimycobacterial chemotherapy and steroids, is discussed.

Chemotherapy-induced cardiotoxicity: current practice and prospects of prophylaxis.

Cardiotoxicity is a potential side effect of few chemotherapeutic agents. The anthracycline class of cytotoxic antibiotics are the most famous, but other chemotherapeutic agents can also cause serious cardiotoxicity and are not so well recognised. Examples include cyclophosphamide, ifosfamide, mitomycin and fluorouracil. Prediction and hence prophylaxis has always been a difficult task. Ideal monitoring techniques, upon which efficient prophylaxis depends, are yet to be determined. Current prophylaxis relies upon early detection of systolic and/or diastolic dysfunction. While somewhat useful, in some cases by the time defects are detected progression of chemotherapy-induced cardiomyopathy is beyond prevention. Prophylaxis would be much more efficient if a biochemical marker of myocardiocyte damage could be reliably used to stop further chemotherapy at the correct time before irreversible progressive 'macroscopic' damage becomes evident upon imaging. Work is currently progressing to identify the role of markers such as troponins and natriuretic peptides in this regard.

The structure and function of the helical heart and its buttress wrapping. I. The normal macroscopic structure of the heart.

The Gordian knot of anatomy has been the architectural arrangement of ventricular muscle mass, which may have finally become understood. The description of Francisco Torrent-Guasp's model of the helical heart is presented, which includes the cardiac structures that produce 2 simple loops that start at the pulmonary artery and end in the aorta. An unscrolled ventricular band is shown, achieved by blunt dissection that extends between the points of origin of the right ventricle, at the pulmonary artery root, to termination at the aortic root, in the left ventricle. These components include a spiral horizontal basal loop that surrounds the right and left ventricular cavities, and changes direction to cause a second spiral, produced by almost vertically oriented fibers, giving rise to the helical configuration of the ventricular myocardial band. These anatomic structures are successively activated, as with a peristaltic wave, starting at the right ventricle (just below the pulmonary artery) and progressing toward the aorta to produce a sequence of narrowing, caused by the basal loop contraction, shortening (related predominantly to the descendant segment contraction), lengthening (produced by the ascendant segment contraction), and widening, as a consequence of several factors that act during ventricular myocardium relaxation. These sequences control the ventricular events responsible for ejection to empty and suction to fill. These mechanical interactions of structure and function are defined in relation to chronologic location of the successive cardiac functional events in the aortic, left ventricular, and left atrial recordings.

The structure and function of the helical heart and its buttress wrapping. III. The electric spiral of the heart: The hypothesis of the anisotropic conducting matrix.

The study of the dissemination of the electric impulse throughout the ventricular myocardium, which gave rise to the current theories, was performed without taking into consideration the complex architecture of the cardiac muscle elucidated by more recent researchers. We propose a novel hypothesis based on the special macroscopic structure of the heart, the anisotropic electric and mechanical behavior of the myocardium, the characteristics of the intercellular matrix and its very special collagen scaffolding, chemical composition, and biochemistry. The unique properties of the intercellular matrix would make it especially suited to function, in conjunction with the specialized conducting system (His-Purkinje system), as an efficient anisotropic conductor for the spread of electric activation in the heart, and to allow an optimal sequence of excitation-contraction coupling that results in the coordination of effective myocardial contraction in birds and mammals of the most varied known heart rates.

The structure and function of the helical heart and its buttress wrapping. IV. Concepts of dynamic function from the normal macroscopic helical structure.

Torrent-Guasp's model of the helical heart is presented, which includes the cardiac muscular structures that produce 2 simple loops and that start at the pulmonary artery and end in the aorta. These components include a horizontal basal loop that surrounds the right and left ventricles, changes direction through a spiral fold in the ventricular band to cause a ventricular helix produced by now obliquely oriented fibers, forming a descending and ascending segment of the apical loop with an apical vortex. These anatomic concepts are successively activated to produce a sequence of narrowing by the basal loop, shortening by the descending segment, lengthening by the ascending segment, and widening in the cardiac cycle that causes ventricular ejection to empty and suction to fill. The factors responsible for internal torsional movements for cardiac output and suction are defined, together with mechanisms responsible for electromechanical activity produced during sequential changes in contraction and relaxation properties. These interactions of mechanical structure and function are defined in relation to pressure-related cardiac events observed from aortic, left ventricular, and left atrial recordings.

Cue dependency of nicotine self-administration and smoking.

A paradox exists regarding the reinforcing properties of nicotine. The abuse liability associated with smoking equals or exceeds that of other addictive drugs, yet the euphoric, reinforcing and other psychological effects of nicotine, compared to these other drugs, are more subtle, are manifest under more restricted conditions, and do not readily predict the difficulty most smokers experience in achieving abstinence. One possible resolution to this apparent inconsistency is that environmental cues associated with drug delivery become conditioned reinforcers and take on powerful incentive properties that are critically important for sustaining smoking in humans and nicotine self-administration in animals. We tested this hypothesis by using a widely employed self-administration paradigm in which rats press a lever at high rates for 1 h/day to obtain intravenous infusions of nicotine that are paired with two types of visual stimuli: a chamber light that when turned on signals drug availability and a 1-s cue light that signals drug delivery. We show that these visual cues are at least as important as nicotine in sustaining a high rate of responding once self-administration has been established, in the degree to which withdrawing nicotine extinguishes the behavior, and in the reinstatement of lever pressing after extinction. Additional studies demonstrated that the importance of these cues was manifest under both fixed ratio and progressive ratio (PR) schedules of reinforcement. The possibility that nicotine-paired cues are as important as nicotine in smoking behavior should refocus our attention on the psychology and neurobiology of conditioned reinforcers in order to stimulate the development of more effective treatment programs for smoking cessation.

Optimizing ventricular shape in anterior restoration.

Ishemic dilated cardiomyopathy results from altered muscle mechanics. Ventricular restoration is aimed at altering the volume and shape changes that follow myocardial infarction. Optimal surgical methods to achieve this goal are not well defined, but it has been shown that sphericity is an important determinant of long-term outcome. We present the rationale and techniques for returning the globular remodeled ventricle to a more elliptical shape. Clinical data from our RESTORE registry does not suggest an improvement in early or late mortality with such methods but opens the way for late evaluation of functional and exercise capacity.

A stepwise approach to the treatment of early onset nephrotic syndrome.

We have retrospectively reviewed our single-center experience of the treatment of early onset nephrotic syndrome (NS). From 1991 to 1998, ten children with NS were treated. Kidney biopsy showed focal sclerosis (n=1), diffuse mesangial sclerosis (n=7), and congenital NS of the Finnish type (n=2). Associated conditions included incomplete Drash syndrome (n=1), Galloway-Mowat syndrome (n=1), and severe mental and motor retardation of unknown origin (n=3). From 1991 to 1997, five children with NS were treated. Bilateral nephrectomy (NX) was performed in three, one patient with severe retardation died at 4 years and NX was not performed in one patient who showed satisfactory growth and development. Three of these children were dialyzed and two were successfully transplanted. One patient was transplanted without previous dialysis. From 1997 to 1998, five children were treated with a regimen that included captopril and indomethacin (CAPTO/INDO). CAPTO/ INDO was successful in increasing serum protein in all patients and producing growth and development in four patients. In two patients CAPTO/INDO was successful only after unilateral NX. Our experience indicates that CAPTO/INDO may be a valuable treatment in patients with early onset NS. An individualized stepwise approach including unilateral NX should be considered to achieve optimal results.

Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding.

RATIONALE: Research on smoking behavior and responsiveness to nicotine suggests that nicotine's effects may depend on the sex of the organism. OBJECTIVE: The present study addressed four questions: 1) Will female rats self-administer nicotine? 2) Does self-administration by females vary as a function of estrous cycle? 3) Does self-administration by females differ from that of males? 4) Does self-administration of nicotine result in up-regulation of nicotinic receptor binding and are these changes similar in males and females? METHODS: Male and female Sprague-Dawley rats were allowed to self-administer nicotine at one of four doses (0.02-0.09 mg/kg, free base) on both fixed and progressive ratio schedules of reinforcement. RESULTS: Females acquired nicotine self-administration across the entire range of doses. Acquisition of self-administration at the lowest dose was faster in females than males. However, few sex differences were found in the number of active responses, number of infusions, or total intake of nicotine during stable fixed ratio self-administration. In contrast, females reached higher break points on a progressive ratio. For both schedules, females had shorter latencies to earn their first infusion of each session and demonstrated higher rates of both inactive and timeout responding. There was no effect of estrous cycle on self-administration during either fixed or progressive ratio sessions. Self-administered nicotine resulted in average arterial plasma nicotine levels between 53 and 193 ng/ml and left hemi-brain levels between 174 and 655 ng/g, depending on dose. Nicotine self-administration produced similar up-regulation of nicotinic receptor binding sites in males and females, as reflected by increased right hemi-brain binding of [3H]-epibatidine, when compared to the brains of untreated control rats. CONCLUSIONS: These results suggest that while males and females may regulate their intake of nicotine similarly under limited access conditions, the motivation to obtain nicotine is higher in females.

Nicotine self-administration in rats on a progressive ratio schedule of reinforcement.

RATIONALE: Robust intravenous (i.v.) nicotine self-administration (SA) in rats has been reported by several laboratories, including our own, using fixed ratio (FR) schedules of reinforcement. Studies on other drugs of abuse, however, suggest that progressive ratio (PR) schedules may provide additional information not gained using FR schedules. OBJECTIVE: Here, we attempt to establish and characterize nicotine SA on a PR. METHODS: One study allowed animals to acquire SA on a FR at four doses of nicotine (0.02, 0.03, 0.06, 0. 09 mg/kg) before being switched to a PR. A second study examined extinction by saline substitution or pretreatment with the nicotinic antagonist, mecamylamine, including a preliminary analysis into the role of secondary reinforcers in the extinction process. RESULTS: SA of nicotine on a PR was stable across repeated sessions. The number of infusions earned on a PR correlated with infusion rate on a FR; however, a large portion of the variance in SA on a PR could not be accounted for by infusion rate on a FR. Infusions on a PR increased across the same range of doses that produced a decrease in the infusion rate on a FR. Extinction of responding occurred after saline substitution or pretreatment with mecamylamine, and animals re-acquired when nicotine was again available without pretreatment. The presence of drug-paired stimuli appeared to lengthen the extinction process. CONCLUSIONS: Nicotine supports stable SA on a PR. Since PR and FR schedules may measure different aspects of nicotine reinforcement, PR schedules may be valuable in further characterizing group and individual differences in nicotine reinforcement.

Artificial abdominal hernia for the treatment of hepatomegaly in a neonate with stage 4S neuroblastoma.

Surgical widening of the abdomen by a silastic pouch has been used very rarely in the management of critically ill infants with hepatomegaly due to neuroblastoma stage 4S. A female newborn baby was referred on the second day of life because of local compressive effects of a massive hepatomegaly, which lead to multiorgan failure. An artificial abdominal hernia was created on the third day of life using a silastic pouch. During the operation oxygenation and ventilation improved and urinary output returned. After chemotherapeutic reduction of hepatic metastases and primary tumor the pouch was successfully removed on day 57 without local complications. The child has survived for more than 1 year and is in complete remission. An artificial abdominal hernia should be considered more often in the critically ill neonate with stage 4S neuroblastoma and massive hepatomegaly.

A physical model describing the mechanism for formation of gas microbubbles in patients with mitral mechanical heart valves.

This study was aimed at developing a physical model, supported by experimental observations, to describe the formation and growth of microbubbles seen in patients with mitral mechanical heart valves (MHV). This phenomenon, often referred to as high intensity transient signals (HITS), appears as bright, intense, high-velocity and persistent echoes detected by Doppler ultrasonography at the instant of closure. The long-term clinical implications of HITS has yet to be determined. However, there are reports of a certain degree of neurological disorder in patients with mitral MHV. The numerical analysis has shown the existence of a twofold process (1) nucleation and (2) microbubble growth as a result of cavitation. While mild growth of nuclei is governed by diffusion, explosive growth of microbubbles is controlled by pressure drop on the atrial side of mitral MHV. It was demonstrated that there exist limits on both microbubble size and regurgitant velocity, above which microbubbles grow explosively, and below which growth is almost nonexistent. Therefore, prevention of excessive pressure drops induced by high closing velocities related to the dynamics of closure of mitral MHV may offer design changes in the future generations of mechanical valves.

A complex, high cloacal malformation: case report.

Cloacal malformations are rare, complex inhibitional anomalies of early embryogenesis. We report a patient with a cloacal malformation in which a septate vagina and a rectal fistula emptied through a common orifice onto an exstrophic bladder plate. Additional anomalies included an omphalocele and malformations of the upper urinary tract and the lower extremities, skeleton, and vertebral column.

Interactions of lymphokine-activated killer cells and A549 lung carcinoma nodules maintained in three-dimensional culture.

Lymphokine-activated killer (LAK) cells were cocultured in the presence of interleukin-2 (IL-2), with pulmonary surfactant secreting A549 lung carcinoma nodules and maintained in continuous three-dimensional culture for 2-6 days in an attempt to test the response of tumor cells which produce LAK cell inhibitory substances. The A549 nodules secrete mucus which envelops them. This mucus is also secreted inside pseudoalveolar structures characteristic of these nodules. The mucus contains the pulmonary surfactant and sialomucins, both LAK cell inhibitory substances. The spontaneous infiltration into the neoplastic tissue and the membrane contacts established between the two cell types were studied by means of histological, immunohistochemical and electron-microscopic methods. Free-floating LAK cells were allowed to sediment and adhere freely to the nodule surface. The cytostatic and cytolytic effects of LAK cells were tested using thymidine incorporation into DNA and flow cytometry. Despite the presence of a mucus envelope, LAK cells adhered to the A549 nodule surface and penetrated spontaneously into them in the presence of IL-2; they settled mainly in the pseudoalveolar structures where they became apoptotic. According to electron-microscopic observations performed on the second day of coculture, the LAK cells, which remained between the cancer cells, established mostly pinpoint contacts with the carcinoma cells, forming cytoplasmic fusions. These fusions indicate the induction of pores in both the cancer cell and the LAK cell membranes. Electron-microscopic observation also displayed LAK-cell-associated apoptotic and necrotic carcinoma cells. However, at this stage of the coculture (day 2), the DNA synthesis rate of the A549 nodules still remained unchanged; it diminished by approximately 3 times on day 4 and almost stopped on day 6: nodule disintegration was then complete. In the free-floating LAK cell component of the cocultures, DNA synthesis was already strongly inhibited (26x) by the second day. Nevertheless, their cytolytic effect remained unaltered, as was tested on A549 monolayer cells. The presence of tumor necrosis factor (TNF) in the coculture supernatant has been demonstrated, and when coculturing took place in the presence of monoclonal TNF antibody, nodule proliferation was significantly enhanced (up to 145%). Our results indicate that, despite the presence of pulmonary surfactant and sialomucins containing mucus, LAK cells were capable of killing lung carcinoma cells in three-dimensional culture at an early stage of coculture (day 2) by direct cell-to-cell contact. Total nodule disintegration, however, was complete much later (on day 6), and taking into account the low amount of LAK cells in the cancer tissue, this seemed to be the result of an indirect effect implying, in particular, the presence of soluble TNF.

Use of amniotic grafts in the repair of gastroschisis.

This article describes the use of amniotic grafts (AG) in the repair of large abdominal wall defects in newborns with gastroschisis. From 1988 to 1995, 22 newborns with gastroschisis underwent surgical repair. In 12 primary closure (PC) was performed; in 10 the abdominal wall defect was covered with an AG. A double layer of AG was used and the graft was additionally covered with a silastic silo in 8 cases. The overall mortality was 14%; 3 children died from necrotizing enterocolitis or sepsis after AG. However, the difference in mortality of newborns with PC versus AG was not statistically significant. Patient characteristics, the postoperative courses, nd the frequency of complications were similar after PC and AG. It is concluded that AG has no negative impact on the postoperative course and yields a low overall mortality. In our opinion there are several advantages in using the AG technique: it is an autoplastic material that is readily available without costs, reefing and removal is unnecessary, and there is a potentially low rate of adhesions.

Long-term functional results and quality of life after colon interposition for long-gap oesophageal atresia.

Out of a series of 146 patients with oesophageal atresia 9 (6.2%) underwent colon interposition from 1963 to 1971. All eight surviving patients were seen at follow-up after a mean of 22 years. Three patients were free of specific symptoms according to the criteria of DeMeester, two had moderate and three severe distress. The mean time for consuming a standardized test meal was 15 minutes, compared to 8 minutes in healthy controls. Patients required 1-9 minutes to transport liquid barium through the transplant, compared to < 10 seconds in control subjects. Histological evaluation revealed a normal architecture of the colonic and ileal epithelium in three patients who underwent endoscopy. In none of these patients were contractions in the colon graft related to the act of swallowing recorded on manometry. Unimpaired quality of life was indicated by the Spitzer index which scored a mean of nine out of ten points. However, on a 100point visual analogue scale patients scored their global quality of life 66 and the mean Gastrointestinal Quality of Life Index was 92.2, compared to 107.6 in healthy control subjects (p < 0.05). This impairment was exclusively due to specific symptoms which scored 49.3 in patients and 59 in healthy individuals (p < 0.05). Physical and social functions, emotions, and inconvenience of a medical treatment were similar to control subjects. We conclude that colon interposition for long-gap oesophageal atresia achieves acceptable long-term functional results. However, specific symptoms lead to a considerable impairment in quality of life.