Extensive acquired cholesteatoma in children: when the penny drops

OBJECTIVES: To determine the factors associated with the diagnosis of acquired cholesteatoma (AC) in children, we performed a retrospective chart review at a tertiary care center. METHODS: We reviewed children with a diagnosis of AC that extended beyond the mesotympanum in the presence of a nonintact tympanic membrane who underwent surgical treatment over a 14-year period. RESULTS: There were 116 children (78 male, 38 female) between 3 and 18 years of age (mean, 9.5 years). Their average period of management in a specialist otolaryngology clinic before the diagnosis of cholesteatoma was made was 3.2 years, and 68% of the children had previously undergone insertion of tympanostomy tubes. Symptoms and signs included chronic otorrhea (59%), recurrent acute otitis media (58%), and conductive hearing loss (51%). The diagnosis of AC was eventually made after office otoscopy (26%), temporal bone computed tomography (24%), or examination under anesthesia (17%). In 33% of children, the diagnosis was made only after surgical exploration of the middle ear and mastoid. CONCLUSIONS: Our data underscore the importance of maintaining a high index of suspicion for AC in managing children with long-standing otologic symptoms, and considering otomicroscopy, computed tomographic scanning, or tympanomastoid exploration if medical treatment fails.     

Heidenhain variant of Creutzfeldt-Jakob disease: An autopsy study from India

Prion diseases are rare, progressive and fatal neurodegenerative diseases characterized by long incubation period and short clinical course. We present a rare case of Heidenhain variant of Creutzfeldt-Jakob disease, occurring in a 55-year-old lady presenting with dementia, cortical blindness, and myoclonic jerks. She succumbed to the disease within 8 weeks of onset of symptoms. MRI revealed hyperintense signals on T2WI and fluid attenuated inversion recovery (FLAIR) images in basal ganglia and fronto-temporal and parietal cortex, sparing thalamus, striate cortex and globus pallidum. Abundant abnormal prion protein deposits (PrP^sc) were detected in caudate, putamen, thalamus, cingulate and striate cortex, in comparison to frontal and parietal cortex while no deposits were found in globus pallidum. MRI changes did not correlate with degree of spongy change, gliosis or prion protein deposition. The cause for abnormal signal changes in MRI and FLAIR images remains unclear.     

An uncommon life-threatening complication after chest tube drainage of pneumothorax in the ED

Re-expansion pulmonary oedema (REPO) after chest tube drainage of pneumothorax is uncommon. We contrast one patient with life threatening against another mildly symptomatic REPO occurring in our emergency department (ED).The mechanism and management of REPO differs distinctly from that of cardiogenic pulmonary oedema. We discuss the predictors of REPO, review clinical details of reported fatalities and suggest preventive measures.     

Termite mounds harness diurnal temperature oscillations for ventilation

Many species of millimetric fungus-harvesting termites collectively build uninhabited, massive mound structures enclosing a network of broad tunnels that protrude from the ground meters above their subterranean nests. It is widely accepted that the purpose of these mounds is to give the colony a controlled microclimate in which to raise fungus and brood by managing heat, humidity, and respiratory gas exchange. Although different hypotheses such as steady and fluctuating external wind and internal metabolic heating have been proposed for ventilating the mound, the absence of direct in situ measurement of internal air flows has precluded a definitive mechanism for this critical physiological function. By measuring diurnal variations in flow through the surface conduits of the mounds of the species Odontotermes obesus, we show that a simple combination of geometry, heterogeneous thermal mass, and porosity allows the mounds to use diurnal ambient temperature oscillations for ventilation. In particular, the thin outer flutelike conduits heat up rapidly during the day relative to the deeper chimneys, pushing air up the flutes and down the chimney in a closed convection cell, with the converse situation at night. These cyclic flows in the mound flush out CO₂ from the nest and ventilate the colony, in an unusual example of deriving useful work from thermal oscillations.Many social insects that live in dense colonies (1, 2) face the problem of keeping temperature, respiratory gas, and moisture levels within tolerable ranges. They solve this problem by using naturally available structures or building their own nests, mounds, or bivouacs (3). A particularly impressive example of insect architecture is found in fungus-cultivating termites of the subfamily Macrotermitinae, individually only a few millimeters in body length, which are well known for their ability to build massive, complex structures (4, 5) without central decision-making authority (6). The resulting structure includes a subterranean nest containing brood and symbiotic fungus, and a mound extending  ～  1–2 m above ground, which is primarily entered for construction and repair, but otherwise relatively uninhabited. The mound contains conduits that are many times larger than a termite (5), and viewed widely as a means to ventilate the nest (7). However, the mechanism by which it works continues to be debated (8–11).Ventilation necessarily involves two steps: transport of gas from underground metabolic sources to the mound surface, and transfer of gas across the porous exterior walls with the environment. Although diffusion can equilibrate gradients across the mound surface (12), it does not suffice to transport gas between nest and surface. (It takes gas  ～  4 d to diffuse 2 m.) Thus, ventilation must rely on bulk flow inside the mound. Previous studies of mound-building termites have suggested either thermal buoyancy or external wind as possible drivers, making a further distinction between steady [e.g., metabolic driving (11), steady wind] and transient [e.g., diurnal driving (9, 10), turbulent wind (8)] sources. However, the technical difficulties of direct in situ measurements of airflow in an intact mound and its correlation with internal and external environmental conditions have precluded differentiating between any of these hypotheses. Here, we use both structural and dynamic measurements to resolve this question by focusing on the mounds of O. obesus (Termitidae, Macrotermitinae), which is common in southern Asia in a variety of habitats (13).In Fig. 1A, we show the external geometry of a typical O. obesus mound, with its characteristic buttresslike structures (flutes) that extend radially from the center (Fig. 1B). The internal structure of the mound can be visualized using by either making a horizontal cut (Fig. 1C) or endocasting (Fig. 1D). Both approaches show the basic design motif of a large central chimney with many surface conduits in the flutes; all conduits are larger than termites, most are vertically oriented, and well connected. (A simple proof of well connectedness is that gypsum injected from a single point can fill all interior conduits.) This macroporous structure can admit bulk internal flow and thus could serve as an external lung for the symbiotic termite–fungus colony.Open in a separate windowFig. 1.Mounds of O. obesus. Viewed from (A) the side, (B) top, and by (C) cross-section. Filling the mound with gypsum, letting it set, and washing away the original material reveals the interior volume (white regions) as a continuous network of conduits, shown in D. Endocast of characteristic vertical conduit in which flow measurements were performed, near ground level, toward the end of flutes, indicated by the arrow (E).To understand how the mound interacts with the environment, we first note that the walls are made of densely deposited granules of clay soil, forming a material with high porosity (37–47% air, by volume; SI Appendix), and small average pore diameter ( ～ 5?μm, roughly the mean particle size). Indeed, healthy mounds have no visible holes to the exterior, and repairs are quickly made if the surface is breached. The high porosity means that the mound walls provide little resistance to diffusive transport of gases along concentration gradients. However, the small pore size makes the mound very resistant to pressure-driven bulk flow across its thickness. Thus, the mound surface behaves like a breathable windbreaker. Finally, the low wind speeds observed around the termite mounds of  ～ 0 ? 5?m/s implies that they are not capable of creating significant bulk flow across the wall, effectively ruling out wind as the primary driving source.Within the mound, a range of indirect measurements of CO₂ concentration, local temperature, condensation, and tracer gas pulse chase (8–10, 11, 14) show the presence of transport and mixing. However, a complete understanding of the driving mechanism behind these processes requires direct measurements of flow inside the mound. This is difficult for several reasons. First, the mound is opaque, so that any instrument must be at least partly intrusive. Second, expected flows are small (≈centimeters per second), outside the operating range of commercial sensors, requiring a custom-engineered device. Third, because conduits are vertical, devices relying on heat dissipation, or larger, high heat capacity setups can generate their own buoyancy-driven (and geometry dependent) flows, making measurements ambiguous (15). Finally, and most importantly, the mound environment is hostile and dynamic. Termites tend to attack and deposit sticky construction material on any foreign object, often within 10 min of entry. If one inserts a sensor even briefly, termites continue construction for hours, effectively changing the geometry and hence the flow in the vicinity of the sensor.To measure airflow directly, we designed and built a directional flow sensor composed of three linearly arranged glass bead thermistors, exposed to the air (SI Appendix). A brief pulse of current through the center bead creates a tiny bolus of warm air, which diffuses outward and is measured in either neighboring bead. (The operating mechanism is similar in principle to that of ref. 16.) Directional flow along the axis of the beads biases this diffusion, and is quantified by the ratio of the maximum response on each bead, measured as a temperature-dependent resistance. In a roughly conduit-sized vertical tube, this resistance–change metric depends linearly on flow velocity, with a slight upward bias due to thermal buoyancy. This allows us to measure both flow speed and direction locally. The symmetry of the probe allows for independent calibration and measurement in two orientations by rotating by 180° (arbitrarily labeled upward and downward; SI Appendix).In live mounds, the sensor was placed in a surface conduit at the base of a flute for ? 5 min at a time to avoid termite attacks, which damage the sensors. For a self-check, the sensor was rotated in place, such that a given reading could be compared on both upward and downward calibration curves. We also measured the flow inside an abandoned (dead), unweathered mound that provided an opportunity for long-term monitoring without having termites damage the sensors. Simultaneous complementary measurements of temperature in flutes and the center were taken. To measure the concentrations of CO₂, a metabolic product, a tube was inserted into the nest; in one mound in the center slightly below ground and another in the chimney at ≈ 1.5 m above. Gas concentration measurements were made every 15 min by drawing a small volume of air through an optical sensor from the two locations for most of one uninterrupted 24-h cycle.Nearly all of the 25 mounds that were instrumented were in a forest with little direct sunlight. In Fig. 2A, we show flow measurements in 78 individual flutes of these mounds as a function of time of day. We see a clear trend of slight upward (positive) flow in the flutes during the day, and significant downward (negative) flow at night. The data saturates for many night values, as the flow speed was larger than our range of reliable calibration (SI Appendix). In Fig. 2B, we show the flow rate for a sample flute in the abandoned mound. Notably, it follows the same trend seen in live mounds, but the flow speeds at night are not nearly as large as for the live mounds. For both live and dead mounds, we also show the difference in temperature measured between the flutes and center, ΔT = T_flute ? T_center, and see that it varies in a manner consistent with the respective flow pattern. This rules out metabolic heating (11) as a central mechanism, because a dead mound shows the same gradients and flows as a live one.Open in a separate windowFig. 2.Diurnal temperature and flow profiles show diurnal oscillations. (Top) Scatterplot of air velocity in individual flutes of 25 different live mounds (?). Error bars represent deviation between upward and downward  ≈  1.5-min flow measurements. The dashed red line is the average difference between temperatures measured in four flutes and the center (at a similar height), ΔT, in a sample live mound (Representative error bar shown at left). (Middle) Corresponding flow and ΔT, continuously measured in the abandoned mound. (Bottom) CO₂ schedule in the nest (?) and the chimney 1.5 m above (?), measured over one cycle in a live mound (Movie S1).In Fig. 2C we show that the accumulation of respiratory gases also follows a diurnal cycle, with two functioning states (Movie S1). During the day, when flows are relatively small, CO₂ gradually builds up to nearly 6% in the nest, and drops to a fraction of 1% in the chimney. At night, when convective flows are large, CO₂ levels remain relatively low everywhere. Although it is surprising that these termites allow for such large periodic accumulations of CO₂, similar tolerance has been observed in ant colonies (17).In addition to measuring these slowly varying flows, we used our flow sensors in a different operating mode to also measure short-lived transient flows similar to those of earlier reports (8, 15). This requires a different heating protocol, wherein the center bead is constantly heated, so that small fluctuations in flow lead to antisymmetric responses from the outer beads. However, the steady heating leads to a trade-off, as thermally induced buoyancy hinders our ability to interpret absolute flow rate. Our measurements found that transients are at most only a small fraction (≈millimeters per second) of average flow speeds under normal conditions, and were not induced by applying steady or pulsing wind from a powerful fan just outside the termite mound. Pulse chase experiments on these mounds, in which combustible tracer gas is released in one location in the mound and measured in another, gave an estimate of gas transport speed (not necessarily the same as flow speed) of the same order (≈centimeters per second), which indicates that our internally measured average flow is the dominant means of gas transport and mixing with no real role for wind-induced flows. Furthermore, temperature measurements in the center at different heights showed that the nest is almost always the coolest part of the mound central axis, additional evidence against the importance metabolic heating (11) (SI Appendix).Taken together, these results point strongly to the idea that diurnally driven thermal gradients drive air within the mound, facilitating transport of respiratory gases. Observations of the well connectedness of the mound and the impermeability of the external walls imply that flow in the center of the mound, to obey continuity, must move in the vertical direction opposite that of the flutes. When the flutes are warmer than the interior, air flows up in the flutes, pushing down cooler air in the chimney. The opposite occurs when the gradient is reversed at night (Fig. 3). (The air flowing down the flutes is significantly warmer than ambient temperature, a situation only possible if it were being pushed by even warmer air flowing up the chimney.)Open in a separate windowFig. 3.(Top) Thermal images of the mound in Fig. 1A, during the day and night qualitatively show an inversion of the difference between flute and nook surface temperature. Bases of flutes are marked with ovals to guide the eye. (Middle and Bottom) Mechanism of convective flow illustrated by schematic of the inverting modes of ventilation in a simplified geometry. Vertical conduits in each of the flutes are connected at top and in the subterranean nest to the vertical chimney complex. This connectivity allows for alternating convective flows driven by the inverting thermal gradient between the massive, thermally damped, center and the exposed, slender flutes, which quickly heat during the day, and cool during the night.This model predicts flow speeds comparable to those observed in the mound (SI Appendix), and is consistent with the quick uptake and gradual decline of CO₂ measured in the chimney; with the evening temperature inversion, convection begins to push rich nest air up the chimney before diffusion across the surface gradually releases CO₂ from the increasingly mixed mound air. (See Movie S1 for a sequence of thermal images of the inversion that accompanies this drop.) This forcing mechanism is inherently transient; if the system ever came to equilibrium and the gradient disappeared, ventilation would stop.It has long been thought that animal-built structures, spectacularly exemplified by termite mounds, maintain homeostatic microhabitats that allow for exchange of matter and energy with the external environment and buffer against strong external fluctuations. Our study quantifies this by showing how a collectively built termite mound harnesses natural temperature oscillations to facilitate collective respiration. The radiatorlike architecture of the structure facilitates a large thermal gradient between the insulated chimney and exposed flutes. The mound harnesses this gradient by creating a closed flow circuit that straddles it, promoting circulation, and flushing the nest of CO₂. Although our data comes entirely from one termite species, the transport mechanism described here is very generic and is likely dominant in similarly massive mounds with no exterior holes that are found around the globe in a range of climates. A natural question that our study raises is that of the rules that lead to decentralized construction of a reliably functioning mound. Although the insect behavior that leads to construction of these mounds is not well understood, it is likely that feedback cues are important. The knowledge of the internal airflows and transport mechanisms might allow us to get a window into these feedbacks and thus serve as a step toward understanding mound morphogenesis and collective decision making.The swarm-built structure described here demonstrates how work can be derived, through architecture, from the fluctuations of an intensive environmental parameter—a qualitatively different strategy than that of most human engineering that typically (18) extracts work from unidirectional flow of heat or matter. Perhaps this might serve to inspire the design of similarly passive, sustainable human architecture (19, 20).     

Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer

Gain-of-function of the androgen receptor (AR) and activation of PI3K/AKT/mTOR pathway have been demonstrated to correlate with progression to castration-resistant prostate cancer (CRPC). However, inhibition of AR or PI3K/mTOR alone results in a reciprocal feedback activation. Therefore, we hypothesized that dual inhibition of the AR and PI3K/mTOR pathway might lead to a synergistic inhibition of cell growth and overcome drug resistance in CRPC. Here, we reported that androgen-depletion increased AR protein level and Akt phosphorylation at Ser473 and Thr308 in LNCaP cells. Moreover, we developed resistance cell lines of LNCaP to Enzalutamide (or MDV3100), an AR inhibitor (named as LNCaP ‘MDV-R’) and PF-04691502, a PI3K/mTOR inhibitor (named as LNCaP ‘PF-R’). MTS analysis showed that LNCaP ‘PF-R’ was strongly resistant to Enzalutamide treatment, and on the other hand, LNCaP ‘MDV-R’ was 6-fold resistant to PF-04691502 treatment. Mechanistically, LNCaP ‘MDV-R’ cells had significantly reduced AR, loss of PSA and increase Akt activity in contrast with LNCaP ‘PF-R’ cells. Combined inhibition of PI3K/mTOR and AR pathways with a variety of small molecular inhibitors led to a synergistic suppression of cell proliferation and a profound increase of apoptosis and cell cycle arrest in both androgen-dependent LNCaP and independent CRPC 22Rv1 cell lines. In conclusion, this study provides preclinical proof-of-concept that the combination of a PI3K/mTOR inhibitor with an AR inhibitor results in a synergistic anti-tumor response in non-CRPC and CRPC models.     

Calcium and bone disorders in pregnancy

Significant transplacental calcium transfer occurs during pregnancy, especially during the last trimester, to meet the demands of the rapidly mineralizing fetal skeleton. Similarly, there is an obligate loss of calcium in the breast milk during lactation. Both these result in considerable stress on the bone mineral homeostasis in the mother. The maternal adaptive mechanisms to conserve calcium are different in pregnancy and lactation. During pregnancy, increased intestinal absorption of calcium from the gut mainly due to higher generation of calcitriol (1,25 dihydroxy vitamin D) helps in maintaining maternal calcium levels. On the other hand, during lactation, the main compensatory mechanism is skeletal resorption due to increased generation of parathormone related peptide (PTHrP) from the breast. Previous studies suggest that in spite of considerable changes in bone mineral metabolism during pregnancy, parity and lactation are not significantly associated with future risk for osteoporosis. However, in India, the situation may not be the same as a significant proportion of pregnancies occur in the early twenties when peak bone mass is not yet achieved. Further, malnutrition, anemia and vitamin D deficiency are commonly encountered in this age group. This may have an impact on future bone health of the mother. It may also probably provide an opportunity for health care providers for prevention. Other metabolic bone diseases like hypoparathyroidism, hyperparathyroidism and pseudohypoparathyroidism are rarely encountered in pregnancy. Their clinical implications and management are also discussed.     

Endovascular aortic coarctation stenting in adolescents and adults: angiographic and hemodynamic outcomes.

OBJECTIVES: To assess the procedural, clinical, angiographic, and hemodynamic outcomes, including ambulatory blood pressure monitoring at 1 year in adolescent and adult patients undergoing primary stenting for treatment of aortic coarctation. BACKGROUND: Stenting is widely used for treatment of aortic coarctation. Data regarding efficacy of this treatment for control of hypertension at 1 year is scant, with only one reported series of planned angiographic follow up. The impact of newer type stents for this procedure is also unknown. METHODS: Thirty-seven patients undergoing stenting for aortic coarctation, over a 3-year period in a tertiary centre were studied as part of an observational protocol. RESULTS: Peak gradient across the coarctation fell from 28.3 +/- 15.1 to 3.7 +/- 4.1 post procedure and was 11.9 +/- 8.9 mmHg (P < 0.05 compared to baseline) at 1 year. There was one major complication (2.7%), with no deaths. Small aneurysms were seen in three patients (13%) on follow up angiography at 1 year. Right arm systolic blood pressures fell from 155 +/- 19 to 132 +/- 22 (P < 0.05) at 6 weeks and was 132 +/- 16 mmHg (P < 0.05 compared to baseline) at 1 year. Ambulatory average systolic blood pressures fell from 142 +/- 14 to 133 +/- 15 at 6 weeks (P < 0.05) and to 125 +/- 12 mmHg (P < 0.05 compared to baseline) at 1 year. No significant differences were seen in procedural outcomes between patients receiving Palmaz and CPNumed stents. CONCLUSION: Primary stenting of aortic coarctation in adolescents and adults results in excellent clinical and angiographic outcomes and sustained hemodynamic benefits at 1 year as evidenced by significant reduction in systolic blood pressure and gradients. Close follow up is required to monitor aneurysm formation.     

Qualitative tuberculin response in the diagnosis of tuberculosis in apparently healthy schoolchildren.

SETTING: School-based cross-sectional study. OBJECTIVE: To assess the value of qualitative tuberculin responses (turgid and non-turgid type) in diagnosis of tuberculosis disease in apparently healthy schoolchildren. DESIGN: Qualitative tuberculin responses were assessed in 548 apparently healthy schoolchildren. Tuberculin-positive (> or = 10 mm) children were investigated for evidence of tuberculosis. The relationship between the types of qualitative tuberculin response and occurrence of tuberculosis was studied. RESULTS: Eighty-eight (16.1%) children were found to be tuberculin-positive. Of these, 68 had non-turgid reaction whereas 20 had turgid reaction. Most of the children with a reaction of 5-9 mm had a non-turgid type of tuberculin reaction. Only four children with non-turgid reaction had tuberculosis, while 18 children with turgid reaction had tuberculosis disease (P < 0.0001). A larger tuberculin reaction was found to be associated with a higher occurrence of tuberculosis (P = 0.016 by linear regression method). CONCLUSION: The observations indicate a possible relation between turgid reaction and tuberculosis disease.