Adaptation in brain glucose uptake following recurrent hypoglycemia.

Brain glucose metabolism is impaired during hypoglycemia, but, if sustained, brain metabolism reverts to normal in animal models--data in man are lacking. We tested the hypothesis that adaptations occur to allow maintenance of normal rates of brain glucose uptake (BGU) following recurrent hypoglycemia in man. Twelve normal humans were studied over 4 days. On the initial day, arterial plasma glucose concentrations were decreased from 4.72 to 2.50 mmol/liter in five 0.56 mmol/liter steps. Cerebral blood flow, brain arteriovenous glucose difference, BGU, and cognitive function were quantitated at each step. BGU was initially impaired at the 3.61 mmol/liter glucose step (P = 0.04) and was antedated by increments in epinephrine that began at 4.16 mmol/liter (P = 0.03). The onset of hypoglycemic symptoms occurred during the 3.61 mmol/liter glucose step (P = 0.02), whereas tests of cognitive function generally deteriorated at the 3.05 mmol/liter step (P < 0.05). During the next 56 hr, mean glucose concentrations were kept at 2.9 +/- 0.1 mmol/liter and reached normal only during meals. The stepped clamp protocol was repeated beginning at 4.16 mmol/liter on the last day. No decrement in BGU was observed at any step; cognitive function was preserved until significantly lower glucose concentrations on the final day relative to the first (P = 0.04). Subjects remained asymptomatic of hypoglycemia until they reached a glucose concentration of 2.50 mmol/liter (P < 0.001 vs. day 1), while initial increments in all counterregulatory hormones were forestalled to lower glucose steps than on day 1. Therefore, adaptations occur that allow normal BGU and cerebral function to be maintained during recurrent systemic hypoglycemia. Counterregulatory events that should result in symptoms of hypoglycemia and increments in endogenous glucose production are prevented until extremely subnormal glucose concentrations.     

Outcome analysis of HIV-positive patients with anal squamous cell carcinoma

PURPOSE: With improved antiretroviral therapy, HIV-positive patients are achieving a longer life expectancy. An increased incidence of anal squamous cell carcinomas has been noted in these patients. The purpose of this study was to determine the outcome of HIV-positive patients with anal squamous cell carcinomas. METHODS: We conducted a review based on our tumor registry from 1980 through 1999. We identified 73 patients with anal squamous cell carcinoma treated at the University of Texas Southwestern Medical Center affiliated hospitals; 23 were HIV positive (18 had AIDS). In the HIV-positive group, 9 had in situ squamous carcinomas and 14 had invasive squamous cell carcinomas. Data collected included age, CD4 count, treatment, complications, and survival; these data were analyzed by Student's t-test. RESULTS: All patients were male. Those with squamous cell cancer of the anus were offered radiation therapy and chemotherapy. Beginning in 1998, all patients received highly active antiretroviral therapy before treatment. Seven of 14 anal squamous cell carcinoma patients had their therapy adjusted owing to toxicity. Morbidity included proctocolitis and diarrhea (n = 2) requiring diversion (n = 1), hemorrhagic cystitis (n = 1), neutropenic fever (n = 3), bone marrow suppression (n = 1), and urethral stricture (n = 1). Mean age was 42 years for anal squamous cell carcinoma patients and 36 years for squamous cell carcinoma in situ patients (P = 0.05). Mean CD4 count was 222 cells/ml in patients with infiltrating carcinoma and 200 in the in situ patients (P = NS). One-year and five-year mortality rates, respectively, were 40 percent and 80 percent for infiltrating carcinoma patients and 17 percent and 50 percent for the in situ patients. Both of the in situ patients who died had CD4 counts <20 cells/ml at diagnosis, whereas the rest had CD4 counts >100 cells/ml and are currently without anal disease. Mean CD4 count at diagnosis for all patients who died was 133 cells/ml, whereas for those surviving, it was 261 cells/ml (P = 0.03). Eight (all with infiltrating carcinoma) of the 10 patients who died had persistent anal disease, but none had metastasis. CONCLUSION: HIV-positive patients with in situ carcinomas present at an earlier age than those with infiltrating lesions. In situ patients with CD4 counts as low as 105 cells/ml do well with local excision. A low CD4 count at diagnosis without highly active antiretroviral therapy predicts a poor prognosis. Because these patients appear to succumb to their HIV status and not the anal disease, anal squamous cell carcinoma should be included with cervical squamous cell carcinoma as an AIDS-defining illness. HIV-positive patients, particularly AIDS patients, with invasive anal cancers and without effective antiretroviral therapy obtain little benefit and significant toxicity from current radiation therapy and chemotherapy. Initiation of highly active antiretroviral therapy in HIV-positive patients before radiation therapy and chemotherapy are begun may decrease toxicity and improve survival. Additional clinical trials are warranted to test this theory.     

Right arm ischemia following intentional stent-graft coverage of an anomalous right subclavian artery.

PURPOSE: To report thoracic aortic stent-graft repair in a patient with abnormal aortic arch anatomy. CASE REPORT: An anomalous right subclavian artery was covered with a stent-graft in a 38-year-old woman being treated for a false aneurysm after coarctation repair. The right arm became relatively ischemic, but was viable and managed conservatively. CONCLUSIONS: Aneurysms close to left or aberrant right subclavian arteries can be safely and effectively treated by endoluminal repair without the need for revascularization procedures; ischemic symptoms that develop are often mild and transient.     

High-sensitivity heat-capacity measurements on Sr2RuO4 under uniaxial pressure

A key question regarding the unconventional superconductivity of Sr2RuO4 remains whether the order parameter is single- or two-component. Under a hypothesis of two-component superconductivity, uniaxial pressure is expected to lift their degeneracy, resulting in a split transition. The most direct and fundamental probe of a split transition is heat capacity. Here, we report measurement of heat capacity of samples subject to large and highly homogeneous uniaxial pressure. We place an upper limit on the heat-capacity signature of any second transition of a few percent of that of the primary superconducting transition. The normalized jump in heat capacity, ΔC/C, grows smoothly as a function of uniaxial pressure, favoring order parameters which are allowed to maximize in the same part of the Brillouin zone as the well-studied van Hove singularity. Thanks to the high precision of our measurements, these findings place stringent constraints on theories of the superconductivity of Sr2RuO4.

Obtaining a full understanding of the superconductivity of Sr2RuO4 is a core challenge for condensed-matter physics. Since soon after its discovery over a quarter of a century ago (1), the superconducting order parameter of Sr2RuO4 has been known to be unconventional (2, 3) and to condense from a well-understood and fairly simple quasi-two-dimensional Fermi liquid metallic state (4–7). Given the profound advances in theoretical techniques in recent decades a full understanding of its superconductivity is an important, and attainable, challenge for the field. The form of the wave-vector-dependent susceptibility of Sr2RuO4 leads to the prediction of a rich superconducting phase diagram in weak-coupling calculations which aim to perform a bias-free estimate of the condensation energies of different order parameters. A notable feature of the results is how close a number of different odd- and even-parity solutions are seen to be in energy (8–10). On the one hand, this emphasizes the potential of Sr2RuO4 as a test-bed material on which to refine the predictive capabilities of modern theories of unconventional superconductivity (11). On the other hand, realizing this potential will likely first require a conclusive experimental determination of which of the many possible order parameters wins out in the real material. This is a particularly exciting stage of the quest to complete this empirical determination, for reasons that we will now outline.For over 20 y the large majority of attention was paid to odd-parity order parameter candidates for Sr2RuO4 (12), because of NMR measurements of spin susceptibility in the superconducting state that seemed to be inconsistent with any even-parity order parameter (13). However, thanks to the discovery of a systematic error in the original NMR measurements (14, 15), that situation has now been more or less completely reversed. Taking into account the most recent measurements of the magnetic field dependence of the spin susceptibility (16), it seems clear that the order parameter must be even-parity or at least dominated by an even-parity component. The spin susceptibility results would be most easily describable in terms of a single-component, likely d-wave, order parameter, but recent thermodynamic evidence from ultrasound experiments is most straightforwardly interpreted in terms of an order parameter with two degenerate components (17, 18). Such order parameters do not of necessity break time-reversal symmetry, but they can, if the two degenerates have the appropriate phase relationship. In the context it is significant that long-standing muon-spin relaxation (μSR) (19, 20) and magneto-optic Kerr rotation measurements (21) have indicated time-reversal symmetry breaking in the superconducting state.To investigate any order parameter with two degenerate components, whether or not it breaks time-reversal symmetry, uniaxial pressure is a powerful probe because it can split the degeneracy, creating a split superconducting phase transition (22). In a significant experimental advance, the muon-spin relaxation experiments have recently been extended to high uniaxial pressures (23). In line with naive expectation, the temperature at which time-reversal symmetry is broken (TTRSB) splits from the main superconducting transition (Tc), with TTRSB remaining nearly pressure-independent while Tc increases under the application of the pressure. However, there has been a long-standing question about whether the Kerr and muon signals correspond to bulk thermodynamic transitions, so it is highly desirable to compare the new muon-spin relaxation data with those from a bulk thermodynamic probe. In this context, it is natural to look at heat capacity, because it has an intrinsic sensitivity to transitions within the superconducting state, as is well known from work on UPt3 (24, 25).     

Predicting the Peritoneal Absorption of Icodextrin in Rats and Humans Including the Effect of α-Amylase Activity in Dialysate

♦ Background:

Contrary to ultrafiltration, the three-pore model predictions of icodextrin absorption from the peritoneal cavity have not yet been reported likely, in part, due to difficulties in estimating the degradation of glucose-polymer chains by α-amylase activity in dialysate. We incorporated this degradation process in a modified three-pore model of peritoneal transport to predict ultrafiltration and icodextrin absorption simultaneously in rats and humans.

♦ Methods:

Separate three-pore models were constructed for humans and rats. The model for humans was adapted from PD Adequest 2.0 including a clearance term out of the peritoneal cavity to account for the absorption of large molecules to the peritoneal tissues, and considering patients who routinely used icodextrin by establishing steady-state plasma concentrations. The model for rats employed a standard three-pore model in which human kinetic parameters were scaled for a rat based on differences in body weight. Both models described the icodextrin molecular weight (MW) distribution as five distinct MW fractions. First order kinetics was applied using degradation rate constants obtained from previous in-vitro measurements using gel permeation chromatography. Ultrafiltration and absorption were predicted during a 4-hour exchange in rats, and 9 and 14-hour exchanges in humans with slow to fast transport characteristics with and without the effect of amylase activity.

♦ Results:

In rats, the icodextrin MW profile shifted towards the low MW fractions due to complete disappearance of the MW fractions greater than 27.5 kDa. Including the effect of amylase activity (60 U/L) resulted in 21.1% increase in ultrafiltration (UF) (7.6 mL vs 6.0 mL) and 7.1% increase in icodextrin absorption (CHO) (62.5% with vs 58.1%). In humans, the shift in MW profile was less pronounced. The fast transport (H) patient absorbed more icodextrin than the slow transport (L) patient during both 14-hour (H: 47.9% vs L: 40.2%) and 9-hour (H: 37.4% vs L: 31.7%) exchanges. While the UF was higher during the longer exchange, it varied modestly among the patient types (14-hour range: 460 – 509 mL vs 9-hour range: 382 – 389 mL). When averaged over all patients, the increases in UF and CHO during the 14-hour exchange due to amylase activity (7 U/L) were 15% and 1.5%, respectively.

♦ Conclusion:

The icodextrin absorption values predicted by the model agreed with those measured in rats and humans to accurately show the increased absorption in rats. Also, the model confirmed the previous suggestions by predicting an increase in UF specific to amylase activity in dialysate, likely due to the added osmolality by the small molecules generated as a result of the degradation process. As expected, this increase was more pronounced in rats than in humans because of higher dialysate concentrations of amylase in rats.     

Palliation via Hybrid Procedure of a 1.4‐kg Patient with a Hypoplastic Left Heart

Despite improvements in survival of patients with hypoplastic left heart syndrome (HLHS) with various palliative procedures, certain risk factors, such as weight less than 2.5 kg, continue to predict increased mortality. We report the palliation of a patient with HLHS weighing 1.4 kg via a hybrid procedure consisting of banding of the pulmonary arteries bilaterally, stenting the ductus arteriosus, and balloon atrial septostomy. We propose that this may be another alternative for palliation in this high‐risk patient group.     

TLR2 engagement on CD4+ T cells enhances effector functions and protective responses to Mycobacterium tuberculosis

We have previously demonstrated that mycobacterial lipoproteins engage TLR2 on human CD4⁺ T cells and upregulate TCR‐triggered IFN‐γ secretion and cell proliferation in vitro. Here we examined the role of CD4⁺ T‐cell‐expressed TLR2 in Mycobacterium tuberculosis (MTB) Ag‐specific T‐cell priming and in protection against MTB infection in vivo. Like their human counterparts, mouse CD4⁺ T cells express TLR2 and respond to TLR2 costimulation in vitro. This Th1‐like response was observed in the context of both polyclonal and Ag‐specific TCR stimulation. To evaluate the role of T‐cell TLR2 in priming of CD4⁺ T cells in vivo, naive MTB Ag85B‐specific TCR transgenic CD4⁺ T cells (P25 TCR‐Tg) were adoptively transferred into Tlr2^?/? recipient C57BL/6 mice that were then immunized with Ag85B and with or without TLR2 ligand Pam₃Cys‐SKKKK. TLR2 engagement during priming resulted in increased numbers of IFN‐γ‐secreting P25 TCR‐Tg T cells 1 week after immunization. P25 TCR‐Tg T cells stimulated in vitro via TCR and TLR2 conferred more protection than T cells stimulated via TCR alone when adoptively transferred before MTB infection. Our findings indicate that TLR2 engagement on CD4⁺ T cells increases MTB Ag‐specific responses and may contribute to protection against MTB infection.