T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy

The origin of T cells after highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus 1 (HIV-1) is now under discussion. The possibility of renewed lymphopoiesis in aged thymuses is still controversial. In this work we combine the analysis of na?ve T cells, T-cell receptor excision circles (TRECs), and computed tomography scanning of thymic tissue to further assess whether the thymus is involved in immune reconstitution. Fifteen antiretroviral-na?ve HIV-1-infected patients were evaluated during 48 weeks of HAART. At baseline, significant correlation was present among age and both thymic volume and TRECs, and between na?ve T cells and TRECs. After starting HAART, there was a significant increase at week 12 in na?ve CD4(+) and CD8(+) T cells, TRECs, and thymic volume. The initial net increases in na?ve T cells and TREC counts were significantly correlated. Changes in thymic volume and TRECs were also indirectly related; splitting the population into 2 groups of high and low baseline TREC levels, only the group with low TREC levels had significant increases in both TRECs and thymic volume. Thus, the increase in thymic volume might be functional, in response to depleted TREC levels. Taken together, our data strongly suggest a thymic role in immune reconstitution, at least in patients with depleted baseline TREC levels. (Blood. 2002;99:3702-3706)     

Flow-cytometric DNA analysis as a means for early detection of malignancy in patients with chronic ulcerative colitis.

A new approach to the problem of monitoring patients with chronic ulcerative colitis is presented and discussed in connection with a case report. When annual colonoscopies are performed, biopsies are taken for histopathological examination and DNA measurements are made using flow-cytometric techniques (FCM). Using the latter approach, gross chromosomal aberrations indicating malignant transformation in a cell population may be detected. In a 46 year old man with a long history of ulcerative colitis, an area with slight mucosal dysplasia at light microscopy was accompanied by two aneuploid cells lines - that is, colonic mucosa cells with an abnormal amount of DNA in the nuclei. An operation one year later revealed a 5 X 2 mm large adenocarcinoma in the corresponding area of the colon. We suggest that flow-cytometric techniques can be used as a complement to already practised methods for monitoring the colorectal mucosa in colitic patients for the early detection of malignancy.     

Interaction between human polymorphonuclear leukocytes and Streptococcus milleri group bacteria.

Because Streptococcus milleri group (SMG) bacteria--Streptococcus constellatus, Streptococcus intermedius, and Streptococcus anginosus--exhibit a striking propensity to cause abscesses, the interaction of these organisms with human polymorphonuclear leukocytes (PMNL) was examined. After incubation in pooled normal human serum, SMG stimulated less chemotaxis than did Staphylococcus aureus, in contrast to viridans streptococci, which caused greater chemotaxis than did S. aureus. PMNL ingested greater numbers of SMG and viridans streptococci than S. aureus but killed these organisms more slowly and less completely. Relative resistance to killing by PMNL is expected in organisms that cause abscesses, and inhibition of chemotaxis may contribute to pathogenicity, because delayed arrival of PMNL gives a head start to proliferating bacteria. This study helps explain the capacity of SMG to cause abscesses. It is unclear, however, why viridans streptococci, bacteria that rarely produce abscesses, share some of these same properties.     

Ischemic colitis of the cecum after renal transplantation masquerading as malignant disease

Fourteen years after kidney transplantation and following protracted rejection of the transplant, a patient developed abdominal pain, fever, and leukocytosis. Ultrasound demonstrated a pericolic abscess, and barium enema a deformity of the ascending colon suggesting malignant growth. Colonoscopy showed ulcerative and necrotic lesions of the cecum, and colonic carcinoma was suspected. At surgery, a granulomatous inflammatory reaction with fibrosis involving the kidney transplant and cecum was found. Histological examination revealed ulcerations secondary to ischemic colitis, but no malignancy. Thus, ischemic colitis should be ruled out in cases with a presumptive diagnosis of colonic malignancy at x-ray or endoscopy.     

Minimally invasive surgical implantation of left ventricular epicardial leads for ventricular resynchronization using video-assisted thoracoscopy

BACKGROUND AND OBJECTIVES: Cardiac resynchronization via left ventricular or biventricular pacing is an option for selected patients with ventricular systolic dysfunction and widened QRS complex. Stimulation through a coronary vein is the technique of choice for left ventricular pacing, but this approach results in a failure rate of approximately 8%. We describe our initial experience with minimally invasive surgical implantation of left ventricular epicardial leads using video-assisted thoracoscopy. PATIENTS AND METHOD: A total of 14 patients with congestive heart failure, NYHA functional class 3.2 (0.6) and mean ejection fraction 22.9 (6.8)% were included in this study. Left bundle branch block, QRS complex >140 ms and abnormal septal motion were observed in all cases. Epicardial leads were implanted on the left ventricular free wall under general anesthesia using video-assisted thoracoscopic surgery. RESULTS: Lead implantation was successful in 13 patients. Conversion to a small thoracotomy was necessary in one patient. All patients were extubated in the operating room. None of the patients died during their hospital stay. Follow-up showed reversal of ventricular asynchrony and significant improvement in ejection fraction and functional class. CONCLUSIONS: Minimally invasive surgery for ventricular resynchronization using video-assisted thoracoscopy in selected patients is a safe procedure that makes it possible to choose the best site for lead implantation and provides adequate short- and medium-term stimulation.     

Sildenafil and vardenafil,types 5 and 6 phosphodiesterase inhibitors,induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells

Type 4 phosphodiesterase (PDE4) inhibitors reportedly induce apoptosis in chronic lymphocytic leukemia (CLL) cells. Following clinical improvement of one previously untreated CLL patient with sildenafil therapy, we evaluated the in vitro induction of apoptosis in CLL cells by 4 PDE5/6 inhibitors, including sildenafil, vardenafil, zaprinast, and methoxyquinazoline (MQZ). After 24 hours of culture, the various PDE inhibitors differed in their ability to induce apoptosis, with zaprinast displaying no killing effect. Normal B cells isolated from control donors were totally resistant to PDE-induced apoptosis. Vardenafil was 3 and 30 times more potent an inducer of apoptosis than sildenafil and MQZ, respectively. Both vardenafil and sildenafil failed to elevate adenosine 3'5' cyclic monophosphate (cAMP) levels, largely excluding an inhibitory effect on cAMP-PDE3, -PDE4, and -PDE7. Vardenafil- or sildenafil-treated B-CLL cells displayed up to 30% intracellular active caspase 3. Drug-induced apoptosis was inhibited by the caspase inhibitor z-VAD.fmk, prevented by interleukin-4 (IL-4), and significantly reduced by stromal-derived factor1-alpha (SDF-1alpha). We conclude that vardenafil and sildenafil induce caspase-dependent apoptosis of B-CLL cells in vitro and thus might be considered in the treatment of CLL patients. However, further in vivo investigations should be warranted.     

Moiréless correlations in ABCA graphene

Atomically thin van der Waals materials stacked with an interlayer twist have proven to be an excellent platform toward achieving gate-tunable correlated phenomena linked to the formation of flat electronic bands. In this work we demonstrate the formation of emergent correlated phases in multilayer rhombohedral graphene––a simple material that also exhibits a flat electronic band edge but without the need of having a moiré superlattice induced by twisted van der Waals layers. We show that two layers of bilayer graphene that are twisted by an arbitrary tiny angle host large (micrometer-scale) regions of uniform rhombohedral four-layer (ABCA) graphene that can be independently studied. Scanning tunneling spectroscopy reveals that ABCA graphene hosts an unprecedentedly sharp van Hove singularity of 3–5-meV half-width. We demonstrate that when this van Hove singularity straddles the Fermi level, a correlated many-body gap emerges with peak-to-peak value of 9.5 meV at charge neutrality. Mean-field theoretical calculations for model with short-ranged interactions indicate that two primary candidates for the appearance of this broken symmetry state are a charge-transfer excitonic insulator and a ferrimagnet. Finally, we show that ABCA graphene hosts surface topological helical edge states at natural interfaces with ABAB graphene which can be turned on and off with gate voltage, implying that small-angle twisted double-bilayer graphene is an ideal programmable topological quantum material.

Two-dimensional (2D) van der Waals heterostructures with an interlayer twist have provided a new avenue for observing emergent tunable many-body electron phenomena. Recent experimental realizations include twisted bilayer graphene (tBG) near the so-called “magic angle” of 1.1° (1–3), twisted double-bilayer graphene (tDBG) (4–6), ABC trilayer graphene on near-perfectly aligned hexagonal boron nitride (hBN) (ABC-tLG/hBN) (7, 8) and transition-metal dichalcogenide heterostructures (9–12) [with predictions on a variety of other systems (13, 14)]. All of these systems host an interplay of two phenomena––the presence of one or more van Hove singularities (which we colloquially refer to as “flat bands” henceforth) at low energy where the density of states is sharply peaked, and the existence of a moiré pattern that creates a unit cell that is about a hundred times larger than the carbon–carbon nearest-neighbor distance in graphene. The large number of electrons with quenched kinetic energy make the flat bands conducive to interaction-driven phases (15). The enlarged moiré unit cell is thought to reduce both the flat-band bandwidth and the interaction energy scales, and also introduces easily accessible integer fillings that create Mott-like insulating states (1–12), the relation of which to nearby superconductivity is debated. A natural question that arises from all of these works is whether the moiré pattern is a necessary condition for the observation of correlated many-body phases, or whether it is simply sufficient to further reduce the flat-band bandwidth and hence the kinetic energy in the heterostructure.In this regard, multilayer rhombohedral (ABC) graphene offers a different perspective toward achieving a flat-band edge without the use of a moiré potential (16). Indeed, in a seminal work (17), it was theoretically shown that the low-energy band structure of multilayer rhombohedral graphene has a sharply peaked density of state (DOS), with the band structure E(k)∝kN (where N is the number of layers) at low energy in the nearest-neighbor hopping approximation. This implies a peak in the DOS at charge neutrality in this material for N>2, with an appreciable fraction of the entire band within this peak (18). Indeed, this physics is already at play in ABC-tLG/hBN (7, 8), where some of the flatness of the bands comes from the intrinsic band structure of ABC graphene, which is then further flattened and isolated by the moiré pattern from the hBN alignment. A facile alternative to flatten the bandwidth without introducing a moiré potential is to simply increase the number of layers of the rhombohedral stacked graphene. Unfortunately, isolating rhombohedral stacked graphene of any thickness is extremely difficult as it is less energetically favorable than the multilayer counterpart, Bernal stacked graphene. Since the difference between rhombohedral and Bernal graphene is simply a lattice shift, and the interlayer van der Waals forces are weak, it is well known that rhombohedral graphene reverts to the Bernal form when samples are processed with heat, pressure, or while performing lithography (19). In this work, we show that twisting two sheets of tDBG by a tiny (<0.1°) angle is a simple and robust method to create large area (up to micrometer-scale) rhombohedral graphene of four-layer thickness (ABCA graphene). We present gate-tunable scanning tunneling microscopy and spectroscopy (STM/STS) measurements at 5.7 K on these regions. We show that correlated phases can be achieved without the need for a moiré pattern and that rhombohedral graphene has unique topological properties.     

Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine

Recent work shows that S-adenosylmethionine (AdoMet) helps maintain normal liver function as chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. The mechanisms by which these nontraditional functions of AdoMet occur are unknown. Here, we use knockout mice deficient in hepatic AdoMet synthesis (MAT1A(-/-)) to study the proteome of the liver during the development of steatohepatitis. One hundred and seventeen protein spots, differentially expressed during the development of steatohepatitis, were selected and identified by peptide mass fingerprinting. Among them, 12 proteins were found to be affected from birth, when MAT1A(-/-) expression is switched on in WT mouse liver, to the rise of histological lesions, which occurs at approximately 8 months. Of the 12 proteins, 4 [prohibitin 1 (PHB1), cytochrome c oxidase I and II, and ATPase beta-subunit] have known roles in mitochondrial function. We show that the alteration in expression of PHB1 correlates with a loss of mitochondrial function. Experiments in isolated rat hepatocytes indicate that AdoMet regulates PHB1 content, thus suggesting ways by which steatohepatitis may be induced. Importantly, we found the expression of these mitochondrial proteins was abnormal in obob mice and obese patients who are at risk for nonalcoholic steatohepatitis.     

Cardiac Aspergillosis with pedunculated mass in the left ventricle

Immunosuppression can allow organisms that are not usually pathogenetic to cause disease; under such circumstances, Aspergillus species frequently form large masses of fungal elements. We describe the case of a 12-year-old girl with hematologic remission of leukemia. She had a left ventricular pedunculated mass that was detected by echocardiographic study; at surgery, the presence of Aspergillus terreus was confirmed.