Therapeutic and diagnostic applications of minor histocompatibility antigen HA-1 and HA-2 disparities in allogeneic hematopoietic stem cell transplantation: a survey of different populations.

Minor histocompatibility antigens (mHags) HA-1 and HA-2 are encoded by biallelic loci, with immunogenic variants, HA-1H and HA-2V, which induce strong HLA-A2-restricted alloreactive T-cell responses, and nonimmunogenic counterparts, HA-1R and HA-2M, which represent functional null alleles that are poorly presented by HLA class I molecules. HA-1 and HA-2 are potential targets of selective graft-versus-leukemia and graft-versus-tumor reactivity after allogeneic hematopoietic stem cell transplantation (HSCT); however, these applications are restricted to a limited number of patients. Here, we show that a far more frequent application of HA-1 and HA-2 disparity relies on their use as markers for the state of host chimerism after allogeneic HSCT. We have determined allelic frequencies of 29.3% and 70.7% for HA-1H and HA-1R, respectively, and of 83.7% and 16.3% for HA-2V and HA-2M, respectively, in >200 healthy individuals from northern Italy. Similar frequencies were observed in nearly 100 patients affected by hematologic malignancies or solid tumors, thus showing that HA-1 and HA-2 variability are not associated with the presence of cancer. On the basis of these data, we predict that HA-1 and HA-2 can be used in 32.8% and 23.5% of Italian transplant patients, respectively, as markers for the state of host chimerism, whereas exploitation of disparity for these mHags for targeted immunotherapy will be possible in 10.7% and 1.1% of Italian patients, respectively. Retrospective HA-2 typing of bone marrow aspirates obtained from a patient during complete remission or recurrence of acute myeloid leukemia after haploidentical HSCT showed the feasibility of using HA-2 as a surrogate marker for disease monitoring. Because of an apparent north-south gradient for HA-1 allelic frequencies, with higher frequencies for the HA-1H variant reported in white populations from Southern Europe as compared with Northern Europe and North America, the diagnostic applicability of HA-1 disparity will be slightly more frequent in transplant patients from the north. Taken together, our data show that determination of HA-1 and HA-2 variability can be an important parameter for the selection of allogeneic stem cell donors, in particular for patients affected by hematologic malignancies without a tumor-specific molecular marker.     

Extrinsic risk factors for compromised blood flow in the vertebral artery: anatomical observations of the transverse foramina from C3 to C7

The vertebral artery (VA) is often involved in the occurrence of complications after spinal manipulative therapy. Due to osteophytes compressing the VA anteriorly from the uncinate process or posteriorly from the facet complex, the VAs are susceptible to trauma in the transverse foramina. Such altered anatomical configurations are of major clinical significance, as spinal manipulations may result in dissection of the VA with serious consequences for the blood supply to the vertebrobasilar region. The purpose of this study is to describe numerous structural features of the third to seventh cervical vertebrae in order to contribute to the understanding of pathological conditions related to the VA. The minimal and maximal diameter of 111 transverse foramina in dry cervical vertebrae were studied. The presence of osteophytes and their influence on the VA were evaluated at the vertebral body and at the superior and inferior articular facets. The diameter of the transverse foramina increased from C3 to C6, while the transverse foramina of C7 had the smallest diameter. At all levels the mean dimensions of the left foramina were greater than those of the right side. Osteophytes from the uncinate process of C5 and C6 vertebrae were found in over 60% of dry vertebrae. Osteophytes from the zygapophyseal joints were more frequent at C3 and C4 vertebrae. About half of the osteophytes of the uncinate and of the superior articular process partially covered the transverse foramina. This was less common with those of the inferior articular facets. Osteophytes covering the transverse foramen force the VAs to meander around these obstructions, causing narrowing through external compression and are potential sites of trauma to the VAs potentially even leading to dissection. We strongly advocate that screening protocols for vertebrobasilar insufficiency (VBI) be used prior to any manipulation of the cervical spine and should include not only extension and rotation but any starting position from which the planned manipulation will be performed.     

The Hunger Games: Homeostatic State-Dependent Fluctuations in Disinhibition Measured with a Novel Gamified Test Battery

Food homeostatic states (hunger and satiety) influence the cognitive systems regulating impulsive responses, but the direction and specific mechanisms involved in this effect remain elusive. We examined how fasting, and satiety, affect cognitive mechanisms underpinning disinhibition using a novel framework and a gamified test-battery. Thirty-four participants completed the test-battery measuring three cognitive facets of disinhibition: attentional control, information gathering and monitoring of feedback, across two experimental sessions: one after overnight fasting and another after a standardised meal. Homeostatic state was assessed using subjective self-reports and biological markers (i.e., blood-derived liver-expressed antimicrobial protein 2 (LEAP-2), insulin and leptin). We found that participants who experienced greater subjective hunger during the satiety session were more impulsive in the information gathering task; results were not confounded by changes in mood or anxiety. Homeostatic state did not significantly influence disinhibition mechanisms linked to attentional control or feedback monitoring. However, we found a significant interaction between homeostatic state and LEAP-2 on attentional control, with higher LEAP-2 associated with faster reaction times in the fasted condition only. Our findings indicate lingering hunger after eating increases impulsive behaviour via reduced information gathering. These findings identify a novel mechanism that may underpin the tendency to overeat and/or engage in broader impulsive behaviours.     

Correction to: How to support dental students in reading radiographs: effects of a gaze‑based compare‑and‑contrast intervention

Advances in Health Sciences Education -     

Cationic amino acid fluxes beyond the proximal convoluted tubule of rat kidney

To investigate the fluxes of cationic amino acids beyond the proximal convolution, we micropunctured and microperfused superficial tubules of male Wistar rats in vivo et situ. In free-flow micropuncture experiments, the concentrations of endogenous L-arginine⁺, [Arg], and of intravenously infused L-homoarginine⁺, [HoArg], were determined by HPLC. Fluorescein isothiocyanatelabeled inulin was detected on-line in the same tubular fluid samples. To determine undirectional fluxes, radiolabeled Arg and inulin were (1) microperfused through short loops of Henle and (2) microinfused into different tubule segments to measure urinary recovery of the radiolabel. At a mean [Arg]_plasma of 116 mol/l, [Arg] was 9.3 mol/l in the late proximal tubule (LPT), and 35.6 mol/l in the early distal tubule (EDT) corresponding to fractional deliveries (FD) of 0.055 in LPT and 0.078 in EDT. Fractional urinary excretion (FE) of Arg was 0.00033 (P<0.05 vs FD_EDT). Infusion of HoArg (2.5 or 7.5 mol/min) led to respective mean [HoArg]_plasma values of 1.44 and 3.73 mmol/l, and resulted in respective FD_LPT values for HoArg of 0.23 and 0.53, respective FD_EDT values of 0.29 and 0.41, and finally, respective FE values for HoArg of 0.25 and 0.58. When short loops of Henle were microperfused with 1 or 50 mmol/l [¹⁴C]Arg (+[³H]inulin), fractional recovery (FR) of ¹⁴C (relative to inulin) in the EDT was 0.13 and 0.36, respectively. During microinfusion of radiolabeled Arg (1 or 50 mmol/l) and inulin into LPT, the urinary FR of the radiolabel was 0.14, or 0.59, respectively. If 0.007, 1 or 50 mmol/l radiolabeled Arg were microinfused into EDT, the respective urinary FR of the radioactivity was 1.02, 1.10, or 1.01. Microperfusion of microinfusion of 1 mmol/l [¹⁴C]Arg plus 50 mmol/l HoArg resulted in a FR_EDT of ¹⁴C of 0.43 (loop, perfusion) and an FE for ¹⁴C of 0.69. Five conclusions can be drawn. First, cationic amino acids can enter and leave the lumen of short loops of Henle through specific carrier(s) at high rates, although, secondly, net transport is small or absent. Thus, medullary tubule cells can be supplied with Arg from the lumen of short loops of Henle for urea and nitric oxide production. Thirdly, the distal convolution of superficial nephrons and the collecting duct are not permeable to Arg. Thus, fourthly, the difference between FD_EDT and urinary FE of Arg must be explained by an inter-nephron heterogeneity between deep and superficial nephrons. Finally, the process responsible for the different Arg handling in deep nephrons is not accessible to HoArg or, if so, it is saturated at millimolar concentrations.