Effects of exercise training on bone mineral density and some health-related outcomes in HIV conditions: A randomized controlled trial.

INTRODUCTION: Human Immunodeficiency Virus (HIV) infection remains prevalent co-morbidity, and among fracture patients. Few studies have investigated the role of exercise interventions in preventing bone demineralization in people who have fractures and HIV. If exercise exposed, HIV-infected individuals may experience improved bone health outcomes (BMD), function, quality of life (QoL). The study will aim to assess the impact of home based exercises on bone mineral density, functional capacity, QoL, and some serological markers of health in HIV infection among Nigerians and South Africans. METHODS AND DESIGN: The study is an assessor-blinded randomized controlled trial. Patients managed with internal and external fixation for femoral shaft fracture at the study sites will be recruited to participate in the study. The participants will be recruited 2 weeks post-discharge at the follow-up clinic with the orthopaedic surgeon. The study population will consist of all persons with femoral fracture and HIV-positive and negative (HIV-positive medically confirmed) aged 18 to 60 years attending the above-named health facilities. For the HIV-positive participants, a documented positive HIV result, as well as a history of being followed-up at the HIV treatment and care center. A developed home based exercise programme will be implemented in the experimental group while the control group continues with the usual rehabilitation programme. The primary outcome measures will be function, gait, bone mineral density, physical activity, and QoL. DISCUSSION: The proposed trial will compare the effect of a home-based physical exercise-training programme in the management of femoral fracture to the usual physiotherapy management programmes with specific outcomes of bone mineral density, function, and inflammatory markers. TRIAL REGISTRATION: The study was prospectively registered with the Pan African Clinical Trials Registry (Reference number - PACTR201910562118957) on October 21, 2019. (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=9425).

Profiling bone morphogenetic proteins and transforming growth factor-ßs by hTGF-ß3 pre-treated coral-derived macroporous bioreactors: the power of one.

To study the expression profile of bone morphogenetic proteins and transforming growth factor-ßs (BMPs and TGFßs), coral-derived calcium carbonate-based macroporous bioreactors with limited conversion to hydroxyapatite (7% HA/CC) were pre-loaded with and without 250 µg hTGF-ß3 and implanted in the rectus abdominis of 3 non-human primates Papio ursinus euthanized on day 60. To investigate the required dose of hNoggin, a BMPs antagonist that controls the induction of bone formation, 7% HA/CC were pre-loaded with 150 µg hNoggin, with 125 µg hTGF-ß3/150 µg hNoggin, with or without 125 µg hTGF-ß3 and implanted in the r. abdominis of 3 additional animals euthanized on day 90. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) evaluated the expression' profile of BMP-2, BMP-3, BMP-4, BMP-6, BMP-7 and TGF-ß1, -ß2, and -ß3 in tissue generating bioreactors as well as in the adjacent r. abdominis muscle. On day 60, 250 µg hTGF-ß3 induced bone formation at the periphery of the implanted bioreactors only. On day 90, 125 µg hTGF-ß3/treated bioreactors showed the induction of bone formation throughout the macroporous spaces. Untreated bioreactors induced bone, 4.11% vs. 2.00% on days 60 and 90, respectively. In hTGF-ß3/treated bioreactors, BMP-2 and BMP-3 were up-regulated at both time periods, both in the homogenized constructs and in the adjacent r. abdominis muscle whilst BMP-4 in the homogenized construct only. In untreated 7% HA/CC constructs, BMP-2 was up-regulated in the macroporous construct only. On day 60, 250 µg hTGF-ß3/treated and untreated macroporous constructs showed up-regulation of TGF-ß1 with a six fold increase vs. TGF-ß1 expression in adjacent muscle of untreated constructs. TGF-ß2 was down regulated in both untreated and 250 µg hTGF-ß3/treated bioreactors. On day 60, 250 µg hTGF-ß3/treated bioreactors showed TGF-ß3 expression in untreated, treated and adjacent muscle tissues. On day 90, BMP-2 was up-regulated, with BMP-3 up-regulation both with and without hNoggin. BMP-4 expression was reduced, with down-regulation of BMP-6 and BMP-7 with and without hNoggin. BMPs expression is finely tuned by hNoggin that blocks BMPs resulting in minimal if any induction of bone formation. The primary differentiating events in untreated bioreactors develop within the macroporous spaces after stem cells invasion and differentiation with lack of BMP-2 expression in the adjacent muscle. In hTGF-ß3/treated bioreactors, both the adjacent muscle and the macroporous bioreactor show BMP-2 up-regulation, correlating with the temporo/spatial rapid induction of bone formation at the periphery of the bioreactors only. The latter may be the result of the initiation of a sequential chain of cellular induction rapidly recruiting pericytic perivascular myoblastic cells adjacent to the implanted bioreactors directly transformed into secreting osteoblasts.

Cognitive function fifty-six years after surgical treatment of temporal lobe epilepsy: A case study.

We report a long-term follow-up investigation of a patient who was operated in 1954 to relieve intractable temporal lobe seizures characterized by automatism and amnesia. Neuropsychological review at 16 months after surgery showed a slight residual impairment of verbal comprehension and verbal recall and good nonverbal skills. Seizure-free since the operation except for two attacks in the early postoperative years, the patient has been off medication for 25 years and has pursued a successful career as an artist. Our investigation at 56 postoperative years focused on cognitive skills, with some emphasis on learning and memory; a clinical examination was also performed, and the anatomical extent of the resection was determined on 3-Tesla magnetic resonance imaging. Four age- and IQ-appropriate women were tested as healthy control subjects. The patient showed material-specific impairments in language and verbal memory compared with the control subjects and also compared with her own earlier performance, but her performance on other cognitive tasks did not differ from that of the control subjects. Thus, her specific deficits had worsened over time, and she was also impaired compared with healthy individuals of her age, but her deficits remained confined to the verbal sphere, consistent with her temporal lobe seizure focus and surgery.

Bilingual brain organization: a functional magnetic resonance adaptation study.

We used functional magnetic resonance adaptation (fMRA) to examine whether intra-voxel functional specificity may be present for first (L1)- and second (L2)-language processing. We examined within- and across-language adaptation for spoken words in English-French bilinguals who had acquired their L2 after the age of 4 years. Subjects listened to words presented binaurally through earphones. In two control conditions (one for each language), six identical words were presented to obtain maximal adaptation. The remaining six conditions each consisted of five words that were identical followed by a sixth word that differed. There were thus a total of eight experimental conditions: no-change (sixth word identical to first five); a change in meaning (different final word in L1); a change in language (final item translated into L2); a change in meaning and language (different final word in L2). The same four conditions were presented in L2. The study also included a silent baseline. At the neural level, within- and across-language word changes resulted in release from adaptation. This was true for separate analyses of L1 and L2. We saw no evidence for greater recovery from adaptation in across-language relative to within-language conditions. While many brain regions were common to L1 and L2, we did observe differences in adaptation for forward translation (L1 to L2) as compared to backward translation (L2 to L1). The results support the idea that, at the lexical level, the neural substrates for L1 and L2 in bilinguals are shared, but with some populations of neurons within these shared regions showing language-specific responses.

Word and nonword repetition in bilingual subjects: a PET study.

Learning a specific skill during childhood may partly determine the functional organization of the adult brain. This hypothesis led us to study brain activation patterns using positron emission tomography (PET), in which we compared word and nonword repetition in 10 right-handed native English-speakers (L1) who were proficient in their second language, French (L2), which was learned after the age of 5 years. Regional cerebral blood flow (rCBF) was measured by the H2 15O intravenous bolus method with intersubject averaging and coregistration of magnetic resonance and PET images. A comparison of CBF changes when repeating words in L2 with those seen when repeating words in (L1) demonstrated that the pattern of CBF was similar across the two conditions, with several significant CBF differences in the vicinity of the left insular cortex, ventral premotor region, and in the striatum. We hypothesize that these regions are activated when subjects are required to repeat known words, showing increased activity when there are increased articulatory demands imposed by speaking L2. Comparisons of nonword repetition in L1 and L2 revealed increased activity for L2 in the left ventral premotor region and in the cerebellum; rCBF increases were also observed in these regions in both L1 and L2 with increased number of syllables and increased articulatory complexity, suggesting a role for these regions in the complex motor control needed for the production of novel sequences.

The medial temporal-lobe amnesic syndrome.

This article has attempted to show how early evidence of the existence of multiple memory systems in the brain arose from the study of a few patients with bilateral damage to the medial structures of the temporal lobe in the hippocampal region, as in the case of the now famous patient HM. Such patients exhibit a profound anterograde amnesia for the experiences of daily life, whereas previously acquired knowledge is well preserved and immediate or primary memory is intact, and other cognitive abilities, including language, perception, and reasoning also are unaffected by the lesion. Despite the seemingly global nature of HM's memory loss, it was possible to show by the appropriate choice of behavioral tasks that many implicit,procedural forms of learning were preserved, and these forms are now known to be mediated by different brain systems. The first major finding was the demonstration of normal acquisition of a motor skill by HM, although he remained unaware that he had done the task before. This finding was followed by the demonstration of preserved perceptual learning,and since then the examples of preserved learning in amnesia have multiplied. In addition, after many false starts, a convincing animal model has now been achieved, with convergent findings for human and nonhuman primates. Although considerable progress has been made since the early 1950s, many questions remain unanswered; particularly, the distinct contributions of the various medial temporal-lobe structures to memory processes and the interaction of these structures with other brain areas need to be clarified. As in the past, the solution of such problems will call for a multidisciplinary approach.

What went where? Impaired object-location learning in patients with right hippocampal lesions.

The role of the right medial temporal-lobe structures in memory for object location was investigated in three studies. In the first two studies, 118 patients with selective amygdalo-hippocampectomy or with anterior temporal lobectomy (either invading or largely sparing the hippocampal region) and 33 healthy participants were tested on array learning. Groups with extensive right hippocampal lesions were impaired on immediate and delayed recall and on learning to criterion. In the third study, magnetic resonance imaging (MRI) was used in 75 of these patients to measure the extent of tissue remaining in the various medial temporal-lobe structures. The extent of right hippocampus remaining was found to be the best predictor of array-learning performance, underlining its critical role in building a representation of objects in space.

Effects of left inferior prefrontal stimulation on episodic memory formation: a two-stage fMRI-rTMS study.

Successful recovery of words from episodic memory relies strongly on semantic processes at the time of encoding. Evidence from several functional magnetic resonance imaging (fMRI) studies has shown that changes in neural activity in the left inferior prefrontal cortex (LIPFC) during semantic encoding predict subsequent memory performance. This evidence has been taken to suggest that LIPFC plays a critical role in memory formation. Functional neuroimaging findings, however, do not establish a causal brain-behavior relationship. To determine whether there is a causal link between LIPFC involvement at encoding and subsequent success in memory performance, we conducted a two-part study in which we first used fMRI to localize encoding-related activation in LIPFC and then employed repetitive transcranial magnetic stimulation (rTMS) to manipulate neural processes in LIPFC during semantic encoding. To demonstrate the neuroanatomical specificity of any observed effect and to control for nonspecific rTMS side effects, we also stimulated neural processes in two control sites. Using frameless stereotaxy, we positioned the stimulation coil to target (1) the LIPF region that was activated during fMRI (mean xyz = -48 35 5); (2) the homologous right-hemisphere region; and (3) an additional left parietal control site. At each site, "stimulated" items (600 msec of 7-Hz rTMS with Cadwell Round Coil) were intermixed with items presented without concurrent stimulation. Subsequently, subjects performed a recognition memory task for the words encountered. We found support for the predicted causal brain-behavior relationship, which was specific to LIPFC. When comparing recognition scores for stimulated items, normalized for variations in performance on nonstimulated trials, we found that words encoded under LIPFC stimulation were subsequently recognized with higher accuracy than words encoded under stimulation in the two cortical control sites. By contrast, no performance difference emerged when the two control sites were compared with each other. Based on additional analyses of the rTMS effects observed directly at the time of encoding (i.e., on semantic-decision performance), we suggest that LIPFC stimulation may have produced its effect on recognition memory, at least in part, through the triggering of more extensive processing of the stimulated items and an ensuing gain in item distinctiveness. Physiological processes of facilitation probably also contributed to the observed memory benefit. Together, these findings suggest that LIPFC does play a causal role in episodic memory formation.

Visual recognition and recall after right temporal-lobe excision in man.

A further effort was made to determine the effects of right anterior temporal lobectomy in man on visual perception and visual memory. Groups of patients with cortical resections from right or left temporal, frontal, or parietal regions were required to recognize photographs of faces within a larger array, after having been shown the faces previously. Three variations of this task were used: in the first, the interval between initial presentation and recognition test was filled with an irrelevant visual task. In the second, the delay remained but the interpolated task was omitted. In the third, there was only minimal delay ("immediate recognition"). On the first two tasks, patients with right temporal-lobe lesions had marked deficits compared with all other groups, but on the third task (minimal delay) no clearcut group differences were seen, because the normal control group did worse than with delay. Normal subjects (unlike patients with right temporal-lobe excisions) apparently use the delay period to consolidate and possibly recode their visual impressions. In the context of other tasks sensitive to right temporal-lobe lesions, the findings suggest a mild impairment in the perception of complex patterns after right anterior temporal lobectomy, and a much more severe one in the retention of the perceived material.

Cerebral organization in a right-handed trilingual patient with right-hemisphere speech: a positron emission tomography study.

Using the method of positron emission tomography, combined with word-generation tasks, we had the opportunity to examine the cerebral representation of multiple languages in the brain in a right-handed patient, RA, with known right-hemisphere speech representation as determined by intracarotid sodium amobarbital testing. Similar patterns of cerebral blood flow were observed across all three languages (French, Spanish and English), when synonym generation was compared with a silent resting baseline. In particular, several regions in the right inferior frontal cortex were activated. These foci are in locations corresponding to those observed in the left hemisphere in normal right-handed volunteers with presumed left-hemisphere dominance, and in patients known to be left-hemisphere dominant for speech. The lack of anatomical separation of the three languages within the same individual, who acquired two languages early and one language later in life, suggests that at least at this single-word level of analysis, age of acquisition was not a significant factor in the determining of functional organization in the brain.

Do I know you? Face perception and memory in patients with selective amygdalo-hippocampectomy.

In 1968, Milner (Neuropsychologia 6 (1968) 191) demonstrated a face-memory impairment in patients with right, but not left, temporal-lobe excisions. Because all the removals included lateral and inferior temporal neocortex together with amygdala, parahippocampal gyrus and varying amounts of hippocampus, a combined-lesion effect could not be ruled out. We therefore examined the contribution of right temporal structures to recognition of previously unfamiliar faces by repeating Milner's original study, testing patients who had undergone selective amygdalo-hippocampectomy (AH), in addition to those with anterior temporal-lobectomy (TL). The paradigm involved selecting 12 previously studied faces from an array of 25 photographs. The Mooney Closure Faces Test was also administered. Subjects included 29 AH patients (14 left (LAH) and 15 right (RAH)) and 59 TL patients (30 L and 29 R) who were categorized further based on extensive (18 LTH and 21 RTH) or minimal (12 LTh and 8 RTh) hippocampal encroachment. Twenty age- and education-matched normal control subjects (NC) were also tested. For the face-memory task, one-way ANOVA revealed a strong group effect (P<0.001), and post-hoc tests confirmed that both the RTH and RAH groups recognized fewer faces than the NC and LAH groups; the RAH group also differed from the LTh, LTH and RTh groups. No group differences were found for the closure test. Our findings suggest that right medial temporal-lobe structures are critically involved in the retention, but probably not in the perception, of new faces.

Differential contributions of the parahippocampal place area and the anterior hippocampus to human memory for scenes.

Past neuroimaging research has identified a parahippocampal place area (PPA) in the posterior medial temporal lobe (MTL), which responds preferentially to visual scenes and plays a role in episodic memory for this class of stimuli. In the present positron emission tomography study, we examined to what extent the functional characteristics of the PPA resemble those of other, more anterior MTL regions across various learning and recognition-memory tasks. We also determined whether the involvement of the PPA in recognition of previously studied scenes is specific to a particular type of scene information. We found that, like the PPA, anterior hippocampal regions showed a novelty response (higher activation for novel than repeated scenes) and a stimulus-related response (higher activation for scenes than objects) during learning, indicating that MTL structures other than the PPA contribute to the encoding of novel stimulus relationships in scenes. However, these anterior hippocampal regions showed no involvement during recognition of either spatial or nonspatial information contained in scenes. The PPA, by contrast, was consistently involved in recognition of all types of scene details, presumably through interactions with co-activated parietal and occipitotemporal cortices. We suggest that MTL contributions from the PPA are sufficient to support recognition of scenes when the task can be based on a perceptually based familiarity process.