Bone tissue engineering in osteoporosis

Osteoporosis is a polygenetic, environmentally modifiable disease, which precipitates into fragility fractures of vertebrae, hip and radius and also confers a high risk of fractures in accidents and trauma. Aging and the genetic molecular background of osteoporosis cause delayed healing and impair regeneration. The worldwide burden of disease is huge and steadily increasing while the average life expectancy is also on the rise. The clinical need for bone regeneration applications, systemic or in situ guided bone regeneration and bone tissue engineering, will increase and become a challenge for health care systems. Apart from in situ guided tissue regeneration classical ex vivo tissue engineering of bone has not yet reached the level of routine clinical application although a wealth of scaffolds and growth factors has been developed. Engineering of complex bone constructs in vitro requires scaffolds, growth and differentiation factors, precursor cells for angiogenesis and osteogenesis and suitable bioreactors in various combinations. The development of applications for ex vivo tissue engineering of bone faces technical challenges concerning rapid vascularization for the survival of constructs in vivo. Recent new ideas and developments in the fields of bone biology, materials science and bioreactor technology will enable us to develop standard operating procedures for ex vivo tissue engineering of bone in the near future. Once prototyped such applications will rapidly be tailored for compromised conditions like vitamin D and sex hormone deficiencies, cellular deficits and high production of regeneration inhibitors, as they are prevalent in osteoporosis and in higher age.     

Effects of O-GlcNAcylation on functional mitochondrial transfer from astrocytes

Mitochondria may be transferred from cell to cell in the central nervous system and this process may help defend neurons against injury and disease. But how mitochondria maintain their functionality during the process of release into extracellular space remains unknown. Here, we report that mitochondrial protein O-GlcNAcylation is a critical process to support extracellular mitochondrial functionality. Activation of CD38-cADPR signaling in astrocytes robustly induced protein O-GlcNAcylation in mitochondria, while oxygen-glucose deprivation and reoxygenation showed transient and mild protein modification. Blocking the endoplasmic reticulum – Golgi trafficking with Brefeldin A or slc35B4 siRNA reduced O-GlcNAcylation, and resulted in the secretion of mitochondria with decreased membrane potential and mtDNA. Finally, loss-of-function studies verified that O-GlcNAc-modified mitochondria demonstrated higher levels of neuroprotection after astrocyte-to-neuron mitochondrial transfer. Collectively, these findings suggest that post-translational modification by O-GlcNAc may be required for supporting the functionality and neuroprotective properties of mitochondria released from astrocytes.     

Do low birth weight infants not see eyes? Face recognition in infancy

BackgroundProgress in neonatal medicine has dramatically improved the survival rate of preterm births, but the evidence suggests that these low-birth weight infants (LBWIs) go on to develop pervasive development disorders and attention deficit hyperactivity disorder (ADHD) at greater rates than the general population. Children with neurodevelopmental disorders are known to suffer from deficits in visual cognition, such as in face perception and attentional functions, the characteristics of which already manifest in early infancy.PurposeThis study aimed to investigate visual cognition in LBWIs during infancy.Subjects20 LBWIs and 20 normal-birth-weight infants (NBWIs: control) of age 9–10 months (corrected age was used for LBWIs).MethodChildren were held seated in front of an eye tracking system by a parent, and presented with facial photos as visual stimuli. During the familiarization phase, the child was presented with two images of the same human face (familiarization stimulus) on the left and right side of a display screen (5 × 10 s trials). Next, during the test phase, the child was presented with the same image on one side of the screen, and a photo of a different person’s face (novel stimulus) on the other (2 × 5 s trials). Gaze behavior was assessed in terms of the total time spent looking at either facial stimulus, and specifically at the eyes of the stimuli, as well as the number of attentional shifts between stimuli, and novelty preference.Results/DiscussionLBWIs spent significant less time looking at facial stimuli overall, and less time at the eye region, than NBWIs. These findings seem to evidence developmental differences in functions related to visual cognition.     

Peripheral nerves are involved in hypomyelinating leukodystrophy-3 caused by a homozygous AIMP1 variant

IntroductionAminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a non-catalytic component of the multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their correct tRNAs. Bi-allelic truncating variants in the AIMP1 gene have been associated with hypomyelinating leukodystrophy-3 (HLD3; MIM 260600), which is characterized by hypomyelination, microcephaly, seizures and decreased life expectancy. Although peripheral nerve involvement has been assumed for HLD3, no compelling evidence is available to date.Case reportThe case was a first-born Filipino male. He showed profound developmental delay, failure to thrive, and spasticity in his limbs. At three months of age he developed refractory epilepsy. Serial magnetic resonance imaging (MRIs) showed profound myelination delay and progressive cerebral atrophy. He showed abnormal nerve conduction studies. Genetic testing revealed a homozygous pathogenic variant in the AIMP1 gene (NM_004757.3: c.115C > T: p.Gln39*). The parents were heterozygous for the same variant.ConclusionHere, we report a patient with a homozygous nonsense AIMP1 variant showing peripheral neuropathy as well as HLD3. Our case suggests that AIMP1 plays a pivotal role in the peripheral nerve as well as the central nervous system.     

Transient hypoglycorrhachia with paroxysmal abnormal eye movement in early infancy

Paroxysmal abnormal eye movement in early infancy is one of the initial symptoms of glucose transporter 1 deficiency syndrome (GLUT1DS). We describe four early infants with transient hypoglycorrhachia presenting with abnormal eye movements. Their symptoms disappeared after the introduction of a ketogenic diet (KD), and their development was normal. Since no variants in SLC2A1 were detected, the CSF-to-blood glucose ratios (C/B) were re-examined, and within normal range. None of the four patients displayed recurrent symptoms after withdrawal from the KD. Because long-term KD has potential adverse effects and could affect the quality of life of patients and their families, re-examination of CSF glucose during late infancy should be considered in the case of absence of the SLC2A1 pathogenic variant.     

Gastric undifferentiated carcinoma with diffuse c-kit overexpression and focal neuroendocrine differentiation

A case of gastric undifferentiated carcinoma with diffuse c-kit overexpression and focal neuroendocrine differentiation is described. A 76-year-old man presented appetite loss for 1 month. Gastric endoscopy showed an exophytic huge nodular mass with central ulceration at the gastric prepylorus. Distal gastrectomy was performed with lymph node dissection. Histology indicated anaplastic medium- to large-sized round tumor cells in discohesive sheets. Adenocarcinomatous areas forming tubular glands or with intracytoplasmic mucin on PAS and Alcian-blue staining were not found in any sections. Immunohistochemistry showed that the tumor cells were diffusely positive for cytokeratin, vimentin, c-kit and focally positive for chromogranin A and synaptophysin.     

Severe Hyperglycemia Immediately After Allogeneic Hematopoietic Stem-Cell Transplantation is Predictive of Acute Graft-Versus-Host Disease

Stress hyperglycemia and acute graft-versus-host disease (GVHD), the major early complication of hematopoietic stem cell transplantation (HSCT), are both associated with excessive release of inflammatory cytokines. We investigated whether new-onset hyperglycemia immediately after HSCT predicts acute GVHD. We studied nondiabetic adult recipients of human leukocyte antigen-matched HSCT (peripheral blood stem cells) for acute leukemia. Using mean morning serum glucose on Days 1–10, we classified hyperglycemia as: mild (6.11–8.33 mmol/L), moderate (8.34–9.98), and severe (minimum of 9.99). Subjects who were GVHD‐free on Day 10 were followed during Days 11–100 for grades II–IV acute GVHD or competing event. Evaluation utilized cumulative incidence-based proportional hazards regression. Subjects (n?=?328) were age 18–74, median of 49 years. Per body mass index (BMI)—25.0 % were obese (BMI, 30–48), 33.8 % overweight (25 to <30), 30.8 % normal weight (21 to <25), and 10.4 % lean (18 to <21). Mild, moderate, or severe hyperglycemia occurred during Days 1–10 in 50.0, 21.3, and 16.8 % of subjects, respectively. Cumulative incidence on Day 100 was 44.8 (±2.8)?% acute GVHD and 7.9 (±1.5)?% competing event. Among normal-to-overweight subjects (n?=?212), severe hyperglycemia developed in 14.2 % (n?=?30) and more than doubled the risk of acute GVHD (hazards ratio, 2.71; 95 % CI, 1.58–4.65—adjusted for donor/recipient characteristics, prophylactic regimen, and mucositis). In contrast, among obese subjects (n?=?82), severe hyperglycemia developed in 30.5 % (n?=?25) but did not significantly affect risk of GVHD. (No lean subjects (n?=?34) developed severe hyperglycemia.) Hyperglycemia that was less than severe had an effect indistinguishable from normoglycemia. In nondiabetic patients, severe hyperglycemia immediately after allogeneic HSCT indicates increased likelihood of acute GVHD. This association is absent in obese patients, who may be primed by obesity-induced inflammation to develop severe hyperglycemia even without experiencing the cytokine storm that is essential to GVHD pathogenesis.     

An anatomic study of the inferior oblique nerve with high-resolution magnetic resonance imaging

Objective

To investigate anatomic features of the inferior oblique nerve (IObN) by high-resolution magnetic resonance (MR) imaging and cadaveric dissection.

Methods

This study enrolled 100 consecutive outpatients, who underwent 3.0 T MR imaging equipped by the 32-channel head coil. The T2-weighted imaging data of IObN were extracted for analysis and compared with the findings of microsurgical dissection in 14 orbits.

Results

50 male and 50 female subjects allotted to the imaging study were aged from 11 to 78 years. In 94 % sides, the IObN was found to separate from the inferior rectus muscle (IRM) at the level just behind to the posterior pole of the bulb. At the midpoint of the IObN part coursing along the orbital floor and above or adjacent to the infraorbital nerve and artery complex, the mean distance from the lateral margin of the IRM was 1.0 mm on the right and 0.9 mm on the left. The IObN showed upward direction change just below the belly of the inferior oblique muscle and innervated to it at the equator level in 78 sides on the right and 89 on the left. Dissected specimens revealed the consistent morphological findings of the IObN.

Conclusions

The IObN seems to be a relatively consistent structure. Anatomic information on the IObN and surrounding structures that are provided by high-resolution MR imaging can be a help for safe surgery.     

Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune-related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.