The hypothalamo-pituitary-adrenocortical (HPA axis) is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons. Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays, whereas anticipatory responses use oligosynaptic pathways originating in upstream limbic structures. Anticipatory responses are driven largely by disinhibition, mediated by trans-synaptic silencing of tonic PVN inhibition via GABAergic neurons in the amygdala. Stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem), promote transsynaptic inhibition by limbic structures (e.g, hippocampus). Glucocorticoids also act at the PVN to rapidly inhibit CRH neuronal activity via membrane glucocorticoid receptors. Chronic stressinduced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency and modality. Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic and brainstem circuits. Importantly, an individual’s response to acute or chronic stress is determined by numerous factors, including genetics, early life experience, environmental conditions, sex and age. The context in which stressors occur will determine whether an individual’s acute or chronic stress responses are adaptive or maladaptive (pathological).
Prader–Willi syndrome (PWS) is recognized as the first example of genomic imprinting, generally due to a de novo paternal 15q11-q13 deletion. PWS is considered the most common genetic cause of marked obesity in humans. Scoliosis, kyphosis, and kyphoscoliosis are commonly seen in children and adolescents with PWS with a prevalence of spinal deformities cited between 15% to 86%. Childhood risk is 70% or higher, until skeletal maturity, with a bimodal age distribution with one peak before 4 years of age and the other nearing adolescence. As few reports are available on treating scoliosis in PWS, we described clinical observations, risk factors, therapeutic approaches and opinions regarding orthopedic care based on 20 years of clinical experience. Treatments include diligent radiographic screening, starting once a child can sit independently, ongoing physical therapy, and options for spine casting, bracing and surgery, depending on the size of the curve, and the child’s age. Similarly, there are different surgical choices including a spinal fusion at or near skeletal maturity, versus a construct that allows continued growth while controlling the curve for younger patients. A clear understanding of the risks involved in surgically treating children with PWS is important and will be discussed.
Cervical cancer is one of the most common gynecological tumors, and the majority of early-stage cervical cancer patients achieve good recovery through surgical treatment and concurrent chemo radiotherapy (CCRT). However, for patients with recurrent, persistent, metastatic cervical cancer, effective treatment is rare, except for bevacizumab combined with chemotherapy. Programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors might be a novel choice to improve the clinical outcomes of these patients. Thus far, some pivotal trials, including Keynote 028, Keynote 158 and Checkmate 358, have indicated established clinical benefit of PD-1/PD-L1 inhibitors in cervical cancer. In light of these data, the FDA has approved pembrolizumab for patients with recurrent or metastatic cervical cancer with disease progression during or after chemotherapy. There are also some ongoing studies that may provide more evidence for the PD-1/PD-L1 pathway as a therapeutic target in cervical cancer. In this review, we have summarized the status and application of PD1/PD-L1 inhibitors in clinical trials for the treatment of cervical cancer and suggested some future directions in this field.
Previous studies have shown that diabetes mellitus (DM) increases the risk of cardiovascular diseases in females to a greater extent than in males. In this cross-sectional study, we evaluated the lipid profiles of type 2 diabetic males and females. Materials and Methods: The study included 107 type 2 diabetic patients (41 males and 66 females), and 122 hypertensive type 2 diabetic patients (39 males and 83 females), aged 15 years and older. Total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C), very low density lipoprotein-cholesterol (VLDL-C) and high density lipoprotein-cholesterol (HDL-C) concentrations were assayed for each group using standard biochemical methods. Results: The mean TC, TG, VLDL-C, HDL-C and LDL-C concentrations, TG/HDL and LDL/HDL ratios were higher in type 2 diabetic and hypertensive type 2 diabetic patients compared with non-diabetic, and hypertensive non-diabetic control subjects, although these were not significant (P > 0.05). Hypertensive type 2 diabetic females had significantly higher serum TC (7.42 ± 1.63 mmol/L) than hypertensive non-diabetic males (5.76±1.57 mmol/L; P < 0.05). All the other lipid and lipoprotein parameters except HDL-C were non-significantly higher in females with type 2 DM and those with hypertension and type 2 DM, compared with type 2 diabetic and hypertensive type 2 diabetic males, respectively (P > 0.05). Conclusion: This study demonstrated that dyslipidemia exists in our type 2 diabetic population with greater TC in hypertensive type 2 diabetic females compared with hypertensive type 2 diabetic males. This suggests that hypertensive type 2 diabetic females are exposed more profoundly to risk factors including atherogenic dyslipidemia compared with males.
Osteoporosis is a well-established extra-articular feature of rheumatoid arthritis (RA). Systemic inflammation seems to play a crucial role in causing an alteration of multiple homeostatic systems implied in bone health, such as the RANK/RANKL/Osteoprotegerin and Wnt/ catenin pathways several other causal factors have been called into question, including the chronic use of corticosteroids. Since vitamin D exerts important immune-regulatory roles, it has been claimed that derangement of the vitamin D/parathyroid hormone (PTH) system, a well-known determinant of bone health, may play a pathogenic role in autoimmunity; animal models and clinical data support this hypothesis. Furthermore, RA patients seem to be relatively refractory to vitamin D-induced PTH suppression. Therefore, the link between RA and osteoporosis might in part be due to alterations in the vitamin D/PTH system. A better understanding of the pathophysiology of this system may be crucial to prevent and cure osteoporosis in patients with inflammatory/autoimmune diseases. A major clinical correlate of the strict cooperation and interdependence between vitamin D and PTH is that correction of the vitamin D deficiency, at least in autoimmune diseases, should be targeted to PTH suppression.