Medical hypotheses最新文献

While many risk factors are modifiable, there remains a compelling need for novel approaches to prevent cognitive impairment. We propose that unstable carotid plaque causes microemboli that, in turn, cause microinfarcts and other adverse pathophysiological cerebral processes, which individually do not manifest clinically but cumulatively manifest as cognitive decline and ultimately cognitive impairment. Animal models support multiple cerebral microemboli having adverse effects on cognition. By addressing the source for microembolization by endarterectomy or stenting, patients with high-grade atherosclerotic stenosis may have better cognitive outcomes. If our hypothesis is verified, then treatment of carotid plaque at elevated risk of generating cerebral microemboli would be effective in preserving cognition, regardless of whether the stenosis is high-grade or causing cerebral hemispheric hypoperfusion.

Perioperative neurocognitive disorder (PND) is a cognitive dysfunction that often occurs after surgery, particularly in elderly patients. The cerebral lymphatic system, which acts as an immune scavenger for the nervous system, may play a crucial role in the development of PND. Recent studies suggest that microglia, by sensing metabolites of ATP (adenosine triphosphate), inhibit neuronal electrical activity. This inhibition may impact the driving force of the cerebral lymphatic system and impair its scavenging function. Investigating the role of microglia in regulating the cerebral lymphatic system through the ATP-AMP (adenosine monophosphate)-ADO (adenosine) pathway could provide new insights into the pathogenesis of PND and identify novel targets and strategies for its prevention and treatment.

Primary Sjögren’s syndrome (pSS) is a systematic autoimmune manifestation of the exocrine glands caused by impaired lymphocytic infiltration, leading to dry eyes and xerostomia. The pathologic hallmark of this disease is the dysfunction of the exocrine glands, which results in dry eyes and mouth. Clinical observations suggest that B cells contribute to the pathogenesis of pSS through the enhanced secretion of autoantibodies, hypergammaglobulinemia, reduced free light chains, and a higher B cell lymphoma. Despite increased evidence of B cell hyperactivation and dysregulated B cell interactions in pSS, detailed speculations into the mechanism by which pSS-specific B cells exhibited abnormal BCR signaling repertoires and the magnitude of downstream signaling responses remain limited. Upon encountering antigens, B lymphocytes produce neutralizing antibodies by phosphorylating immune receptor tyrosine activation motifs (ITAMs). Despite these advancements, we still do not understand how pSS-specific B cells influence the surface clustering of BCRs and subsequent downstream immune responses. This paper hypothesizes that pSS-specific B cells encountering surrogate antigens will undergo a coordinated series of events that initiate B cell activation and spatiotemporal dynamics of BCRs. Additionally, we assume that pSS individuals have aberrant BCR repertoire and clonal expansion. In the future, these studies can provide detailed therapeutic entanglements for B cell-linked autoimmune and other hypersensitive disorders.

Hydrocephalus can be obstructive or communicating. In cases of communicating hydrocephalus, patients will typically have enlarged brain ventricles. It has long been thought that the reason for this is obstruction to the outflow of cerebrospinal fluid from the subarachnoid space, which also results in raised intracranial pressure (ICP). However, there are several clinical and anatomic observations that are not well explained by this idea. These are for example, the conditions of Normal pressure hydrocephalus (NPH) which has normal ICP but ventriculomegaly, and idiopathic intracranial hypertension (IIH) which has raised ICP but normal sized ventricles. This hypothesis states that the mechanism for raised ICP and large ventricles seen in communicating hydrocephalus (ventriculomegaly) are different and seeks to explain the cause of ventriculomegaly using illustrative examples. It also suggests explanations for why ventriculomegaly occurs in NPH, infectious or carcinomatous meningitis, but is absent in IIH, or dural venous sinus thrombosis. Based on operative neurosurgical observations it states that the arachnoid membranes in the basal cisterns serve as part of a directional CSF flow mechanism consisting of fluid diodes, or “Tesla valves” of arachnoid membrane, containing CSF that is propelled by brain pulsations from the point of exit from the 4th ventricle to its points of absorption. This hypothesis suggests explanations for the physiologic appearance of a near uniform subarachnoid space, as well as the occurrence of the syndrome of the trephined and external hydrocephalus seen following a decompressive craniectomy. Also suggested are avenues of further research testing with MRI phase contrast CSF flow studies, classification of anatomic and peri-operative observations and rationale for creation of novel experiments to test the hypothesis, and aid diagnosis and treatment of a number of cranial CSF disorders.

Diabetes is a chronic metabolic disorder. Among different types, type 2 diabetes mellitus (T2DM) is the most prevalent accounting for 90 % to 95 % of all reported cases. T2DM is more prevalent in men compared to women. According to several literature reports, men with low testosterone levels and/or decreased androgen receptor (AR) expression are prone to T2DM. Consistently, androgen therapy was effective in treating T2DM in several preclinical and clinical studies. Activation of AR has been shown to induce the gene expression of NGN3 and NEUROD1 which helps in pancreatic β-cell differentiation, regeneration, and proliferation. AR activation can also increase the gene expression of glucose transporter (GLUT4) in the hepatocytes, skeletal muscle fibers, and adipocytes. An increase in GLUT4 expression could augment the activity of insulin and could help to reduce the insulin dose. However, testosterone therapy even for the short term was found to produce significant adverse effects. The rate-limiting being the increase in the hematocrit value. Hence, to minimize or avoid the serious adverse effects associated with androgen therapy, selective androgen receptor modulators (SARMs) could be employed to harness the goodness of the AR. A preliminary study based on the network analysis of the genes associated with T2DM has also pointed towards the importance of AR in T2DM.

TMJOA as a progressive degenerative disease of the TMJ, is featured as enhanced inflammation, chondrocyte apoptosis, ECM degradation and subchondral bone remodeling, resulting in local pain and functional impairment that further reduces patients’ quality of life. However, its etiology is ambiguous, leading to no consensus regarding the most effective treatment for patients with TMJOA. L-arg is a conditionally essential amino acid that participates in regulating inflammation, ECM orchestration, cellular growth and proliferation, but the role and mechanism of L-arg in TMJOA remain unclear. L-arg exerts different functions in contexts- and tissue microenvironments-dependent manner. For example, excess L-arg induces acute pancreatitis via the JAK2/STAT3 pathway, the iNOS/NO pathway and the HMGB1/TLR4/NF-κB pathway; Arg-Ⅱ in advanced atherosclerosis impairs endothelial autophagy through regulation of mTOR signaling. Interestingly, these signaling pathways are tightly involved in the reported pathological process of TMJOA. We here unexpectedly found that L-arg is significantly elevated in the plasma of TMD patients using mass spectrometry. Thus, through literature review and analysis, we proposed that the upregulation of L-arg activated iNOS/NO pathway, Arg-Ⅱ pathway, mTOR pathway and NF-κB pathway to prompt TMJOA development. Related pathway inhibitors could be an alternative treatment strategy for TMJOA.

The outside world carries many dangers for the new-born baby especially in primitive societies. One danger undoubtedly is the risk of serious early enteric infections. Neonatal gastric acid is the principal defense.

This author proposes that this acid defense is increased in two main ways;

1. An immediate temporary acidity created by maternal gastrin transfer during spontaneous labor.

2. A progressively rising acidity which culminates in a temporary peak acidity at approximately 3 weeks and is due to a late maturation of the negative feed-back between gastrin and gastric acidity.

The author contends that there is an immature negative-feed-back between neonatal gastrin and gastric acidity at birth which matures around 3 weeks of life. Until maturity, both gastrin and acid secretion rise without restraint.

In this way rising gastrin will stimulate acid secretion as well as enhance the development of gastric parietal cells to allow them, after feed-back matures, to independently provide an acid defense.

One consequence of this new physiology is that it allows us to simply explain why pyloric stenosis of infancy occurs--the most common and hitherto unexplainable cause of milk vomiting in the neonate.

Calcineurin inhibitors (CNIs) are a class of immunosuppressants utilized to manage autoimmune disorders and to prevent rejection in solid organ transplantations. CNIs are associated with various side effects, including new-onset diabetes, dyslipidemia, hypertension, nephrotoxicity, cardiovascular risks, electrolyte imbalances, and neurotoxicity. Preventing these complications is crucial for improving the patients’ quality of life and survival. One strategy widely used to prevent these side effects is to employ a multi-drug immunosuppressive regimen to eliminate or reduce the CNI dose. However, the efficacy of this strategy is relatively low and there is a possibility of causing side effects by other drugs. As a result, novel approaches are needed to prevent or manage complications related to CNIs. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a type of antidiabetic medication that has gained increased usage. Preliminary clinical trials suggest that administering these drugs to diabetic patients is linked to improved renal and cardiovascular outcomes. Their prescription has also been recommended for non-diabetic patients with chronic kidney disease (CKD) and heart failure (HF). Our hypothesis is that SGLT2is can prevent or delay metabolic and vascular complications associated with CNIs due to their anti-diabetic, anti-hypertensive, anti-inflammatory, anti-fibrotic, antioxidant, and anti-apoptotic effects, as well as their ability to improve endothelial function. Additionally, SGLT2is have the potential to reverse electrolyte imbalances and neurological disorders caused by CNIs based on their effects on tubular function and neuroprotective properties. If the hypothesis were to be confirmed, the implications for science would be the prolongation of lifespan in patients treated with CNIs by targeting several side effects mechanisms with one drug.

Disturbances in the circadian rhythms are generally present in adults subjects with Attention Deficit Hyperactivity Disorder. However, may present in children with the same clinical condition. Poor sleep quality interferes with neural inputs and outputs in areas that are fundamental in neurobiological aspects, such as the dorsolateral prefrontal cortex, which can affect circadian rhythm, cognition, emotional and social control. The dorsolateral prefrontal cortex is an area involved in executive functions and sleep–wake regulation and is underactivated in subjects Attention Deficit Hyperactivity Disorder, which may be one of the main causes of alterations in the circadian cycle. Currently, studies with non-invasive therapeutic methods for adult populations and children with these disorders remain scarce, revealing a significant gap in understanding and treatment. In this context, the aim is investigate the potential effectiveness of repetitive transcranial magnetic stimulation as alternative non-invasive treatment of these disorders. In the present study, it is suggested that use excitatory currents from 10 Hz to 20 Hz in the right dorsolateral prefrontal cortex leads to an improvement in the circadian rhythm mechanism. This is because the excitatory current will promote an increase in dopamine (a neurotransmitter that regulates the circadian cycle) and an increase in glutamate and glutamine concentrations to restore homeostasis in brain regions linked to the sleep–wake cycle.

Developmental stuttering is a speech disorder that affects about one percent of the adult population worldwide. The cause is still unknown, but not a few researchers have suspected poor auditory-motor integration to be a causal factor. Almost all people who stutter are more or totally fluent in certain conditions, for instance, when speaking in chorus or alone to themselves, in time with the clicking of a metronome, or with delayed or frequency-altered auditory feedback. Understanding why stuttering disappears in these specific conditions could help understand why it occurs in normal speaking conditions. Here, the first unified account for the effect is proposed, based on evidence that receptive speech processing depends on attention to the speech signal. It is proposed that fluency-enhancing conditions re-allocate the speaker’s attention, that is, the perceptual and processing capacities, by drawing attention to the auditory feedback of speech. This improves auditory-motor integration, which reduces stuttering. The hypothesis is discussed for all well-known fluency-enhancing conditions, and consequences for therapy are outlined.