Journal of Internal Medicine最新文献

Dear Editor,

I appreciate Giaquinto et al. sharing the findings of their case–control study on cardiac abnormalities in patients with Paget's disease of the bone (PDB) [1]. Even though patients and controls were matched for several cardiovascular risk factors such as age, sex, body mass index, and history of arterial hypertension, it remains unclear if the abnormal echocardiographic parameters the authors recognized in PDB patients resulted from either the disease itself or other unrelated conditions. The most specific cardiovascular manifestation of PDB is high-output heart failure due to the extensive arteriovenous shunting that leads to markedly increased blood flow through the Pagetic bone [2]. This is a rare complication that typically occurs in patients with advanced and metabolically active disease involving large portions of the skeleton. However, only 21 out of the 69 PDB patients they reported on had active disease according to elevated blood levels of total alkaline phosphatase, and 31 out of 69 had a limited involvement of the skeleton with a monostotic rather than polyostotic disease [1]. Furthermore, no significant differences in echocardiographic parameters were observed between patients with active and those with inactive disease and between patients with monostotic and those with polyostotic disease [1]. These findings lend support to the hypothesis that coexisting conditions may be at play in damaging the myocardial function and structure, at least in a proportion of PDB patients. To rule out any interference, however, Giaquinto et al. excluded cases and controls with a spectrum of potential causes of cardiac impairment, but transthyretin cardiac amyloidosis (TTA) was not investigated [1]. The coexistence of TTA could have been suggested by some demographic, clinical, and echocardiographic characteristics that appear to be shared by both the PDB patients reported by Giaquinto et al. and the typical patients with TTA cardiomyopathy [3]. No study has so far ascertained the relative importance of TTA in PDB patients, and only one report has described a single patient with both PDB and TTA [4]. It is worth addressing the problem of unrevealed TTA as a source of bias when investigating the cardiovascular manifestations of PDB and the impact on the current analyses in the study by Giaquinto et al. It would be of interest if the authors could provide information on this issue.

The author declares no conflicts of interest.

Increasing temperatures and water scarcity pose threats to animals living in the wild and humans. Here, we review biological mechanisms animals use to prevent dehydration. Fat and glycogen generate water during metabolism that can be used by many animals as a source of water. In hibernating animals, fat production is stimulated in the autumn by a vasopressin-dependent, carbohydrate-based metabolism that leads to thirst, increased water intake, and storage of glycogen and fat. As fall advances, the animals switch to fat-based metabolism with falling vasopressin levels, and actual entrance into torpor can be triggered when water becomes unavailable and/or unpredictable. Once in torpor, metabolic water is generated by fat metabolism along with a suppression of vasopressin and fall in serum osmolality that blocks thirst. We suggest that water production from fat does not keep up with demands, and that respiratory acidosis also develops as a consequence of hypoventilation, and this leads to the necessity of interbout arousals (IBA), in which the animal rewarms with a switch to carbohydrate metabolism that causes a rapid increase in water availability from the breakdown of glycogen that facilitates the ventilation needed to correct the acidemia. The animal then drops its metabolic rate again, allowing fat metabolism to continue. The observation that water deficit may be a stimulus for fat storage in hibernation carries significance for human obesity, especially in response to salt and sugar, as it suggests that hydration may be protective. These studies also provide an understanding of how glucagon-like peptide-1 agonists may cause weight loss.

Dear Editor,

We thank Dr. Shamsulddin for his perspective [1] on our meta-analysis on intensive versus standard systolic blood pressure (SBP) control [2]. Although our findings show consistent benefits of intensive SBP control, we agree that identifying individuals who are most likely to benefit or experience harm remains a significant challenge.

Generalizability is a common limitation of trial-level meta-analyses, particularly when the included studies are geographically concentrated. In our analysis, most participants were enrolled in studies conducted in North America and East Asia. Although heterogeneity across study populations may compromise the precision and interpretability of pooled effect estimates, a certain degree of clinical and methodological variation is essential to support the external validity and applicability of meta-analytic findings. Besides geographical diversity, the included studies enrolled patients with different risk profiles, including diabetes, history of stroke, and cardiovascular disease of varying severity. Nonetheless, our subgroup analyses did not show significant heterogeneity of treatment effect across these clinical strata, suggesting a consistency that could be interpreted as a pragmatic proxy for real-world variability. However, this does not serve as a substitute for specifically designed regional studies, which would be required to confirm the benefits of intensive SBP control in genetically diverse populations and within different healthcare systems.

Finally, the risk of adverse events, such as the incidence of syncope, acute kidney injury and electrolyte disturbances, may also differ between geographical and clinical subgroups. These aspects of heterogeneity are rarely addressed in clinical trials and meta-analyses, which are often limited to subgroup analyses for efficacy outcomes.

Although we welcome the call for global validation, we believe our findings provide robust evidence supporting the benefits of intensive blood pressure lowering across diverse populations. Clinicians should use this evidence to guide personalized treatment decisions.

The authors declare no conflicts of interest.

Chronic pain is a major medical problem that requires new therapeutic options. Discovered by Victor Mutt in 1982, neuropeptide Y (NPY) is rapidly emerging as a master regulator of pain relief. Genetic knockdown of NPY or pharmacological inhibition of its receptors demonstrates that NPY signaling tonically inhibits indices of chronic inflammatory and neuropathic pain. Primary targets of NPY analgesia include neurons in the dorsal horn of the spinal cord and the parabrachial nucleus of the brain that express the Npy1r (Y1) receptor. NPY signaling is enhanced following injury, and endogenous analgesic synergy between Y1 receptors and mu opioid receptors maintain chronic pain sensitization in a latent state of remission. We propose that disruptions to endogenous NPY analgesia may mediate pathological transitions from acute to chronic pain, which could be treated by CNS administration of Y1 agonists or Npy2r (Y2) agonists or antagonists, depending on the pain state. Chemogenetic manipulations or targeted ablations in rodent models of chronic inflammation or peripheral nerve injury establish that spinal Y1-interneurons are necessary and sufficient to elicit behavioral signs of both the sensory and affective dimensions of pain. Transcriptomic and in situ hybridization studies revealed three primary subpopulations of spinal Y1-interneurons that are conserved in higher order mammals, including non-human primates and humans. Spinally directed (intrathecal) administration of Y1-selective pharmacological agonists inhibit pronociceptive neurons that co-express Y1 and gastrin-releasing peptide to inhibit neuropathic pain. To circumvent highly invasive administration routes, ongoing studies are leveraging the intranasal route for delivery of NPY into the brain.

The benefits of a low-protein diet (LPD) in patients with altered kidney function remain controversial. Dietary intake studies are inherently complex and may present numerous biases that must be understood and controlled. Due to these challenges, the scientific evidence in this area remains limited and is subject to dispute. However, there is abundant literature showing that excessive protein intake in these patients is linked to cardiovascular issues, oxidative stress, hyperphosphatemia, bone mineral disease, metabolic acidosis, inflammation, and gut dysbiosis, contributing to kidney damage and other concurrent systemic disorders. An LPD remains a valuable recommendation for non-dialysis chronic kidney disease (CKD) patients if age, nutritional status, and disease complications are carefully considered to ensure optimal outcomes. On the one hand, excessive protein intake may lead to the accumulation of nitrogenous waste products, thereby burdening renal function. On the other hand, overly restrictive protein consumption can lead to muscle mass loss, potentially worsening clinical outcomes and patient prognosis. This narrative review highlights the harmful impact of a high-protein diet on kidney function, particularly for those with preexisting kidney impairment or a predisposition to CKD. It also discusses the importance of an individualized and well-monitored protein intake strategy to balance the benefits of protein restriction with the risks of malnutrition.