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Blue toe syndrome, also referred to as cholesterol crystal embolism is characterized by the distal embolization of cholesterol crystals originating from ruptured atherosclerotic plaques. This condition commonly arises in the context of cardiovascular procedures. Emboli from the thoracoabdominal aorta primarily affect the downstream extremities and intra-abdominal viscera, often resulting in fatal atheroembolic renal failure. Owing to its insidious and delayed onset, antemortem diagnosis of cholesterol crystal embolism is often underrecognized. Two cases of blue toe syndrome secondary to cardiovascular procedures are presented. In Case 1, the patient died 35 days after coronary angioplasty, whereas in Case 2, the patient developed toe necrosis 95 days after endovascular aortic repair, leading to progressive renal failure over the following five years. A comprehensive forensic autopsy included external examination, skin biopsy, histopathological examination of major organs, and serum biochemical evaluation of renal function parameters. Two cases of blue toe syndrome secondary to cardiovascular procedures are presented. In Case 1, the patient died 35 days after coronary angioplasty, whereas in Case 2, the patient developed toe necrosis 95 days after endovascular aortic repair, leading to progressive renal failure over the following five years. A comprehensive forensic autopsy included external examination, skin biopsy, histopathological examination of major organs, and serum biochemical evaluation of renal function parameters. This report underscores the importance of including systemic cholesterol crystal embolism in the differential diagnosis of blue toe syndrome, particularly in patients with a history of cardiovascular procedures. Fingertips serve as reliable indicators of impaired blood perfusion. To assess blue toe syndrome accurately, we highlight the value of focusing on the toe tips where cholesterol crystal embolism can be consistently detected.

Leptin is a well-known hunger-sensing peptide hormone. The role of leptin in weight gain and metabolic homeostasis has been explored for the past two decades. In this review, we have tried to shed light upon the impact of leptin signaling on health and diseases. At low or moderate levels, this peptide hormone supports physiological roles, but at chronically higher doses exhibits detrimental effects on various systems. The untoward effects we observe with chronically higher levels of leptin are due to their receptor-mediated effect or due to leptin resistance and are not well studied. This review will help us in understanding the non-anorexic roles of leptin, including their contribution to the metabolism of various systems and inflammation. We will be able to get an alternative perspective regarding the physiological and pathological roles of this mysterious peptide hormone.

Bizarre parosteal osteochondromatous proliferation (BPOP), or Nora’s lesion, is a rare benign bone tumour that most commonly affects the bones of the hands and feet. It presents diagnostic challenges due to its aggressive imaging features, high recurrence rate and histological overlap with malignant lesions. We report the case of an adolescent girl who presented with a hard, ulcerated swelling over the distal phalanx of the right great toe. Imaging revealed corticomedullary continuity of the lesion with the underlying phalanx, raising suspicion for osteochondroma or subungual exostosis. Surgical excision was performed, and histopathology confirmed BPOP, showing binucleated chondrocytes, endochondral ossification and the characteristic ‘blue bone’. No recurrence was observed during a 1-year follow-up period. This case highlights the importance of considering BPOP in the differential diagnosis of toe lesions particularly when atypical radiological features are present. Histopathological examination remains the cornerstone for definitive diagnosis.

Acral soft tissue tumors are common neoplasms, a subset of which pose a diagnostic challenge. We report 10 cases of a previously unrecognized acral benign soft tissue tumor. These tumors arose on the fingers and toes and involved bone in half of cases. Histologically, the tumors were lobulated and displayed an abundant stroma made of variable fibrous, chondroid and myxoid material reminiscent of cartilaginous or myoepithelial differentiation. Tumor cells harbored small round to reniform nuclei with clear chromatin and inconspicuous nucleoli along with scant eosinophilic cytoplasm. The cells were mostly arranged haphazardly in the stroma but also in small clusters. No mitotic activity was detected. No specific feature was identified in recurrent cases. By immunohistochemistry, the cells consistently stained for CD34 (10/10), ERG (9/10), and SOX9 (7/10). Whole RNA sequencing identified a previously undescribed recurrent in frame THBS1-ADGRF5 gene fusion in all cases. The transcript was confirmed by RT-PCR and was not found in the control group of mimickers including soft tissue chondromas. We propose the name of Acral FibroChondroMyxoid Tumors for this new entity.

How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named \"logic of monsters\" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures.

Background Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly. Objective To characterise the genotypic and phenotypic findings in individuals with GLI2 variants and clarify clinical findings in individuals with loss-of-function mutations. Methods Through the National Institutes of Health and collaborating centres, ∼400 individuals with HPE spectrum disorders, endocrine disorders or craniofacial anomalies were screened for GLI2 mutations. Results were combined with all published cases. We compared the clinical and molecular features of individuals with truncating mutations to individuals with variants of unknown significance (defined as not resulting in protein truncation, reported in normal controls and/or deemed unlikely to be pathogenic by functional prediction software). Results 112 individuals with variants in GLI2 were identified, with 43 having truncating mutations. Individuals with truncating mutations were more likely to have both pituitary anomalies and polydactyly versus those with variants of unknown significance (p<0.0001 by Fisher’s exact test); only 1 of 43 had frank HPE. These individuals were more likely to have recognised penetrance (polydactyly or pituitary anomalies or both) than those without truncating mutations (p=0.0036 by Fisher's exact test). A common facial phenotype was seen in individuals (with midface hypoplasia, cleft lip/palate and hypotelorism) with truncating mutations. Conclusions Individuals with truncating mutations in GLI2 typically present with pituitary anomalies, polydactyly and subtle facial features rather than HPE. This will be helpful in screening populations for GLI2 mutations and for counselling affected patients. Trial registration 98-HG-0249/04-HG-0093.

Neurofibromas, rare benign tumors of the peripheral nerve sheath, present diagnostic challenges, particularly in diabetic patients with toe ulcers. This case involves a 55-year-old female with type 2 diabetes mellitus who developed an enlarging ulcer on her right second toe. The initial evaluation suggested a diabetic ulcer; however, advanced imaging revealed a mass-like lesion. Partial excision and biopsy confirmed a neurofibroma with spindle cells within the myxoid stroma and S100 protein expression. One month later, total excision and Z-plasty reconstruction were performed under general anesthesia. The patient’s postoperative recovery was uneventful, and the patient was discharged without complications. Follow-up revealed successful healing with no recurrence or functional issues. This case highlights the importance of considering neurofibromas in the differential diagnosis of diabetic toe ulcers to avoid misdiagnosis and ensure appropriate management.

Background Amputation is the standard of care even for early-stage subungual melanomas (SUMs), known as nail apparatus melanoma, because the nail bed and nail matrix are close to the distal phalanx. However, a recent study demonstrated that not all patients with SUMs had histologic invasion of the underlying distal phalanx. As most SUMs occur in the thumb or big toe, amputation of either the thumb or big toe substantially interferes with activities of daily living, including poor cosmesis, loss of function, and phantom pain. Non-amputative digit preservation surgery can thus be applied in such cases without compromising patient prognosis. Methods We are conducting a multi-institutional single-arm trial to confirm the safety and efficacy of non-amputative digit preservation surgery. We will compare our results with those reported in the Japanese Melanoma Study, in which patients underwent amputation for SUMs as a traditional standard of care. Patients aged between 20 and 80 years with stage I, II, or III without evidence of tumor invasion to the underlying distal phalanx on preoperative radiograph are included in the study. The primary endpoint is major relapse-free survival (major RFS), which does not include local recurrence as an event; secondary endpoints include overall survival, digit-preservation survival, relapse-free survival, local relapse-free survival, partial relapse-free survival, and incidence of adverse events. A total of 85 patients from 21 Japanese institutions will be recruited within 5.5 years, and the follow-up period will last at least 5 years. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in August 2017, and patient enrollment began in November 2017. Ethical approval was obtained from each institution’s Institutional Review Board prior to patient enrollment. Discussion This is the first prospective trial to confirm the safety and efficacy of non-amputative digit preservation surgery for SUM without distant metastasis or bony invasion. The results of this trial could provide evidence to support this less-invasive surgery as a new standard of care to preserve adequately functioning digits. Trial registration Registry number: UMIN000029997 . Date of Registration: 16/Nov/2017. Date of First Participant Enrollment: 12/Dec/2017.

BackgroundIngrown toenails are a common nail pathology. When conservative treatments are ineffective, a surgical approach is often utilised. Despite recent narrative reviews, there is a need for an up-to-date and rigorous systematic review of surgical methods for treating ingrown toenails.MethodsFive databases (MEDLINE, Embase, CINAHL, Web of Science and CENTRAL) and two registers (Clinicaltrials.gov and ISRCTN) were searched to January 2022 for randomised trials evaluating the effects of a surgical intervention(s) for ingrown toenails with a follow-up of at least 1 month. Two independent reviewers screened records, extracted data, assessed risk of bias and certainty of evidence.ResultsOf 3,928 records identified, 36 (3,756 participants; 62.7% males) surgical interventions were included in the systematic review and 31 studies in the meta-analysis. There was very low quality evidence that using phenol with nail avulsion vs nail avulsion without phenol reduces the risk of recurrence (risk ratio [RR] 0.13 [95% CI 0.06 to 0.27], p < 0.001). No favourable effect was observed between chemical or surgical vs conservative management (0.55 [0.19 to 1.61], p = 0.280; 0.72 [0.33 to 1.56],p = 0.410), chemical or surgical vs other (e.g., CO2 laser, electrocautery) (1.61 [0.88 to 2.95], p = 0.120; 0.58 [0.25 to 1.37], p = 0.220), chemical vs surgical (0.75 [0.46 to 1.21], p = 0.230), surgical vs surgical (0.42 [0.21 to 0.85]), chemical vs chemical (0.19 [0.01 to 3.80], p = 0.280), surgical vs surgical + chemical (3.68 [0.20 to 67.35], p = 0.380), chemical vs surgical + chemical (1.92 [0.06 to 62.30], p = 0.710), local anaesthetic vs local anaesthetic + adrenaline (1.03 [0.22 to 4.86], p = 0.970), chemical timings 30 s vs 60 s (2.00 [0.19 to 21.41]) or antibiotics vs no antibiotics (0.54 [0.12 to 2.52], p = 0.430). Central toenail resection was the only procedure to significantly relieve symptoms (p = 0.001) but data were only available up to 8 weeks post-surgery.ConclusionDespite the high number of publications, the quality of research was poor and the conclusions that can be inferred from existing trials is limited. Phenolisation of the nail matrix appears to reduce the risk of recurrence following nail ablation, and with less certainty 1 min appears to be the optimum time for application. Despite this being a widely performed procedure there remains a lack of good quality evidence to guide practice.