Macular amyloidosis diagnostic outcomes of skin biopsy: A systematic review.

Macular amyloidosis (MA) is a primary localized cutaneous amyloidosis, characterized by amyloid deposition in the papillary dermis. The clinical presentation includes pruritic hyperpigmented macules and patches with a reticulated or rippled pattern, primarily found on the upper back and extremities. Biopsy is an essential diagnostic tool for confirming MA. This systematic review focused on the biopsy outcomes in patients diagnosed with MA.

Evaluation and comparison of Q-switched Nd: YAG laser 1064 nm and Er: YAG laser 2940 nm in the treatment of macular amyloidosis.

Macular amyloidosis (MA) is one of the most common types of primary localized cutaneous amyloidosis (PLCA), distributed predominantly over the trunk and extremities. Due to the vast therapeutic options, this study aims to compare the effectiveness of Q-switched Nd: YAG laser 1064 nm and Er: YAG laser 2940 nm in treating MA. This clinical trial was performed in 2020-2021 on 33 women with MA. In each patient, the lesion was randomly divided into two areas, A and B. Area A underwent four treatment sessions with 4-week intervals of Q-switched Nd: YAG laser 1064 nm. Area B underwent four treatment sessions with an Er: YAG laser 2940 nm at 4-week intervals. Degree of basal pigmentation and degree of pigmentation after treatment, pruritus intensity, before and after the treatment, and patient and physicians' satisfaction were measured and compared. The pruritus in patients improved significantly after the study (P < 0.001), but no significant differences could be observed between the two groups regarding the improvements (P > 0.05). We also found no significant differences between the two groups of patients regarding patient and physicians' satisfaction rates (P > 0.05). The use of both Q-switched Nd: YAG laser and Er: YAG laser resulted in improvements in terms of pruritus, patient and physicians' satisfaction, and total improvement in pigmentation of the lesions.

Trypsin-induced aggregation of transthyretin Valine 30 variants associated with hereditary amyloidosis.

Amyloid fibrils of transthyretin (TTR) consist of full-length TTR and C-terminal fragments starting near residue 50. However, the molecular mechanism underlying the production of the C-terminal fragment remains unclear. Here, we investigated trypsin-induced aggregation and urea-induced unfolding of TTR variants associated with hereditary amyloidosis. Trypsin strongly induced aggregation of variants V30G and V30A, in each of which Val30 in the hydrophobic core of the monomer was mutated to less-bulky amino acids. Variants V30L and V30M, in each of which Val30 was mutated to bulky amino acids, also exhibited trypsin-induced aggregation. On the other hand, pathogenic variant I68L as well as the nonpathogenic V30I did not exhibit trypsin-induced aggregation. The V30G variant was extremely unstable compared with the other variants. The V30G mutation caused the formation of a cavity and the rearrangement of Leu55 in the hydrophobic core of the monomer. These results suggest that highly destabilized transthyretin variants are more susceptible to trypsin digestion.

Single Nucleotide Polymorphisms Associated with AA-Amyloidosis in Siamese and Oriental Shorthair Cats.

AA-amyloidosis in Siamese and Oriental shorthair cats is a lethal condition in which amyloid deposits accumulate systemically, especially in the liver and the thyroid gland. The age at death of affected cats varies between one and seven years. A previous study indicated a complex mode of inheritance involving a major locus. In the present study, we performed a multi-locus genome-wide association study (GWAS) using five methods (mrMLM, FASTmrMLM, FASTmrEMMA, pLARmEB and ISIS EM-BLASSO) to identify variants associated with AA-amyloidosis in Siamese/Oriental cats. We genotyped 20 affected mixed Siamese/Oriental cats from a cattery and 48 healthy controls from the same breeds using the Illumina Infinium Feline 63 K iSelect DNA array. The multi-locus GWAS revealed eight significantly associated single nucleotide polymorphisms (SNPs) on FCA A1, D1, D2 and D3. The genomic regions harboring these SNPs contain 55 genes, of which 3 are associated with amyloidosis in humans or mice. One of these genes is SAA1, which encodes for a member of the Serum Amyloid A family, the precursor protein of Amyloid A, and a mutation in the promotor of this gene causes hereditary AA-amyloidosis in humans. These results provide novel knowledge regarding the complex genetic background of hereditary AA-amyloidosis in Siamese/Oriental cats and, therefore, contribute to future genomic studies of this disease in cats.

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Evaluation of Psychopathologies and Health-Related Quality of Life in Patients With Macular Amyloidosis. / [Artículo traducido] Evaluación de psicopatologías y calidad de vida relacionada con la salud en pacientes con amiloidosis macular.

Macular amyloidosis (MA) is a skin condition with predominance in young women. We aimed to evaluate quality of life (QoL) and psychopathologies in these patients. In this cross-sectional study, patients with MA referring to the Imam Reza Hospital, Mashhad during 2018-2020, and their matched controls were included. Participants completed the 36-item short form survey (SF-36), the revised symptom checklist-90 (SCL-90-R), and the dermatology life quality index (DLQI). Overall, 40 women with a mean age of 36.80±10.19 years were studied. In the MA group, the SF-36 score was lower (P<0.001), and the SCL-90-R score was higher (P<0.001). The DLQI score was correlated with age (r=0.447; P=0.048) and pruritus severity (r=0.776; P<0.001), and was lower in patients with uncovered lesions (P=0.005). MA was associated with impaired QoL, which was determined by pruritus severity and lesion location; these patients can benefit from psychiatric interventions in this regard.

Localized Cutaneous Nodular Amyloidosis in a Patient with Sjögren's Syndrome.

Primary localized cutaneous nodular amyloidosis (PLCNA) is included in the primary forms of cutaneous amyloidosis along with macular and lichenoid amyloidosis. It is a rare disease attributed to plasma cell proliferation and deposition of immunoglobulin light chains in the skin. We present the case of a 75-year-old woman with a personal history of Sjogren's syndrome (SjS), who consulted for asymptomatic yellowish, waxy nodules on the left leg. Dermoscopy of the lesions showed a smooth, structureless, yellowish surface with hemorrhagic areas and few telangiectatic vessels. Histopathology revealed an atrophic epidermis and deposits of amorphous eosinophilic material in the dermis with a positive Congo red stain. The diagnosis of nodular amyloidosis was made. Periodic reevaluation was indicated after the exclusion of systemic amyloidosis. PLCNA is often associated with autoimmune connective tissue diseases, and up to 25% of all PLCNA cases occur in patients with SjS. Therefore, in addition to ruling out systemic amyloidosis, screening for possible underlying SjS should be performed when the diagnosis of PLCNA is confirmed.

Evaluation of Psychopathologies and Health-Related Quality of Life in Patients With Macular Amyloidosis.

Macular amyloidosis (MA) is a skin condition with predominance in young women. We aimed to evaluate quality of life (QoL) and psychopathologies in these patients. In this cross-sectional study, patients with MA referring to the Imam Reza Hospital, Mashhad during 2018-2020, and their matched controls were included. Participants completed the 36-item short form survey (SF-36), the revised symptom checklist-90 (SCL-90-R), and the dermatology life quality index (DLQI). Overall, 40 women with a mean age of 36.80±10.19 years were studied. In the MA group, the SF-36 score was lower (P<0.001), and the SCL-90-R score was higher (P<0.001). The DLQI score was correlated with age (r=0.447; P=0.048) and pruritus severity (r=0.776; P<0.001), and was lower in patients with uncovered lesions (P=0.005). MA was associated with impaired QoL, which was determined by pruritus severity and lesion location; these patients can benefit from psychiatric interventions in this regard.

Natural history and survival rate of familial amyloidosis with polyneuropathy: A nationwide databank.

OBJECTIVE: Hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy, a rare autosomal-dominant disease, has gained attention in recent years owing to treatment improvements. However, epidemiological real-world mega database of nationwide natural history and survival rates, especially with the specific mutation of Ala97Ser, are limited. METHODS: Taiwan National Health Insurance Research Database contains data from over 23 million individuals; Among them, 175 ATTRv amyloidosis patients validated by rare disease registry were enrolled. Multivariable Cox proportional hazard analyses were applied to investigate the association between baseline characteristics and all-cause mortality. FINDINGS: From 2008 to 2020, the annual incidence and prevalence rates of specific mutations (Ala97Ser) leading to ATTRv amyloidosis with polyneuropathy were 0.04-1.14 and 0.04-4.79 per million in Taiwan, respectively. In Taiwan, these patients exhibited male predominance with a mean age at validation of 62.75 years. At the 5th year after validation, patients exhibited a survival rate of approximately 50%, with higher mortality in male patients (hazard ratio [HR]: 2.22, 95% confidence interval [CI]: 1.15-4.31) and patients older at validation (HR: 1.10, 95% CI: 1.06-1.15). The two most common departments in outpatient were neurology and family medicine, and neurology and cardiology in inpatient. The three most common causes of death registered were unspecified amyloidosis (30.6%), organ-limited amyloidosis (20.9%), and neuropathic heredofamilial amyloidosis (9.7%). INTERPRETATION: The annual prevalence rate of specific mutation (Ala97Ser)-dominant ATTRv amyloidosis with polyneuropathy in Taiwan is comparable to the mid- to high-prevalence country level of the research by Schmidt et al. The extraordinarily high mortality, especially among patients older at validation, may reflect the inadequate awareness and the necessity of early intervention with novel disease-modifying regimens.

AHNAK, regulated by the OSM/OSMR signaling, involved in the development of primary localized cutaneous amyloidosis.

BACKGROUND: Primary localized cutaneous amyloidosis (PLCA) is a chronic skin disease characterized by aberrant keratinocyte differentiation, epidermal hyperproliferation, and amyloid deposits. Previously, we demonstrated OSMR loss-function mutants enhanced basal keratinocyte differentiation through the OSMR/STAT5/KLF7 signaling in PLCA patients. OBJECTIVE: To investigate the underlying mechanisms involved in basal keratinocyte proliferation in PLCA patients that remain unclear. METHODS: Patients with pathologically confirmed PLCA visiting the dermatologic outpatient clinic were involved in the study. Laser capture microdissection and mass spectrometry analysis, gene-edited mice, 3D human epidermis culture, flow cytometry, western blot, qRT-PCR and RNA sequencing were used to explore the underlying molecular mechanisms. RESULTS: In this study, we found that AHNAK peptide fragments were enriched in the lesions of PLCA patients, as detected by laser capture microdissection and mass spectrometry analysis. The upregulated expression of AHNAK was further confirmed using immunohistochemical staining. qRT-PCR and flow cytometry revealed that pre-treatment with OSM can inhibit AHNAK expression in HaCaT cells, NHEKs, and 3D human skin models, but OSMR knockout or OSMR mutations abolished this down-regulation trend. Similar results were obtained in wild-type and OSMR knockout mice. More importantly, EdU incorporation and FACS assays demonstrated the knockdown of AHNAK could induce G1 phase cell cycle arrest and inhibit keratinocyte proliferation. Furthermore, RNA sequencing revealed that AHNAK knockdown regulated keratinocyte differentiation. CONCLUSION: Taken together, these data indicated that the elevated expression of AHNAK by OSMR mutations led to hyperproliferation and overdifferentiation of keratinocytes, and the discovered mechanism might provide insights into potential therapeutic targets for PLCA.

Depictions of penises in historical paintings reflect changing perceptions of the ideal penis size.

OBJECTIVES: To investigate alterations in depicted penis size by evaluating nude male paintings from the 15th to 21st centuries. MATERIALS AND METHODS: Nude-male paintings were identified from various art history websites and analysed to determine changes in penis size over time. Two observers organised the paintings according to the century in which they were created and made the calculations. Penile length to ear length (PtEL) or penile length to nose length (PtNL) were calculated to standardise the measurements using professional image analysis software. PtEL was first attempted for all paintings; if PtEL could not be ascertained, then nose length was used instead of the ear, as the nose length is defined as equal to ear length according to the golden ratio. Thus, PtNL was ensured and both ratios were then referred to using a common term: penis depiction ratio (PDR). Further analysis was performed by dividing the paintings into three groups according to the historical development of art: Renaissance Period (1400-1599; 15th-16th centuries), Baroque-Rococo and Impressionism Period (1600-1899; 17th-19th centuries) and Contemporary Art Period (1900-2020; 20th and 21st centuries). RESULTS: Of 232 identified paintings, 72 (31.1%) were excluded because they depicted images of adolescents or an erect penis. The PDR was found to differ significantly between paintings created in different centuries (P < 0.001). Subgroup analysis revealed that paintings from the 21st century demonstrated significantly higher PDRs than paintings from previous centuries (P = 0.001). CONCLUSIONS: In paintings depicting nude males, the size of the penis has gradually increased throughout the past seven centuries, and especially after the 20th century. This observation illustrates the changing sociocultural inputs into male body image and emphasises the need for improved understanding of the sociocultural factors associated with the perception of penis size in men.

Distribution and progression of cerebral amyloid angiopathy in early-onset V30M (p.V50M) hereditary ATTR amyloidosis.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is becoming the most common and serious complications in long-lived hereditary ATTR amyloidosis patients. It is therefore imperative to elucidate the characteristics of ATTR-type CAA and develop useful biomarkers. METHODS: We enrolled 34 ATTRv amyloidosis patients with the V30M (p.V50M) variant for analysis with three-dimensional stereotactic surface projection z score imaging of Pittsburgh compound B (PiB)-PET. RESULTS: Eight patients exhibited central nervous system (CNS) symptoms. Seven patients suffered transient focal neurologic episodes, and 2 patients each experienced cerebellar haemorrhages or cognitive decline. The amount of 11C-PiB accumulation increased as a function of disease duration. 11C-PiB-PET abnormalities were seen at 8 years from onset and were associated with CNS manifestations from 12 years. The annual increase rate of the standardised uptake value ratio (SUVR) in female patients was significantly higher than in male patients. CNS amyloid deposition started in the upper middle surface of the cerebellar cortex, and then spread out over the entire surface of the cerebellum, Sylvian fissure, and anterior part of the longitudinal fissure of the cerebrum. CONCLUSIONS: PiB-PET is a useful biomarker for the early detection and treatment evaluation of ATTR-type CAA. Female gender is associated with more rapid progression of ATTR-type CAA.