Hb Kalavasos [HBA2: c.275T > A; p.Leu92His]: a Novel α Chain Hemoglobin Variant

We present a case of a novel pathogenic variant, Hb Kalavasos [α91(FG3)Leu→His (α2); HBA2: c.275T?>?A; p.Leu92His (NM_000517.4)]; this codon was previously numbered 91 on the α2-globin gene that was discovered following routine Hb A_1c testing on a 65-year-old female of Cypriot origin. The band, seen by high performance liquid chromatography (HPLC) but not capillary zone electrophoresis (CZE), was confirmed as a hitherto undescribed a chain variant, that we have named Hb Kalavasos for the Cypriot village of family origin of the proband.     

Hb Calais [β76(E20)Ala→Pro]: A Family Study of a Variant With Decreased Oxygen Affinity

Secondary to the detection of a chronic anemia with a slightly increased Hb F level in a 7‐year-old boy carrying a hemoglobin (Hb) variant, we investigated the members of his family and found that they were related to the original case of Hb Calais. In the present study, we report the clinical and biological impacts of this Hb variant in various members of three generations of this family.     

咳嗽变异性哮喘65例误诊分析

目的探讨咳嗽变异性哮喘(CVA)临床特点和误诊原因,提高其诊断水平。方法对65例CVA患者的临床资料进行回顾性分析。结果 65例患者全部误诊,其中误诊为急性上呼吸道感染25例(38.5%),慢性支气管炎18例(27.7%),急性支气管炎13例(20.0%),慢性咽炎8例(12.3%),过敏性鼻炎1例(1.5%)。治疗1周后,咳嗽基本消失21例(32.3%),明显缓解31例(47.7%),部分缓解13例(20.0%)。结论医师对本病认识不足、基层医院缺少必要的辅助检查是导致误诊的主要原因。     

Constant Transmission Properties of Variant Creutzfeldt-Jakob Disease in 5 Countries

Variant Creutzfeldt-Jakob disease (vCJD) has been reported in 12 countries. We hypothesized that a common strain of agent is responsible for all vCJD cases, regardless of geographic origin. To test this hypothesis, we inoculated strain-typing panels of wild-type mice with brain material from human vCJD case-patients from France, the Netherlands, Italy, and the United States. Mice were assessed for clinical disease, neuropathologic changes, and glycoform profile; results were compared with those for 2 reference vCJD cases from the United Kingdom. Transmission to mice occurred from each sample tested, and data were similar between non-UK and UK cases, with the exception of the ranking of mean clinical incubation times of mouse lines. These findings support the hypothesis that a single strain of infectious agent is responsible for all vCJD infections. However, differences in incubation times require further subpassage in mice to establish any true differences in strain properties between cases.     

Cancer cachexia: drugs in the patent literature

Background: The therapeutic approach to the neoplastic patient with cachexia is very frustrating for the physician. Indeed, we can say that a cure for cancer cachexia does not exist. Numerous therapeutic strategies have been tested in the last few decades with discouraging or at least conflicting results. Methods: Drugs patented for the treatment of cancer cachexia are evaluated and discussed. Results: New drugs such as ghrelin splice variant, small-molecule melanocortin-4 receptor antagonists and selective androgen receptor modulators have been discovered, evaluated with promising results, and patented. It is expected that soon they will be tested in humans through adequate clinical trials in experimental studies. Other compounds such as retinoid X receptor agonists, the inhibitor of LPS-induced TNF-α factor (LIPAF) protein, novel inhibitors of TNF-α production or release and tumour cytotoxic factor II need to be tested first in experimental models of cancer cachexia. Conclusion: With the recent discovery of new, effective drugs, it seems that a new scenario is opening up in the therapy of cancer cachexia.     

A new Unstable α2‐Globin Gene Variant: Hb Chartres [α33(B14)Phe→Ser]

Hb M Akita disease is a cyanotic hemoglobinopathy found in Akita Prefecture, Japan. The abnormal hemoglobin was found to be the same as Hb M Hyde Park (692 His → Tyr) by chemical analysis in 1967. In this disease signs of accelerated hemolysis (serum bilirubin, 2.4 mg/dl; splenomegaly, 2 finger breadths; Hb, 10.7 g/dl; reticulocyte index, 2.7) were noted, but the causes of its slight anemia were revealed to be fairly complex by ferrokinetic study, RBC life-span measurement, and ^mTc myeloscintigram.

The anemia in this disease is caused not only by shortened erythrocyte survival (T 1/2 = 11.5 days by ⁵¹Cr-tagging method) and sequestration of red cells in the spleen (Spleen: liver ratio = 2.5 ～ 3.0 by ⁵¹Cr-surface counting), hut also by slow supply of erythro-cytes to the peripheral blood from the bone marrow, presumably, related to the existence of unstable Hb M Akita and its derivative (Hb Akita) in the erythroid cells. Both Carrell's isopropanol test and Heinz body formation test were positive. In spite of maximally increased total erythropoiesis (8 times as high as the normal level; M:E ratio = 0.22:1.0), supply of red cells from the bone marrow to the peripheral blood was significantly decreased. The distribution of hemato-poietic sites throughout the body was reasonably uniform.     

Two New Hemoglobin Variants: Hb Tallahassee [α3(A1)Ser→Tyr; HBA2: c.11C>A] and Hb Madison-NC [β119(GH2)Gly→Ser; HBB: c.358G>A]

Of the 1570 reported hemoglobin (Hb) variants detected to date, 390 are α2-globin chain (some variants have yet to be identified by DNA analyses and are therefore presumed) and 827 are the result of mutations of the β-globin chain. Due to their location on the Hb structure, only a minority of these variants result in a clinical phenotype; most are silent and are detected during routine surveillance, are found incidentally during other disease-related investigations or following newborn screening programs. In this report we discuss phenotype/genotype and molecular characteristics of two new Hb variants, both of which were clinically silent. One is an α2-globin chain variant located at codon 3 [α3(A1)Ser→Tyr; HBA2: c.11C?>?A] named Hb Tallahassee and the other is a β-globin chain variant located at codon 119 [β119(GH2)Gly→Ser; HBB: c.358G?>?A] called Hb Madison-NC.     

Comparison of the clinical characteristics and outcomes of COVID-19 in children before and after the emergence of Delta variant of concern in Japan

Delta variant of concern (VOC) is the current predominant severe acute respiratory coronavirus type 2 strain causing coronavirus disease 2019 (COVID-19); however, information regarding the impact of the Delta VOC on clinical features and outcomes in pediatric patients with COVID-19 is limited. We conducted a retrospective observational study using the data of patients <18 years of age in COVIREGI-JP, the COVID-19 registry in Japan. The patients were divided into two groups according to the timing of enrollment in the registry (pre-Delta VOC era, October 2020 to May 2021; and Delta VOC era, August to October 2021), and the clinical characteristics and outcomes were compared between the two groups. During the study period, 950 and 349 pediatric patients were registered in the pre-Delta VOC and Delta VOC eras, respectively. The median patient age was younger and the proportion of patients with underlying diseases was higher in the Delta VOC era than that in the pre-Delta VOC era (10.0 vs 7.0 years, P < 0.001, and 7.4% [n = 70] vs. 12.6% [n = 44], P = 0.004, respectively). Significantly more patients were admitted to the intensive care unit in the Delta VOC era than in the pre-Delta VOC era (1.4% [ n = 5] vs. 0.1% [n = 1], P = 0.006), but no patient in either group died or required mechanical ventilation or extracorporeal membrane oxygenation throughout the study period, suggesting that the overall outcomes in children with COVID-19 remained favorable even in the Delta VOC era in Japan.     

Detection of Hb Anti-Lepore Hong Kong (NG_000007.3: g.63154_70565dup) in Chinese Individuals

We have identified four Chinese individuals from three unrelated families with raised Hb A₂ levels. The anti-Lepore hybrid hemoglobin (Hb) variant was amplified using a pair of primers, 5′ to the β-globin gene Cap site and 3′ to the δ-globin gene polyadenylation site (polyA) region, respectively. Direct sequencing of the βδ fusion products confirmed the anti-Lepore Hong Kong (NG_000007.3: g.63154_70565dup) variant. We found that this anti-Lepore variant is positioned in zone 3 on the capillary electrophoresis system. It may help in differential diagnosis of Hb variants and providing better information in clinical counseling.     

A Clinical Update of the Hb Siirt [β27(B9)Ala→Gly; HBB: c.83C>G] Hemoglobin Variant

We report a clinical update of the hemoglobin (Hb) variant [β27(B9)Ala→Gly; HBB: c.83C>G], named Hb Siirt, that was previously described as a silent variant in a 23-year-old Kurdish female. The patient was also a carrier of the codon 5 (–CT) (HBB: c.17_18delCT) frameshift mutation and of the ααα ^{anti 3.7} triplication. Her initial moderate β-thalassemia intermedia (β-TI) phenotype worsened with time, causing the patient to become a transfusion-dependent subject at the age of ～40 years. Subsequent molecular characterization of both parents revealed that the Hb Siirt variant was inherited by the mother, while the other two globin alterations (HBB: c.17_18delCT and ααα^{anti 3.7} triplication) were genetically transmitted by the father. The latter remained a carrier of a mild β-TI phenotype throughout his life, at least until the age of 65 years. We hypothesize that the worsened clinical conditions in the daughter were due to the additional, maternally inherited Hb Siirt variant. However, protein 3D conformational analysis did not seem to reveal substantial overall structural changes. Among the other three described variants [Hb Volga (HBB: c.83C>A), Hb Knossos (HBB: c.82?G>T), Hb Grange-Blanche (HBB: c.83C>T] that are due to nucleotide substitutions at codon 27 of the β-globin gene; only Hb Knossos causes a β⁺-thalassemia (β⁺-thal) phenotype.