Neonatal Fever in the COVID-19 Pandemic: Odds of a Serious Bacterial Infection.

OBJECTIVES: A sepsis workup is recommended in young infants 56 days or younger with fever to rule out a serious bacterial infection (SBI). Given the reduction in non-severe acute respiratory syndrome - coronavirus 2 viral infections observed in multiple studies during the coronavirus diseases 2019 (COVID-19) pandemic, we sought to determine if the reduction in viral infections led to a change in the incidence of SBI in this vulnerable patient population. METHODS: We performed a multicenter, retrospective study of infants 56 days or younger presenting with fever to emergency departments of 6 community hospitals. We compared the incidence of SBIs, viral meningitis, and viral bronchiolitis during March 2020 to February 2021 (pandemic year) with the same calendar months in the 2 preceding years (prepandemic years). RESULTS: From March 2018 to February 2021, 543 febrile infants presented to the emergency departments, 95 during the pandemic year (March 2020 to February 2021) compared with 231 and 217 in the prepandemic years (March 2018 to February 2019 and March 2019 to February 2020, respectively).During the pandemic year, 28.4% of infants (27 of 95) were diagnosed with an SBI compared with 11.7% and 6.9% (P < 0.001) in the prepandemic years (27 of 231 and 15 of 217, respectively). Five patients were diagnosed with bacterial meningitis over the 3-year period, 4 of them during the pandemic year (4 of 95 [4.2%]). Positivity for viral cerebrospinal fluid polymerase chain reaction during the pandemic year was 6.4% (3 of 47) compared with 20.8% (25 of 120) and 20.4% (23 of 113) in prepandemic years (P = 0.070). During the pandemic year, 2.1% (2 of 95) febrile young infants were admitted with a comorbid diagnosis of bronchiolitis compared with 4.3% and 6.0% in the prepandemic years (P = 0.310). CONCLUSIONS: The COVID-19 pandemic led to an increase in the incidence of SBIs in febrile infants 56 days or younger, likely a result of reduction in non-severe acute respiratory syndrome - coronavirus 2 viral infections. Greater vigilance is thus warranted in the evaluation of febrile infants during the COVID-19 pandemic.

Casein Kinase II (CK2) as a Therapeutic Target for Hematological Malignancies.

BACKGROUND: Casein kinase II (CK2) is a pro-oncogenic protein, which is emerging as a promising therapeutic target in cancer. Recent studies have revealed an important role for CK2 in tumorigenesis. High levels of CK2 are noted in many malignancies including leukemia. Use of CK2 inhibitors in various malignancies including breast, prostate, and lung cancer are being tested. Although many CK2 inhibitors exist, only a few have emerged as selective inhibitors that are potent and effective. CX-4945 is a selective, orallybioavailable small molecule inhibitor, which has shown encouraging results in pre-clinical models of leukemia. METHODS: In this review we will elaborate on the structure and physiological function of the CK2 protein as well as its role in cancer. We will review, in depth, the role of CK2 in leukemia and its mechanisms of tumorigenesis via phosphorylation of the tumor suppressor protein Ikaros. We will discuss both the importance of Ikaros in leukemia suppression and the restoration of Ikaros' tumor suppressor function after CK2 inhibition by CX-4945 (a CK2-specific inhibitor). RESULTS: CK2 is an oncogene that is overexpressed in hematological malignancies. In high risk Pre-B ALL, CK2 phosphorylates Ikaros tumor suppressor and promotes leukemogenesis. Inhibition of CK2 using CX4945 restores Ikaros function and leads to anti leukemic effects in vitro and in pre-clinical leukemia models. CONCLUSION: CK2 is an attractive target in treatment of various cancers. Currently only a few specific CK2 inhibitors are available. Preclinical studies using CK2 inhibitor, CX4945 in high risk pediatric leukemias have shown promising results and warrants further testing in other types of leukemia.

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia.

Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL). The mechanisms of Ikaros tumor suppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B). Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation. Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros. In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros-mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2). Inhibition of CK2 results in increased binding of the Ikaros-HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation. In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B. In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL.

Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia.

Ikaros (IKZF1) is a tumor suppressor that binds DNA and regulates expression of its target genes. The mechanism of Ikaros activity as a tumor suppressor and the regulation of Ikaros function in leukemia are unknown. Here, we demonstrate that Ikaros controls cellular proliferation by repressing expression of genes that promote cell cycle progression and the phosphatidylinositol-3 kinase (PI3K) pathway. We show that Ikaros function is impaired by the pro-oncogenic casein kinase II (CK2), and that CK2 is overexpressed in leukemia. CK2 inhibition restores Ikaros function as transcriptional repressor of cell cycle and PI3K pathway genes, resulting in an antileukemia effect. In high-risk leukemia where one IKZF1 allele has been deleted, CK2 inhibition restores the transcriptional repressor function of the remaining wild-type IKZF1 allele. CK2 inhibition demonstrated a potent therapeutic effect in a panel of patient-derived primary high-risk B-cell acute lymphoblastic leukemia xenografts as indicated by prolonged survival and a reduction of leukemia burden. We demonstrate the efficacy of a novel therapeutic approach for high-risk leukemia: restoration of Ikaros tumor suppressor activity via inhibition of CK2. These results provide a rationale for the use of CK2 inhibitors in clinical trials for high-risk leukemia, including cases with deletion of one IKZF1 allele.

Portal hypertension with visceral leishmaniasis.

We conducted this study to observe evidence of portal hypertension in children with visceral leishmaniasis (VL). Eighty-eight consecutive cases (50 male) of VL were subjected to ultrasonography. Those with evidence of portal hypertension also underwent upper gastrointestinal endoscopy and liver biopsy. Eight patients had portal hypertension as evidenced by dilated caliber of portal and splenic veins. Two patients had periportal, splenic and peripancreatic collaterals and one patient had cavernous transformation of portal vein. Out of eight patients, four patients had esophageal and gastric varices. Liver biopsy was done in four patients and revealed hepatic sinusoidal dilations without any evidence of fibrosis. Portal hypertension may be an independent manifestation of VL and remain undiagnosed unless a physician maintains a high index of suspicion.

Unusual presentations of Visceral leishmaniasis.

We report 3 cases of Visceral leishmaniasis, who presented with unusual clinical manifestations. One child was diagnosed as hemophagocytic syndrome; another masqueraded with features of leukemoid changes alongwith hemophagocytosis and trilineage myelodysplasia; the third case presented with pyothorax. All the three patients showed amastigote forms of Leishmania donovani and positive serology (rk39 antigen). They showed complete clinical, hematological and parasitological resolution with Amphotericin B therapy.

H-reflex and motor nerve conduction studies in growth retarded newborn babies.

OBJECTIVE: To demonstrate the accelerated postnatal maturation/myelination in growth retarded babies compensating the deficit suffered by them during intrauterine life. METHODS: We studied 16 babies within the first 3 days of birth. These included 6 full term appropriate for gestational age babies (FT AGA) and 10 full term intrauterine growth retarded (FT IUGR). A separate group of 16 babies was examined at 2 months of age. In this group 7 were FT AGA and 9 were FT IUGR at the time of birth. H-reflex latency (HRL), motor nerve conduction velocity (MNCV) and H-reflex excitability (H/M) were measured in the right lower limb. Anthropometric measurements of the babies were also recorded meticulously. All the babies were neurologically normal on clinical evaluation. RESULT: At birth, MNCV was significantly lower in FT IUGR babies compared to FT AGA babies. However at the age of 2 months the MNCV of both FT AGA and FT IUGR was comparable. Other parameters (HRL and H/M) in the IUGR babies were comparable with normal babies both at birth and 2 months of age. In FT IUGR babies crown-heel length and weight was significantly lower than FT AGA babies both at the time of birth and at 2 months of age. CONCLUSION AND SIGNIFICANCE: The findings suggest that FT IUGR babies demonstrate accelerated postnatal peripheral neural maturation. At 2 months of age, the motor nerve conduction velocity of these growth retarded babies was comparable to that observed in normal AGA babies of similar age. This provides an insight into the functional aspect of the proven theories of decreased peripheral myelination in FT IUGR babies with subsequent rapid postnatal myelination that renders these babies neurologically equivalent to FT AGA babies despite not achieving comparable anthropometric parameters.