Preexisting posterior capsule defect progressing to white mature cataract.

We present two children discovered to have a total cataract in one eye with a posterior subcapsular cataract in the other eye. Sequential photography documented rapid progression of the posterior subcapsular cataract to a preexisting posterior capsule defect and subsequently to a white, mature cataract. We propose that early intervention be considered in cases with any posterior subcapsular changes (no matter how subtle) and history of total cataract in the fellow eye, especially in any situation where loss of follow-up is likely to occur. In the event surgery is not advised, parents should be warned about possible cataract progression and the importance of regular follow-up examinations.     

Dihydropyridine inhibition of neuronal calcium current and substance P release

Dihydropyridine (DHP) calcium channel antagonists, which inhibit the slowly inactivating or L-type cardiac calcium (Ca) current, have been shown to be ineffective in blocking⁴⁵Ca influx and Ca-dependent secretion in a number of neuronal preparations. In the studies reported here, however, the antagonist DHP nifedipine inhibited both the L-type Ca current and potassium-evoked substance P (SP) release from embryonic chick dorsal root ganglion (DRG) neurons. These results suggest that, in DRG neurons. Ca entry through L-type channels is critical to the control of secretion. The inhibition of Ca current by nifedipine was both voltage and time-dependent, significant effects being observed only on currents evoked from relatively positive holding potentials maintained for several seconds. As expected from these results, nifedipine failed to inhibit L-type Ca current underlying the brief plateau phase of the action potential generated from the cell's normal resting potential; likewise, no significant effect of the drug was observed on action potential-stimulated SP release evoked by electrical field stimulation. The results of this work are discussed in terms of an assessment of the role of L-type Ca channels in neurosecretion.This work was supported by United States Public Health Service Grant NS16483 (KD) and by a USPHS Postdoctoral Fellowship (SGR)     

A STAT4-dependent Th1 response is required for resistance to the helminth parasite Taenia crassiceps

To determine the role of STAT4-dependent Th1 responses in the regulation of immunity to the helminth parasite Taenia crassiceps, we monitored infections with this parasite in resistant mice lacking the STAT4 gene. While T. crassiceps-infected STAT4(+/+) mice rapidly resolved the infection, STAT4(-/-) mice were highly susceptible to infection and displayed large parasite loads. Moreover, the inability of STAT4(-/-) mice to control the infection was associated with the induction of an antigen-specific Th2-type response characterized by significantly higher levels of Th2-associated immunoglobulin G1 (IgG1) and total IgE as well as interleukin-4 (IL-4), IL-10, and IL-13 than those in STAT4(+/+) mice, who produced significantly more gamma interferon. Furthermore, early after infection, macrophages from STAT4(-/-) mice produced lower levels of the pro-inflammatory cytokines IL-12, tumor necrosis factor alpha, IL-1 beta, and nitric oxide (NO) than those from STAT4(+/+) mice, suggesting a pivotal role for macrophages in mediating protection against cysticercosis. These findings demonstrate a critical role for the STAT4 signaling pathway in the development of a Th1-type immune response that is essential for mediating protection against the larval stage of T. crassiceps infection.     

Parathyroid Carcinoma: A Single-Institution Experience with an Emphasis on Histopathological Features

Parathyroid carcinoma (PC) is a rare malignancy that poses a diagnostic challenge on histologic examination. We analyzed various clinicopathologic features of PC. Pathology reports and slides were reviewed to evaluate the diagnostic histopathologic features of archived cases of PC from the years of 2004–2018. The study cohort comprised twenty cases of PC. The median age was 49 years (range 21–73 years) with equal gender distribution (M:F = 1:1). Most patients presented with symptoms of hypercalcemia (n = 7, 54%). Serum calcium and serum parathyroid hormone were elevated in all but one patient. The right inferior parathyroid was commonly involved (n = 8/14, 57%). The mean tumor size was 2.4 cm (range 0.8–3.5 cm). On frozen section examination, PC was diagnosed in 8 out of 9 cases. Vascular (n = 19/20, 95%) and soft tissue invasion (n = 10/20, 50%) were the most common characteristic histologic findings. Capsular invasion was identified in all cases. Perineural invasion or metastasis at presentation was absent in all cases. Other histological features noted were intratumoral fibrous bands (70%), nodular growth pattern (70%), moderate nuclear atypia (30%), prominent nucleoli (20%), and necrosis (20%). Regional lymph nodes were negative for metastatic disease in all cases (n = 10). Eight out of 16 patients received adjuvant radiotherapy. Follow-up was available in 16 cases (median 21.5 months). Two patients died of disease. Vascular and soft tissue invasion are the most common diagnostic histologic features of PC. Capsular invasion is important to distinguish PC from its benign counterparts. Intraoperative frozen section examination can be used for accurate diagnosis and surgical management.     

Mosaic pathogenic variants in AKT3 cause capillary malformation and undergrowth

Capillary malformations are slow-flow vascular malformations that affect the microcirculation including capillaries and post capillary venules and can be associated with growth differences. Specifically, the association of capillary malformations with undergrowth is a vastly understudied vascular syndrome with few reports of genetic causes including PIK3CA, GNAQ, and GNA11. Recently, a somatic pathogenic variant in AKT3 was identified in one child with a cutaneous vascular syndrome similar to cutis marmorata telangiectatica congenita, undergrowth, and no neurodevelopmental features. Here, we present a male patient with a capillary malformation and undergrowth due to a somatic pathogenic variant in AKT3 to confirm this association. It is essential to consider that mosaic pathogenic variants in AKT3 can cause a wide spectrum of disease. There is a need for future studies focusing on capillary malformations with undergrowth to understand the underlying mechanism.     

A comparison of two techniques for cervical plexus blockade: evaluation of efficacy and systemic toxicity

We compared two techniques of cervical plexus blockade (CPB) for carotid endarterectomy. Cervical plexus nerve block was performed with a combination of bupivacaine and lidocaine, with injections at the C2-C3, C3-C4, and C4-C5 transverse processes in 11 patients (classical CPB) or with a single injection after localization of the cervical plexus with a nerve stimulator in 12 patients (interscalene CPB). Pain scores were obtained during block placement and at predetermined phases of the operation. Arterial blood was sampled before and 3, 5, 8, 10, 15, 25, 40, and 60 min after CPB for measurement of bupivacaine and lidocaine concentrations. Interscalene CPB was less painful than classical CPB. The techniques appeared equally effective. Patients in both groups required equivalent supplementation with IV fentanyl and additional local infiltration with lidocaine during the most painful stages of surgery. The maximal concentration of bupivacaine was lower in interscalene CPB compared with classical CPB (1.0 microg/mL versus 1.5 microg/mL, P < 0.01). The time required to reach the maximal concentration of bupivacaine was 15 (10-40) min in interscalene CPB and 10 (5-17) min in classical CPB (P < 0.05). Lidocaine maximal concentration was similar in both groups, however the time required to reach the maximal concentration was longer (P < 0.05) in interscalene CPB (15 [10-60] min) than in classical CPB (10 [8-20] min). We conclude that the interscalene CPB is as effective as the classical CPB as a regional technique for carotid endarterectomy and may be associated with a lower systemic absorption of bupivacaine. IMPLICATIONS: Cervical plexus blockade for carotid endarterectomy can be effectively performed with a single injection after localization of the cervical plexus with a nerve stimulator. This technique is simple and was associated with less systemic absorption of local anesthetic than the multiple-injection technique.     

Preemptive intravenous morphine-6-glucuronide is ineffective for postoperative pain relief

BACKGROUND: Morphine-6-glucuronide (M-6-G), a major metabolite of morphine, is reported to be more potent than morphine when administered intrathecally; however, its efficiency remains under debate when administered intravenously. This study was designed to assess the analgesic efficiency of intravenous M-6-G for the treatment of acute postoperative pain. METHODS: After informed consent was obtained, 37 adults (American Society of Anesthesiologists physical status I-II) who were scheduled for elective open knee surgery were enrolled in the study. General anesthesia was induced with thiopental, alfentanil, and vecuronium and was maintained with a mixture of nitrous oxide/isoflurane and bolus doses of alfentanil. At skin closure, patients were randomized into three groups: (1) morphine group (n = 13), which received morphine 0.15 mg/kg; (2) M-6-G group (n = 12), which received M-6-G 0.1 mg/kg; and (3) placebo group (n = 12), which received saline. At the time of extubation, plasma concentration of morphine and M-6-G was measured. Postoperative analgesic efficiency was assessed by the cumulative dose of morphine delivered by patient-controlled analgesia. Opioid-related side effects were also evaluated. RESULTS: No difference was noted in patient characteristics and opioid-related side effects. Morphine requirements (mean +/- SD) during the first 24 h in the M-6-G group (41+/-9 mg) and the placebo group (49+/-8 mg) were significantly greater (P<0.05) compared with the morphine group (29+/-8 mg). CONCLUSION: A single intravenous bolus dose of M-6-G was found to be ineffective in the treatment of acute postoperative pain. This might be related to the low permeability of the blood-brain barrier for M-6-G.     

The impact of CYP2C9 genetics and oral contraceptives on cytochrome P450 2C9 phenotype.

CYP2C9-dependent drug metabolism is subject to large interindividual variation. To some extent, this is explained by genetic polymorphism with expression of enzyme variants that differ in catalytic activity. The aim of this study was to characterize the variation in CYP2C9 phenotype in relation to genotype, with further analysis of the CYP2C9 gene in metabolic outliers. A study population of 126 healthy white subjects were recruited and genotyped for the variant alleles, CYP2C9*1-3. In CYP2C9 phenotyping with losartan, three subpopulations were distinguished that differed in the number of CYP2C9*3 alleles (0, 1, or 2). A three-fold higher metabolic ratio (MR; urinary losartan/carboxymetabolite) was found comparing CYP2C9*1/*3 (n = 20) to CYP2C9*1/*1 (n = 81), but there was considerable variation within each genotype. Subjects genotyped as CYP2C9*1/*1, but with an unexpectedly slow oxidation of losartan, were selected for DNA-sequencing analysis of the CYP2C9 gene. Interestingly, single nucleotide polymorphisms (SNPs) could not be identified either in the 5'-flanking region, the nine exons, or exon-intron boundaries. However, sequencing of the CYP2C9 gene was also carried out in patients genotyped as CYP2C9*1/*1 but with an exceptionally low steady-state clearance of S-warfarin. Here, five different SNPs were identified. In further analysis of the healthy volunteers, it became evident that women on oral contraceptives (OCs) had slower oxidation of losartan (MR of losartan: 1.7) than women without OCs (MR of losartan: 0.86). This novel finding was not explained by a different frequency of variant alleles. In summary, CYP2C9 genotype and oral contraceptives both contribute to a large interindividual variation in CYP2C9 activity.