Israel Medical Association Journal

Background: Immunoglobulin 4 (IgG4) is the least abundant immunoglobulin in the sera of healthy individuals; however, its levels can vary in different diseases such as IgG4-related disease (high) or Sjögren's syndrome (low). While previous studies have suggested the importance of IgG4 in autoimmune diseases, the clinical and biological significance of high or low levels remains unclear.

Objectives: To investigate the association between IgG4 antibody levels and systemic sclerosis (SSc), as well as the clinical features of the disease.

Methods: We measured IgG4 levels in the sera of 74 SSc patients from the years 2000 to 2019 and compared them to IgG4 levels in 80 healthy donors from the Israeli national blood bank. We performed correlation analyses between IgG4 levels and various factors, including age, sex, disease subtype, disease duration, organs involved, and medications taken by the patients.

Results: Our findings revealed significantly lower IgG4 levels in SSc patients compared to healthy participants. SSc patients receiving steroid treatment exhibited prominently lower IgG4 levels. In addition, SSc patients with Raynaud's phenomenon tended to have lower IgG4 levels compared to those without Raynaud's phenomenon.

Conclusions: Our study demonstrates that IgG4 levels are lower in SSc patients. Further research is needed to elucidate whether this observation contributes to the etiology of the disease or if it represents a common manifestation among other autoimmune diseases.

Background: Acquired hepatocerebral degeneration (AHD) is a neurologic complication of severe chronic liver disease (CLD) with portosystemic shunts. The proposed etiology is manganese accumulation in the brain tissue, especially in the basal ganglia. Combination of clinical manifestation, mostly extrapyramidal movement disorders, and hyperintensities on T1-weighted brain magnetic resonance imaging (MRI) is diagnostic. Although liver transplantation controversial, it is suggested for AHD.

Objectives: To depict clinical and neuroimaging characteristics and response to treatments in patients diagnosed with AHD at Sheba Medical Center.

Methods: Review of patients with AHD diagnosis at the Liver Diseases Center at Sheba Medical Center between 2012 and 2017, data of clinical and neuroimaging, follow-up, and response to treatments, including liver transplantation were recorded.

Results: Five patients with diagnosis of AHD were identified, median age at diagnosis 55 years (range 45–64 years). Four patients had cirrhosis at the time of AHD diagnosis. The main risk factor for AHD was the presence of portosystemic shunts. The most prevalent clinical manifestations were movement disorders, specifically a combination of extrapyramidal and cerebellar signs including instability, rigidity, tremor, bradykinesia, and cognitive impairment. Brain MRI revealed hyperintensities on T1-weighted images in the basal ganglia in all patients. Administration of antiparkinsonian drugs showed clinical improvement, whereas liver transplantation performed in two patients was not associated to neurological improvement.

Conclusions: AHD is related to portosystemic shunts. The combination of Parkinsonism and cerebellar signs and MRI pallidal lesions should alert physicians to the diagnosis. The role of liver transplantation in AHD is still controversial.

Background: New direct acting antiviral agent (DAA) therapies are associated with a high sustained virological response rate (SVR) in hepatitis C virus (HCV) patients. The understanding of the impact of SVR on fibrosis stage is limited.

Objectives: To determine the effect of treatment with the DAAs on long-term liver fibrosis stages, as determined by shear-wave elastography (SWE) or FibroTest©.

Methods: Fibrosis stage was determined at baseline and at 6-month intervals after end of treatment (EOT), using two‐dimensional SWE or FibroTest©; APRI and FIB-4 scores.

Results: The study comprised 133 SVR12 patients. After a median follow-up of 15 months (range 6–33), liver fibrosis stage decreased by at least 1 stage in 75/133 patients (56%). Cirrhosis reversal was observed in 24/82 (29%). Repeated median liver stiffness SWE values in cirrhotic patients were 15.1 kPa at baseline (range 10.5–100), 13.4 kPa (range 5.5–51) at 6 months, and 11.4 kPa (range 6.1–35.8) at 12 months after EOT, P = 0.01. During the second year after EOT, no statistically significant differences in liver fibrosis stage in 12, 18, and 24 months were found. Splenomegaly was the only significant negative predictor of liver fibrosis regression during all time points of repetitive noninvasive assessment.

Conclusions: Following successful DAA treatment, the majority of our HCV patients with advanced fibrosis demonstrated significant improvement, as assessed by non-invasive methods. Advanced fibrosis stage was a negative predictor of fibrosis regression. Longer follow-up periods are required to further establish the impact of DAAs treatment in HCV patients with advanced fibrosis

Background: Methylene blue (MB), an inhibitor of nitric oxide synthesis and its effects is a potentially effective treatment against distributive shock states such as septic shock and vasoplegic syndrome. MB has been shown to alleviate vasoplegia and promote an increase in blood pressure. It may reduce mortality. However, in the pediatric population, there are few case reports and only one controlled study on administration of MB use for vasoplegia, sepsis, or shock in general.

Objectives: To summarize the experience of administering MB for vasoplegic shock in a tertiary care pediatric intensive care unit.

Methods: A retrospective chart review of seven pediatric cases treated with MB for vasoplegic shock was conducted. MB was administered as a bolus followed by continuous infusion. The authors measured blood pressure, vasopressor, and inotropic support. Patient outcome was monitored.

Results: The authors observed a favorable hemodynamic response with an increase in blood pressure and a reduction in vasopressor and inotropic support needed following MB administration in six patients. No side effects were observed. Three patients eventually died one to two days later, secondary to their underlying disease.

Conclusions: This case series adds to the small body of evidence in the pediatric population supporting the use of MB for distributive shock states and emphasizes the need for larger, randomized trials evaluating its role in vasoplegic shock treatment.

Background: Accurate assessment of liver fibrosis is crucial for the management of patients with hepatitis C virus (HCV) infection.

Objectives: To evaluate the performance of liver segment-to-spleen volume ratio in predicting the severity of liver fibrosis.

Methods: Sixty-four consecutive HCV patients were enrolled in this retrospective study. All patients underwent contrast-enhanced computed tomography (CT) and were divided into three groups based on their hepatic fibrosis stage evaluated by shear-wave elastography (SWE): non-advanced (F0–F1, n=29), advanced (F2, n=19) and severe fibrosis (F3–F4, n=16). Using semi-automated liver segmentation software, we calculated the following liver segments and spleen volumes for each participant: total liver volume (TLV), caudate lobe (CV), left lateral segment (LLV), left medial segment (LMV), right lobe (RV) and spleen (SV), a well as their ratios: CV/SV, RV/SV, LLV/SV, LMV/SV and TLV/SV.

Results: RV/SV was found to discriminate between patients with non-advanced and advanced fibrosis (P = 0.001), whereas SV, CV, RV, TLV/SV, LMV/SV and RV/SV discriminated between patients with advanced and severe fibrosis (P < 0.05). RV/SV ≤ 3.6 and RV ≤ 2.9 were identified as the best cutoff values to differentiate non-advanced from advanced fibrosis and advanced from severe fibrosis with sensitivities of 72.2% and 92.7%, specificities of 72.7% and 77.8%, and with an area under the receiver operating characteristic (ROC) curve of 0.797 and 0.847, respectively (P ≤ 0.002).

Conclusions: RV/SV may be used for the assessment and monitoring of liver fibrosis in HCV patients prior to the administration of antiviral therapy, considering SWE as the reference method.

Objectives: To examine the difference in motor function and behavioral symptoms between patients with severe dementia who wander and those who do not.

Methods: We conducted a retrospective study reviewing the medical records of 72 patients with severe dementia, all residents of a dementia special care unit. Motor and behavioral aspects were compared between "wanderers" and “non-wanderers.”

Results: No difference was found in motor performance including the occurrence of falls between the wanderers and non-wanderers. A significant difference was found in aggressiveness and sleep disturbances, which were more frequent among the wanderers. There was no preference to wandering at a certain period of the day among the patients with sleep disturbances who wander.

Conclusions: In a protected environment wandering is not a risk factor for falls. Sleep disturbances and wandering co-occur, but there is no circumstantial association between the two symptoms.

Background: High frequency oscillatory ventilation based on optimal lung volume strategy is one of the accepted modes of ventilatory support for respiratory distress syndrome in very low birth weight infants. In 1999 it was introduced in our unit as the primary ventilation modality for RDS[1].

Objectives: To evaluate if the shift to HFOV[2] influenced the outcome of ventilated VLBW[3] infants in the neonatal intensive care unit of Carmel Medical Center.

Methods: Data were obtained from the medical charts of VLBW infants born at Carmel Medical Center, and late mortality data were taken from the Israel Ministry of Internal Affairs records. A retrospective analysis and a comparison with a historical control group ventilated by the conventional method were performed.

Results: A total of 232 VLBW infants with RDS were mechanically ventilated, from 1995 to 2003: 120 were ventilated using HFOV during the period 1999–2003 and 102 infants using CV[4] during 1995–1999. The mean gestational age of survivors was 27.4 ± 2 weeks in the HFOV group and 28.4 ± 2 in the conventional ventilation group (P = 0.03). The sub-sample of infants with birth weights <1000 g ventilated with HFOV showed higher survival rates than the infants in the conventional ventilation group, 53 vs. 25 (64.6% vs. 44.6%) respectively (P < 0.05). A trend for lower incidence of pulmonary interstitial emphysema was observed in the HFOV group.

Conclusions: The introduction of HFOV based on optimal lung volume strategy proved to be an efficient and safe method of ventilation support for VLBW infants in our unit.

Background: The Fibrotest-Actitest™ is a six-parameter scoring system that allows quantification of liver fibrosis and inflammation. This test has been validated by several studies in hepatitis B and C viruses and alcoholic liver disease, with a high correlation between the liver biopsy and the results of the FT-AT[1] (AUROC between 0.78 and 0.95).The FT-AT was introduced in Israel (Rambam Laboratory) in March 2005.

Objectives: To assess the results of HCV[2] patients who underwent the test during the period March 2005 to February 2006.

Methods: Serum was taken and brought to the central laboratory performing the tests within 4 hours. Six parameters were evaluated using commercial kits approved by the designer of the test (Biopredictive): total bilirubin, gamma-glutamyltransferase, alpha-2 macroglobulin, haptoglobin, alanine aminotransferase, and apolipoprotein-A1. The results were sent to the website of Biopredictive (France), which provided the FT-AT score online using a patented formula.

Results: Of the 325 patients tested, only 4 were not interpretable because of hemolysis. Patients' age ranged from 7 to 72 years (median 42); 54% were female. Liver biopsy was performed in 81 patients and was compared with the results of the Fibrotest. Findings were as follows: 27% of the patients were F0, 19% F1, 20% F2, 17% F3 and 17% F4; 18% were A0, 32% A1, 28% A2 and 22% A3. The AUROC curve comparing the Fibrotest with liver biopsy with a cutoff point at F2 and A2 for significant fibrosis and inflammation was 0.85 and 0.79 respectively.

Conclusion: Fibrotest is a simple and effective method to assess liver fibrosis and inflammation and can be considered an alternative to liver biopsy in most patients with HCV.

Background: Exposure of newborn animals to high concentrations of oxygen leads to diffuse alveolar damage similar to that seen in bronchopulmonary dysplasia in human infants. Therefore, neonatal rats are a suitable practical model of hyperoxic lung damage in human infants.

Objective: To determine the involvement of tumor necrosis factor-alpha and interleukin-6 in lung injury in neonatal rats exposed to 100% O2 concentration.

Methods: A randomized controlled study was designed in which litters of term Sprague-Dawley rat pups were assigned to experimental or control groups. The pups in the experimental group were placed in 100% O2 from birth for 9 days, while the control pups were placed in room air. Twelve to 15 pups from each group were sacrificed on day 1, 3, 6, 9 and 13 after birth for bronchoalveolar lavage collection and lung histologic study. The bronchoalveolar lavage fluid was assayed for TNFα and IL-6.

Results: Newborn rats exposed to 100% O2 for the first 9 days of life showed severe pulmonary edema and hypercellularity on days 1 and 3, which then improved to nearly complete resolution on days 6 and 9. Pulmonary TNFα was produced early on O2 exposure (day 3) and pulmonary IL-6 later (days 6 and 9).

Conclusions: Hyperoxia induces sequential production of pulmonary TNFα and IL-6, which corresponds to the severity of the pathological findings and the known inflammatory and anti-inflammatory role of these cytokines.

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TNFα= tumor necrosis factor-alpha

IL-6= interleukin-6