Diagnostic and therapeutic approach to adult central nervous system vasculitis.

The clinical manifestations of central nervous system (CNS) vasculitis are highly variable. In the absence of a positive CNS biopsy, CNS vasculitis is particularly suspected when markers of both vascular disease and inflammation are present. To facilitate the clinical and therapeutic approach to this rare condition, CNS vasculitis can be classified according to the size of the involved vessels. Vascular imaging is used to identify medium vessel disease. Small vessel disease can only be diagnosed with a CNS biopsy. Medium vessel vasculitis usually presents with focal neurological signs, while small vessel vasculitis more often leads to cognitive deficits, altered level of consciousness and seizures. Markers of CNS inflammation include cerebrospinal fluid pleocytosis or elevated protein levels, and vessel wall, parenchymal or leptomeningeal enhancement. The broad range of differential diagnoses of CNS vasculitis can be narrowed based on the disease subtype. Common mimickers of medium vessel vasculitis include intracranial atherosclerosis and reversible cerebral vasoconstriction syndrome. The diagnostic workup aims to answer two questions: is the neurological presentation secondary to a vasculitic process, and if so, is the vasculitis primary (i.e., primary angiitis of the CNS) or secondary (e.g., to a systemic vasculitis, connective tissue disorder, infection, malignancy or drug use)? In primary angiitis of the CNS, glucocorticoids and cyclophosphamide are most often used for induction therapy, but rituximab may be an alternative. Based on the available evidence, all patients should receive maintenance immunosuppression. A multidisciplinary approach is necessary to ensure an accurate and timely diagnosis and to improve outcomes for patients with this potentially devastating condition.

The Management of Persistent Distal Occlusions after Mechanical Thrombectomy and Thrombolysis: An Inter- and Intrarater Agreement Study.

BACKGROUND AND PURPOSE: The best management of patients with persistent distal occlusion after mechanical thrombectomy with or without IV thrombolysis remains unknown. We sought to evaluate the variability and agreement in decision-making for persistent distal occlusions. MATERIALS AND METHODS: A portfolio of 60 cases was sent to clinicians with varying backgrounds and experience. Responders were asked whether they considered conservative management or rescue therapy (stent retriever, aspiration, or intra-arterial thrombolytics) a treatment option as well as their willingness to enroll patients in a randomized trial. Agreement was assessed using κ statistics. RESULTS: The electronic survey was answered by 31 physicians (8 vascular neurologists and 23 interventional neuroradiologists). Decisions for rescue therapies were more frequent (n = 1116/1860, 60%) than for conservative management (n = 744/1860, 40%; P < .001). Interrater agreement regarding the final management decision was "slight" (κ = 0.12; 95% CI, 0.09-0.14) and did not improve when subgroups of clinicians were studied according to background, experience, and specialty or when cases were grouped according to the level of occlusion. On delayed re-questioning, 23 of 29 respondents (79.3%) disagreed with themselves on at least 20% of cases. Respondents were willing to offer trial participation in 1295 of 1860 (69.6%) cases. CONCLUSIONS: Individuals did not agree regarding the best management of patients with persistent distal occlusion after mechanical thrombectomy and IV thrombolysis. There is sufficient uncertainty to justify a dedicated randomized trial.

NCCT Markers of Intracerebral Hemorrhage Expansion Using Revised Criteria: An External Validation of Their Predictive Accuracy.

BACKGROUND AND PURPOSE: Several NCCT expansion markers have been proposed to improve the prediction of hematoma expansion. We retrospectively evaluated the predictive accuracy of 9 expansion markers. MATERIALS AND METHODS: Patients admitted for intracerebral hemorrhage within 24 hours of last seen well were retrospectively included from April 2016 to April 2020. The primary outcome was revised hematoma expansion, defined as any of a ≥6-mL or ≥33% increase in intracerebral hemorrhage volume, a ≥ 1-mL increase in intraventricular hemorrhage volume, or de novo intraventricular hemorrhage. We assessed the predictive accuracy of expansion markers and determined their association with revised hematoma expansion. RESULTS: We included 124 patients, of whom 51 (41%) developed revised hematoma expansion. The sensitivity of each marker for the prediction of revised hematoma expansion ranged from 4% to 78%; the specificity, 37%-97%; the positive likelihood ratio, 0.41-7.16; and the negative likelihood ratio, 0.49-1.06. By means of univariable logistic regressions, 5 markers were significantly associated with revised hematoma expansion: black hole (OR = 8.66; 95% CI, 2.15-58.14; P = .007), hypodensity (OR = 3.18; 95% CI, 1.49-6.93; P = .003), blend (OR = 2.90; 95% CI, 1.08-8.38; P = .04), satellite (OR = 2.84; 95% CI, 1.29-6.61; P = .01), and Barras shape (OR = 2.41, 95% CI; 1.17-5.10; P = .02). In multivariable models, only the black hole marker remained independently associated with revised hematoma expansion (adjusted OR = 5.62; 95% CI, 1.23-40.23; P = .03). CONCLUSIONS: No single NCCT expansion marker had both high sensitivity and specificity for the prediction of revised hematoma expansion. Improved image-based analysis is needed to tackle limitations associated with current NCCT-based expansion markers.

[Cryptogenic stroke management : where are we ?] / Prise en charge de l'AVC cryptogénique : où en sommes-nous ?

Cryptogenic stroke is an old definition that designates an ischemic stroke with no identifiable cause. The term of the embolic stroke of undetermined source was then introduced to identify non-lacunar strokes in whom thromboembolism was the likely mechanism. This subgroup of cryptogenic strokes remains heterogeneous with many potential and possibly associated embolic causes. Covert atrial fibrillation is probably less often involved than initially expected, in contrast to intracranial and extracranial atherosclerosis. The cardiologist should be involved in the search of underlying causes of ischemic stroke by helping the neurologist to identify the most likely diagnosis. Further research is necessary to select populations that may benefit from more effective and individualized treatment.

Differential induction of c-Jun NH2-terminal kinase and c-Abl kinase in DNA mismatch repair-proficient and -deficient cells exposed to cisplatin.

The c-Abl nonreceptor tyrosine kinase and the c-Jun NH2-terminal kinase (JNK/stress-activated protein kinase) are activated during the injury response to the DNA-damaging agent cisplatin. Loss of DNA mismatch repair activity results in resistance to cisplatin in human cancer cells, suggesting that the mismatch repair proteins function as a detector for cisplatin DNA adducts. To identify signaling pathways activated by this detector, we investigated the effect of the loss of DNA mismatch repair function on the ability of cisplatin to activate the JNK and c-Abl kinases. The results demonstrate that cisplatin activates JNK kinase 3.8 +/- 0.2-fold more efficiently in DNA mismatch repair-proficient than repair-deficient cells, and that activation of c-Abl is completely absent in the DNA mismatch repair-deficient cells. Furthermore, the results show that cisplatin-induced activation of JNK occurs through a stress-activated protein kinase/extracellular signal-regulated kinase kinase 1-independent mechanism. We conclude that activation of JNK and c-Abl by cisplatin is in part dependent upon the integrity of DNA mismatch repair function, suggesting that these kinases are part of the signal transduction pathway activated when mismatch repair proteins recognize cisplatin adducts in DNA.

In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair.

In vitro studies have shown that loss of DNA mismatch repair due to lack of either hMSH2 or hMLH1 activity results in low-level resistance to cisplatin but not to oxaliplatin, an analogue that produces a different type of DNA adduct. No information is currently available on whether this low-level resistance is sufficient to result in enrichment of mismatch repair-deficient cells during drug exposure in vitro or to account for clinical failure of treatment in vivo. Mixed populations of cells containing a minority of DNA mismatch repair-deficient cells constitutively expressing green fluorescence protein were exposed repeatedly in vitro to cisplatin and oxaliplatin. Treatment with cisplatin resulted in a gradual enrichment for DNA mismatch repair-deficient cells, whereas treatment with oxaliplatin did not. MSH2-/- and MSH2+/+ embryonic stem cells were established as xenografts in athymic nude mice. Animals were treated 48 h after tumor implantation with a single LD10 dose of either cisplatin or oxaliplatin. MSH2-/- tumors were significantly less responsive to cisplatin than MSH2+/+ tumors, whereas there was no difference in sensitivity to oxaliplatin. These results demonstrate that the degree of cisplatin resistance conferred by loss of DNA mismatch repair is sufficient to produce both enrichment of mismatch repair-deficient cells during treatment in vitro and a large difference in clinical responsiveness in vivo. The results identify loss of DNA mismatch repair as a mechanism of resistance to cisplatin but not oxaliplatin.

The role of DNA mismatch repair in platinum drug resistance.

Loss of DNA mismatch repair occurs in many types of tumors. The effect of the loss of DNA mismatch repair activity on sensitivity to cisplatin and a panel of analogues was tested using two pairs of cell lines proficient or deficient in this function. HCT116+ch2, a human colon cancer cell line deficient in hMLH1, was 2.1-fold resistant to cisplatin and 1.3-fold resistant to carboplatin when compared to a subline complemented with chromosome 3 expressing a wild-type copy of hMLH1. Likewise, the human endometrial cancer cell line HEC59, which is deficient in hMSH2, was 1.8-fold resistant to cisplatin and 1.5-fold resistant to carboplatin when compared to a subline complemented with chromosome 2 with a wild-type hMSH2. In contrast to cisplatin and carboplatin, which form the same types of adducts in DNA, there was no difference in sensitivity between the DNA mismatch repair-proficient and -deficient cell lines for oxaliplatin, tetraplatin, transplatin, JM335, or JM216. The formation of protein-DNA complexes that contained hMSH2 and hMLH1 was documented by mobility shift assay when nuclear extracts were incubated with DNA platinated with cisplatin but not with oxaliplatin. These results demonstrate a correlation between failure of the DNA mismatch repair proteins to recognize the platinum adduct and low-level resistance, suggesting a role for the DNA mismatch repair system in generating signals that contribute to the generation of apoptotic activity. They also identify the use of drugs whose adducts are not recognized as a strategy for circumventing resistance due to loss of DNA mismatch repair.

Modulation of cisplatin cytotoxicity by human recombinant interferon-gamma in human ovarian cancer cell lines.

Cytotoxic interactions between recombinant human interferon-gamma (IFN gamma) and cisplatin have been studied in six ovarian cell lines (IGROV1, NIHOVCAR3, SKOV3, OVCCR1, 2008 and its cisplatin resident variant 2008/C13*). Studies were performed using a cell survival assay. Results were assessed using median effect analysis. Synergy between these two drugs was observed in cell lines sensitive to IFN gamma, whatever their relative sensitivity or resistance to cisplatin, suggesting that IFN gamma enhances the cytotoxic activity of cisplatin. This interaction is not due to an increase in platinum accumulation in cells. This combination of drugs should be evaluated against human ovarian cancer xenografts in nude mice before its use in clinical practice.

Loss of DNA mismatch repair due to knockout of MSH2 or PMS2 results in resistance to cisplatin and carboplatin.

Loss of DNA mismatch repair is a common finding in hereditary nonpolyposis colon cancer as well as in many types of sporadic human tumors. The effect of loss of DNA mismatch repair activity on sensitivity to cisplatin and carboplatin was tested using MSH2 and PMS2 knockout cell lines. The knockout dMsh2 embryonic stem cell line was 2.1-fold more resistant to cisplatin and 1.7-fold more resistant to carboplatin when compared to the isogenic wild-type wt-2 cell line. Likewise, the PMS2(-/-) mouse fibroblasts were 1.9-fold more resistant to cisplatin and 1.5-fold more resistant to carboplatin when compared to the isogenic PMS2(+/+) fibroblasts. These findings demonstrate that loss of mismatch repair due to knockout of either MSH2 or PMS2 results in low-level resistance to cisplatin and carboplatin, drugs that form the same types of adducts in DNA. These data validate results previously obtained using non-isogenic mismatch repair-proficient and -deficient cell lines, and indicate that simple recognition of the cisplatin adduct by the MSH2/MSH6 heterodimer is not sufficient for full detector function, but that PMS2 is also required for the pro-apoptotic signal to be generated from this detector.

Swan-Ganz catheter: comparison of insertion techniques.

One hundred eighty-nine Swan-Ganz catheters were inserted in 165 critically ill patients with different techniques. Percutaneous catheterization through the subclavian, internal jugular, and antecubital veins and antecubital venous cutdown with or without fluoroscopy were compared. The antecubital approach, percutaneously or through a venous cutdown, was associated with most complications. We conclude that the method of choice is the percutaneous insertion of the balloon-tipped catheter through the subclavian or internal jugular veins and that fluoroscopy is unnecessary.

Epidermal growth factor enhances cisplatin-induced apoptosis by a caspase 3 independent pathway.

PURPOSE: Activation of the epidermal growth factor (EGF) receptor has previously been shown to increase the sensitivity of cancer cells to DNA-damaging agents, including cisplatin, UV-B, and gamma-radiation. We now investigated the mechanisms by which EGF enhances the sensitivity of human ovarian cancer cells to cisplatin. RESULTS: The effect of EGF on cisplatin sensitivity could not be entirely explained by alterations in the cellular detoxification of cisplatin by glutathione or DNA repair of transcribed genes, as assessed by a plasmid reactivation assay. Furthermore, EGF did not affect the levels of several proteins that regulate apoptotic pathways, including bcl2, bclXL, bax and p53. Cisplatin treatment resulted in activation of caspase 3 and subsequent cleavage of specific substrates containing the DEVD (Asp-Glu-Val-Asp) amino acid sequence, including PARP (poly(ADP-ribose) polymerase). The EGF-mediated increase in cisplatin-induced apoptosis, however, did not result in increased caspase 3 activity. Moreover, apoptosis induced by cisplatin alone was completely inhibited by the caspase 3 inhibitor DEVD-CHO, whereas cell death induced by combined treatment with cisplatin and EGF was not prevented by inhibition of caspase 3. CONCLUSION: Our results suggest that, although cisplatin alone induces apoptosis by a caspase 3 dependent pathway, EGF enhances cisplatin-induced cell death by activating an apoptotic pathway that is independent of caspase 3.

Groin hernias in elderly patients. Management and prognosis.

In a 10 year period, 1,496 patients aged 65 years or older were treated for groin hernias. A total of 1,755 hernias were diagnosed, of which 243 were incarcerated and 1,279 were surgically repaired. Emergency operations were performed in 235 patients with a mortality rate of 7.5 percent, compared with 1.3 percent for the elective cases. The postoperative morbidity rate was 56 percent in emergency cases and 20 percent in the elective cases. Patients with cardiovascular and pulmonary diseases had the worst prognosis. Local anesthesia had the least sequelae. We conclude that groin hernias in elderly patients should be repaired under elective conditions in the properly prepared patient, preferably while under local anesthesia.

Diastematomyelia and structural spinal deformities.

Sixty patients with diastematomyelia were seen over a thirty-year period and congenital scoliosis was found in 60 per cent. All of the patients had associated vertebral abnormalities and most (87 per cent) had a neural deficit. Myelography was helpful in the diagnosis, particularly prior to any procedure that might cause traction on the spinal cord. Laminectomy for removal of the spur was indicated when neural deficits were progressive or before corrective surgery on the spine, and in ten patients the operation alleviated neural sequelae. Observation of patients with diastematomyelia who have no neural deficit or a stable, non-progressing deficit is recommended.

The impact of total parenteral nutrition on antithrombin III.

A prospective study was undertaken to elucidate the effect, if any, of total parenteral nutrition on plasma Antithrombin III levels. A total of 309 patients were included in the study. The patients suffered from cancer, or chronic illness, or major trauma which necessitated total parenteral nutrition. Each patient acted as his own control. Pre and postinfusion Antithrombin III levels were measured at regular intervals. Statistically, the results of the study have shown that total parenteral nutrition does not significantly alter Antithrombin III levels.

Age-associated changes in quantitative ultrasonometry (QUS) of the os calcis in Lebanese women-assessment of a Lebanese reference population.

OBJECTIVE: This study was aimed to assess age changes in quantitative ultrasonometry (QUS) in a large sample of Lebanese women to determine a Lebanese reference population. DESIGN: Cross-sectional study. SUBJECTS AND METHODS: Broadband ultrasound attenuation (BUA) and speed of sound (SOS) and the stiffness index (SI) of the os calcaneus was measured in 4,320 women with a mean age of 52.5 years (age range 20 to 79 years) using three identical Achilles Express (GE/Lunar) and one Achilles Plus (GE/Lunar) ultrasonometry devices. Women were randomly selected and asked to participate in a nationwide screening program using the media, conferences, telephone calls etc. Measurements were performed at Red Cross centers located all over the country. No inclusion or exclusion criteria were used. RESULTS: There was an overall decline of 19.2% for BUA, 3.1% for SOS and 30.3% for SI between late adolescence and old age. In premenopausal women, BUA decreased only slightly by 3%, while postmenopausal women showed a significant decline of 16.2%. In contrast, SOS continuously decreased from the age of 42; there was a decline of 0.8% from adolescence to the menopause; postmenopausal women showed a larger decline of 2.4%. The SI of premenopausal women decreased by 6%, while postmenopausal women showed a significantly larger decline of 24.3%. SI value for the female Lebanese young adult reference is 8% lower than that of the American and European women (92 SI units compared to 100). At the age of 42, SI value for the Lebanese women is 10.4% lower than the American women and 7.5% lower than the European women (86 SI units compared to 96 and 93, respectively). At the age of 75, SI values for the Lebanese women is 4.4% lower than the American women and the European women (65 SI units compared to 68). The decline in stiffness index for the Lebanese women between age 20 and 75 years is about 30.3% compared to 32% for the American or European reference curves. The rate of decrease for the Lebanese women was 0.2 SI units per year for the premenopausal period, and 0.7 SI units per year for the postmenopausal period. CONCLUSION: The age-related female, Lebanese reference curve was significantly different from the American and the European reference curves used by the manufacturer. Therefore, the use of our standardized reference data instead of the proposed US or European database reduces the risk of overestimating osteoporosis in the Lebanese population. The impact of our results on the prevalence of osteoporotic fracture in Lebanon has to be evaluated later on.

Osteoporosis: combination therapy for better or worse.

Osteoporosis is a condition that is associated with an increased susceptibility for fractures. In the past few years, several drugs have become available that can reduce the incidence of fractures in patients with osteoporosis. Since these drugs work through different cellular mechanisms, combining agents of different classes may have an additive or multiplicative effect on fracture risk reduction. Combination treatments that have been evaluated in clinical trials include bisphosphonates with estrogen, raloxifene or PTH/ bisphosphonates and PTH/ estrogen. In general, these trials have shown increases in bone mineral density over that observed with each agent alone. However, whether anti-fracture efficacy is improved, or worsened remains to be established. This article reviews the combination treatments that have been evaluated in clinical trials, with a discussion of the potential benefits and risks that those treatments entail. Integrating safety and cost issues will eventually determine whether those combinations will become the standard of care.

Paget's disease of the male breast: a collective review and case report.

A brief review of the world literature is presented, of which 19 cases are accepted as genuine Paget's disease of the male breast, and one new case is reported. Emphasis is put on early diagnosis by biopsy, and definite treatment by radical mastectomy.

Kawasaki syndrome. An abdominal crisis.

Three new cases of hydrops of the gallbladder associated with mucocutaneous lymph node (Kawasaki) syndrome are presented. The increasing frequency of association of those two entities is emphasized. Ultrasonography is ideal for confirming the diagnosis of gallbladder hydrops and for follow-up. The preferred treatment is medical, and surgical intervention is indicated only for peritonitis and complications of acute acalculus cholecystitis.

Ciliated epithelial esophageal cyst: case report and review of the literature.

A brief review of the world literature on esophageal cysts is presented and a new case of ciliated esophageal cyst is reported. Emphasis is put on roentgenography and endoscopic examination as essential for diagnosis and on exploratory thoracotomy for definite diagnosis and treatment.

Obstetrical brachial plexus palsy. Prediction of outcome in upper root injuries.

Thirty obstetrical brachial plexus palsies involving the upper roots were retrospectively reviewed. There were 20 C5-C6 palsies and ten C5-C6-C7 palsies in which recovery of C7 occurred by the end of the first month. Recovery of elbow flexion at 3 months, C7 involvement and high birthweight were the best early predictors of outcome, but all were unreliable when used separately. In combination, recovery of elbow flexion and birthweight predicted the final outcome reasonably satisfactorily, particularly when elbow flexion at 9 months, and not 3 months was considered (risk of error = 13%). Brachial plexus reconstruction may therefore be justified when there was initial C7 involvement associated with increased birthweight and poor elbow flexion at 6-9 months.