Clarifying the Cause and Treatment of Paroxysmal Hypertension (Pseudopheochromocytoma).

PURPOSE OF REVIEW: To review the clinical characteristics of paroxysmal hypertension (pseudopheochromocytoma), its previously unsuspected cause, and effective treatment approaches. RECENT FINDINGS: Patients with paroxysmal hypertension experience recurrent, sudden, unprovoked, symptomatic, and severe elevations of blood pressure that occur independently of current stress or perceived emotional distress. Recent findings point to a previously unsuspected psychosomatic etiology, linked in most to a past history of abuse, trauma, or prolonged severe stress, often with repression of pertinent emotions, or to a repressive coping style. Consistent with this understanding, treatment with an antidepressant is thus far the only pharmacologic intervention demonstrated to be effective in preventing recurrent paroxysms, and is effective in most patients. Other treatment approaches are discussed, including medications to acutely lower blood pressure during paroxysms, and, in some cases, the possibility of emotional healing.  Recent findings indicate that paroxysmal hypertension is a psychosomatic disorder frequently linked to a past history of trauma or prolonged severe stress, usually with longstanding repression of pertinent emotions. Data strongly encourage treatment with an antidepressant in patients with recurrent or severe paroxysms. Further studies are needed.

Spin Heat Engine Coupled to a Harmonic-Oscillator Flywheel.

We realize a heat engine using a single-electron spin as a working medium. The spin pertains to the valence electron of a trapped ^{40}Ca^{+} ion, and heat reservoirs are emulated by controlling the spin polarization via optical pumping. The engine is coupled to the ion's harmonic-oscillator degree of freedom via spin-dependent optical forces. The oscillator stores the work produced by the heat engine and, therefore, acts as a flywheel. We characterize the state of the flywheel by reconstructing the Husimi Q function of the oscillator after different engine run times. This allows us to infer both the deposited energy and the corresponding fluctuations throughout the onset of operation, starting in the oscillator ground state. In order to understand the energetics of the flywheel, we determine its ergotropy, i.e., the maximum amount of work which can be further extracted from it. Our results demonstrate how the intrinsic fluctuations of a microscopic heat engine fundamentally limit performance.

Scalable Creation of Long-Lived Multipartite Entanglement.

We demonstrate the deterministic generation of multipartite entanglement based on scalable methods. Four qubits are encoded in ^{40}Ca^{+}, stored in a microstructured segmented Paul trap. These qubits are sequentially entangled by laser-driven pairwise gate operations. Between these, the qubit register is dynamically reconfigured via ion shuttling operations, where ion crystals are separated and merged, and ions are moved in and out of a fixed laser interaction zone. A sequence consisting of three pairwise entangling gates yields a four-ion Greenberger-Horne-Zeilinger state |ψ⟩=(1/sqrt[2])(|0000⟩+|1111⟩), and full quantum state tomography reveals a state fidelity of 94.4(3)%. We analyze the decoherence of this state and employ dynamic decoupling on the spatially distributed constituents to maintain 69(5)% coherence at a storage time of 1.1 sec.

Phase-Stable Free-Space Optical Lattices for Trapped Ions.

We demonstrate control of the absolute phase of an optical lattice with respect to a single trapped ion. The lattice is generated by off-resonant free-space laser beams, and we actively stabilize its phase by measuring its ac-Stark shift on a trapped ion. The ion is localized within the standing wave to better than 2% of its period. The locked lattice allows us to apply displacement operations via resonant optical forces with a controlled direction in phase space. Moreover, we observe the lattice-induced phase evolution of spin superposition states in order to analyze the relevant decoherence mechanisms. Finally, we employ lattice-induced phase shifts for inferring the variation of the ion position over the 157 µm range along the trap axis at accuracies of better than 6 nm.

The Phenotypic Spectrum of COL4A3 Heterozygotes.

Introduction: The penetrance and phenotypic spectrum of autosomal dominant Alport Syndrome (ADAS), affecting 1 in 106, remains understudied. Methods: Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined ADAS, we matched COL4A3 heterozygotes 1:5 to nonheterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. Results: COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and kidney failure (P < 0.05 for all comparisons) but not bilateral sensorineural hearing loss (P = 0.9). Phenotypic severity was more severe for collagenous domain glycine missense variants than protein truncating variants (PTVs). For example, patients with Gly695Arg (n = 161) had markedly increased risk of dipstick hematuria (odds ratio [OR] 9.50; 95% confidence interval [CI]: 6.32, 14.28) and kidney failure (OR 7.02; 95% CI: 3.48, 14.16) whereas those with PTVs (n = 119) had moderately increased risks of dipstick hematuria (OR 1.64; 95% CI: 1.03, 2.59) and kidney failure (OR 3.44; 95% CI: 1.28, 9.22). Less than a third of patients had albuminuria screening completed, and fewer than 1 of 3 were taking inhibitors of the renin-angiotensin-aldosterone system. Conclusion: This study demonstrates a wide spectrum of phenotypic severity in ADAS due to COL4A3 with phenotypic variability by genotype. Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.

The Phenotypic Spectrum of COL4A3 Heterozygotes.

Most data on Alport Syndrome (AS) due to COL4A3 are limited to families with autosomal recessive AS or severe manifestations such as focal segmental glomerulosclerosis (FSGS). Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants (0.2%) who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined autosomal dominant AS, we matched COL4A3 heterozygotes 1:5 to non-heterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and end-stage kidney disease (ESKD) (p<0.05 for all comparisons) but not bilateral sensorineural hearing loss (p=0.9). Phenotypic severity tended to be more severe among patients with glycine missense variants located within the collagenous domain. For example, patients with Gly695Arg (n=161) had markedly increased risk of dipstick hematuria (OR 9.47, 95% CI: 6.30, 14.22) and ESKD diagnosis (OR 7.01, 95% CI: 3.48, 14.12) whereas those with PTVs (n=119) had moderately increased risks of dipstick hematuria (OR 1.63, 95% CI: 1.03, 2.58) and ESKD diagnosis (OR 3.43, 95% CI: 1.28, 9.19). Less than a third of patients had albuminuria screening completed, and fewer than 1/3 were taking inhibitors of the renin-angiotensin-aldosterone system (RAASi). Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.

Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity.

This study examined the role of cisplatin-induced p53 activation in regulation of caspases and cellular injury during cisplatin nephrotoxicity. The executioner caspase-6 and -7 but not caspase-3 were identified as transcriptional targets of p53 in cisplatin injury as revealed by chromatin immunoprecipitation, a reporter gene and electrophoretic mobility shift assays, and real-time PCR following overexpression and inhibition of p53. DNA binding by p53 involved the first introns of the human and mouse caspase-7 gene and the mouse caspase-6 gene. Studies in human kidney, breast, ovary, colon, and prostate tumor cell lines also validated these findings. Treatment of p53 (-/-) cells with cisplatin did not induce caspase-6 and -7 expression and subsequent activation. In caspase-3 (-/-) cells, inhibition of caspase-6 and -7 activations markedly prevented cisplatin-induced cell death. In an in vivo model of cisplatin nephrotoxicity inhibition of p53 activation by a p53 inhibitor suppressed transactivation of the caspase-6 and -7 genes and prevented renal failure. p53 (-/-) mice were resistant to cisplatin nephrotoxicity as assessed by renal function and histology. These studies provide first evidence for p53-dependent transcriptional control of the caspase-6 and -7 genes and its functional significance in cisplatin injury to renal cells and functional implication of cisplatin-induced p53 induction in vitro and in vivo in cisplatin nephrotoxicity.

Primary amoebic meningoencephalitis due to Naegleria fowleri.

Primary amoebic meningoencephalitis (PAM) due to Naegleria fowleri was detected in a 36-year-old, Indian countryman who had a history of taking bath in the village pond. He was admitted in a semi comatosed condition with severe frontal headache, neck stiffness, intermittent fever, nausea, vomiting, left hemiparesis and seizures. Computerized tomography (CT) scan of brain showed a soft tissue non-enhancing mass with erosion of sphenoid sinus. However CSF findings showed no fungal or bacterial pathogen. Trophozoites of Naegleria fowleri were detected in the direct microscopic examination of CSF and these were grown in culture on non-nutrient agar. The patient was put on amphotericin-B, rifampicin and ceftazidime but his condition deteriorated and was taken home by his relatives in a moribund condition against medical advice and subsequently died. A literature review of 7 previous reports of PAM in India is also presented. Four of theses eight cases were non lethal. The mean age was 13.06 years with male: female ratio of 7:1. History of contact with water was present in four cases. Trophozoites could be identified in all 8 cases in this series.

Practical consensus recommendations on management of HR + ve early breast cancer with specific reference to genomic profiling.

Breast cancer is a heterogeneous disease and patients are managed clinically based on ER, PR, HER2 expression, and key risk factors. The use of gene expression assays for early stage disease is already common practice. These tests have found a place in risk stratifying the heterogeneous group of stage I-II breast cancers for recurrence, for predicting chemotherapy response, and for predicting breast cancer-related mortality. Most guidelines for hormone receptor (HR)-positive early breast cancer recommend addition of adjuvant chemotherapy for most women, leading to overtreatment, which causes considerable morbidity and cost. Expert oncologist discussed about strategies of gene expression assays and aid in chemotherapy recommendations for treatment of HR + ve EBC and the expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists.

Practical consensus recommendations regarding the use of hormonal therapy in metastatic breast cancer.

Metastatic breast cancer (MBC) is cancer that has spread from the breast to another part of the body or has come back in another distant location. Treatment options for MBC depend on several factors. One of these factors is the levels of hormone receptors (HRs) in the tumor. Cancers with high levels of HRs, called HR-positive, use the hormones estrogen and progesterone to grow and spread. Hormonal therapy is a type of treatment specifically for HR-positive breast cancer. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of hormonal therapy and the management of HR-positive MBC for the benefit of community oncologists.

Practical consensus recommendations on ovarian suppression in early breast cancer (adjuvant).

Substantial survival benefits exist for patients with early-stage breast cancer who undergo treatment with single-modality ovarian suppression, but its value is uncertain. Expert oncologist discussed to determine whether additional benefits exist with ovarian suppression plus multiple adjuvant therapy which provides a new treatment option that reduces the risk of recurrence in early breast cancer. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists.

Cryogenic setup for trapped ion quantum computing.

We report on the design of a cryogenic setup for trapped ion quantum computing containing a segmented surface electrode trap. The heat shield of our cryostat is designed to attenuate alternating magnetic field noise, resulting in 120 dB reduction of 50 Hz noise along the magnetic field axis. We combine this efficient magnetic shielding with high optical access required for single ion addressing as well as for efficient state detection by placing two lenses each with numerical aperture 0.23 inside the inner heat shield. The cryostat design incorporates vibration isolation to avoid decoherence of optical qubits due to the motion of the cryostat. We measure vibrations of the cryostat of less than ±20 nm over 2 s. In addition to the cryogenic apparatus, we describe the setup required for an operation with 40Ca+ and 88Sr+ ions. The instability of the laser manipulating the optical qubits in 40Ca+ is characterized by yielding a minimum of its Allan deviation of 2.4 ⋅ 10-15 at 0.33 s. To evaluate the performance of the apparatus, we trapped 40Ca+ ions, obtaining a heating rate of 2.14(16) phonons/s and a Gaussian decay of the Ramsey contrast with a 1/e-time of 18.2(8) ms.

Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation.

Neuronal active Caspase-6 (Casp6) is associated with Alzheimer disease (AD), cognitive impairment, and axonal degeneration. Caspase-1 (Casp1) can activate Casp6 but the expression and functionality of Casp1-activating inflammasomes has not been well-defined in human neurons. Here, we show that primary cultures of human CNS neurons expressed functional Nod-like receptor protein 1 (NLRP1), absent in melanoma 2, and ICE protease activating factor, but not the NLRP3, inflammasome receptor components. NLRP1 neutralizing antibodies in a cell-free system, and NLRP1 siRNAs in neurons hampered stress-induced Casp1 activation. NLRP1 and Casp1 siRNAs also abolished stress-induced Casp6 activation in neurons. The functionality of the NLRP1 inflammasome in serum-deprived neurons was also demonstrated by NLRP1 siRNA-mediated inhibition of speck formation of the apoptosis-associated speck-like protein containing a caspase recruitment domain conjugated to green fluorescent protein. These results indicated a novel stress-induced intraneuronal NLRP1/Casp1/Casp6 pathway. Lipopolysaccharide induced Casp1 and Casp6 activation in wild-type mice brain cortex, but not in that of Nlrp1(-/-) and Casp1(-/-) mice. NLRP1 immunopositive neurons were increased 25- to 30-fold in AD brains compared with non-AD brains. NLRP1 immunoreactivity in these neurons co-localized with Casp6 activity. Furthermore, the NLRP1/Casp1/Casp6 pathway increased amyloid beta peptide 42 ratio in serum-deprived neurons. Therefore, CNS human neurons express functional NLRP1 inflammasomes, which activate Casp1 and subsequently Casp6, thus revealing a fundamental mechanism linking intraneuronal inflammasome activation to Casp1-generated interleukin-1-ß-mediated neuroinflammation and Casp6-mediated axonal degeneration.

Sequencing and enhanced expression of the gene encoding diadenosine 5',5'''-P1, P4-tetraphosphate (Ap4A) phosphorylase in Saccharomyces cerevisiae.

The gene, DTP, coding for diadenosine 5',5'''-P1, P4-tetraphosphate (Ap4A) phosphorylase was isolated from a Saccharomyces cerevisiae genomic DNA library in lambda gt11. In yeast and Escherichia coli transformed with the multicopy vector, YEp352, containing the cloned DTP gene, the Ap4A phosphorylase was produced at levels nine- to 17-fold higher than in untransformed hosts. The nucleotide (nt) sequence was determined. The gene codes for a polypeptide chain of 321 amino acids (aa). Two-aa sequence motifs of possible significance were identified: a potential adenine nt binding site and a potential phosphorylation site. The DTP gene is located on yeast chromosome III and is present as a single copy. Although multicopy vector expression increased the Ap4A phosphorylase activity ninefold above the endogenous activity in transformed yeast, the intracellular concentration of Ap4A did not decrease and the growth rate of the yeast was unchanged.

Thalidomide protects endothelial cells from doxorubicin-induced apoptosis but alters cell morphology.

Antiangiogenesis agents are now being used in clinical trials to reduce the risk of recurrence of cancer. Several of these agents, however, are associated with thrombosis, especially when used in combination with chemotherapy. Antiangiogenesis and thrombosis are both endothelial-related activities, and we therefore evaluated one presumed antiangiogenesis agent (thalidomide) on intact cultured endothelial cells, and on cultured endothelial cells injured by preincubation with doxorubicin. We evaluated cell viability, caspase-3 activation, morphology of cells using light microscopy, and protease activated receptor-1 (PAR-l) expression. In our experiments, doxorubicin induced a dose- and incubation time-dependent and caspase-3-mediated apoptosis of endothelial cells. Thalidomide alone caused no changes in intact endothelial cells in terms of morphology, cell viability or activation of caspase-3. In contrast, when thalidomide was added to doxorubicin-injured endothelial cells, there was protection from cell death, increase in viability of endothelial cells, induction of differentiation and formation of neotubules. Doxorubicin reduced the expression of thrombin receptor, PAR-1, as evaluated by immunostaining and flow cytometry. Thalidomide did not alter PAR-1 expression in untreated cells but restored its expression reduced by doxorubicin. These findings suggest that thalidomide may be procoagulant, not by enhancing doxorubicin-mediated endothelial cell injury, but by altering the expression of PAR-1 on injured endothelium and resulting in endothelial dysfunction, which may explain hypercoagulability in patients treated with chemotherapy followed by thalidomide.

Risk of seizures and neurocysticercosis in household family contacts of children with single enhancing lesions.

A small, single enhancing lesion (SEL) is often noted upon computed tomography (CT) in children and young adults with recent focal or generalized seizures. A high frequency of seizures has been reported in family members of persons with SEL. We studied the prevalence of seizures and cysticercus electro-immuno-transfer blot (EITB) based seropositivity among family members, specifically household family contacts of pediatric subjects with a SEL. An attempt was also made to determine the etiology of seizures in household family contacts using magnetic resonance imaging (MRI). Information regarding seizure semiology, personal and food habits and detailed family pedigrees was obtained from 20 consecutive pediatric subjects with a SEL and 51 of their household family contacts. EITB sero-assays and stool examinations were performed on all participating subjects. MRIs were done on all EITB positive household family contacts. A family history of seizures was obtained in six index children (30%) (five household first-degree relatives and two distant relatives). Seventeen index children (85%) and 14 family contacts (27%) were EITB positive. A tendency towards clustering of EITB positive cases within individual families was observed. Stool examinations did not reveal Taenia species ova in any of EITB positive subjects. Neuroimaging studies revealed abnormalities consistent with active or inactive neurocysticercosis in all five household family contacts with history of seizures. Four of these five subjects were EITB positive and one was EITB negative. We concluded that children with SEL and seizures may have a family history of seizures. There is a high seropositivity rate in household family contacts of pediatric subjects with solitary cysticercus granulomas (SCGs). EITB based seropositivity in household family contacts with seizures, strongly predicts a cysticercal etiology for seizures. It may be worthwhile to screen household family contacts of children with SEL for taeniasis-cysticercosis.

Hepatotoxicity in rat induced by partially purified toxins from Eupatorium adenophorum (Ageratina adenophora).

A group of rats were administered a methanolic extract of Eupatorium adenophorum (Ageratina adenophora) oven-dried (60 degrees C) leaf powder and a partially purified fraction from the methanolic extract. Administration of the methanolic extract and the partially purified fraction elicited a significant increase in total and conjugated bilirubin, alkaline phosphatase, 5'-nucleotidase and transaminases. Histopathology of the livers from these animals revealed dilated bile ducts and proliferative changes. Hepatocytes around the bile ducts showed necrotic changes. Biochemical and histopathological changes resembled those observed in response to administration of whole leaf powder. The hepatotoxin present in E. adenophorum leaves can be extracted with methanol and partially purified further using the procedure described.

Radiotherapy of brain tumours: reduced irradiation of normal brain.

We analysed the dose-volume distribution in normal brain in eight patients undergoing localized external beam radiotherapy for brain tumours. The results have been represented as integral dose-volume histograms and show that large volumes of normal brain receive clinically significant doses of radiation. A mean of 43% (range 24%-57%) of normal brain volume received more than 50% and a mean of 22% (range 9%-38%) received more than 85% of the maximum tumour dose. The amount of normal brain irradiated increased with enlarging target volume. With the use of customized shielding blocks the mean volume reduction of normal brain receiving more than 50% and 85% maximum tumour dose was 178 ml (median 183 ml; range 89-244 ml) and 110 ml (median 110 ml; 40-179 ml) respectively. This represents an average reduction of 13% and 8% of normal brain volume. Although clinically important this may not be sufficient for a significant improvement in therapeutic ratio.

Incidence of dengue fever in relation to climatic factors in Ludhiana, Punjab.

An outbreak of dengue fever occurred in Ludhiana in 1996 and 1997. A total of 505 patients who attended the hospital attached to Dayanand Medical College, Ludhiana were clinically diagnosed to have dengue fever. Of these, 460 cases were noticed between October and December 1996 while during 1997 only 45 dengue fever cases were observed. Serological examination using dengue IgG and IgM blot was performed with single serum samples of 189 patients. Of these, 129 serum samples were detected positive for anti dengue antibodies. Twenty eight patients died in the dengue epidemic, 12 of whom suffered from dengue haemorrhagic fever (DHF) and six with dengue shock syndrome (DSS). Male patients outnumbered the female patients. Seasonal and cyclic pattern of the disease incidence was observed.