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.

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.

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.

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.

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.

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.

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.

Socio-demographic characteristics of cancer patients: hospital based cancer registry in a tertiary care hospital of India.

AIM: To determine the socio-demographic characteristics of cancer patients. MATERIALS AND METHODS: Review of the Cancer registry, and patient interview. Information on socio-demographic profile, medical history, family history and previous treatment, if any, was retrieved from the patient. If the patient couldn't be contacted then information was taken from pathology/radiotherapy or medical records department. RESULTS: A total of 684 patients participated in the study. More than 40% of males and 53.7% of females were illiterate, P < 0.05. The majority (33.5%) of participants were of low socioeconomic status. The most frequently reported cancer (ca) in males it was ca lung (40.9) and ca oesophagus (9.8). In females most common cancer were ca breast (23.9) followed by ca cervix (11.7).

The inside mystery of jejunal gastrointestinal stromal tumor: a rare case report and review of the literature.

Gastrointestinal stromal tumors (GISTs) are malignant and rare form of soft tissue sarcoma of the digestive tract. The incidence of gastrointestinal stromal tumors is very low Kramer et al. 2005 Jejunal GISTs are extremely rare. Here we present a rare case of jejunal GIST with unusually large size at presentation. The patient presented with severe abdomen pain, exophytic growth, and dimorphic anemia. Surgical resection of the tumor was carried out, and operative findings revealed a 15 × 10 cm growth, arising from serosal surface of jejunum, at the antimesenteric surface. Diagnosis in this case was made by subjecting the resected specimen to immunohistochemical analysis. In view of large size of the resected tumor, and high-risk histopathological features, imatinib mesylate 400 mg once daily was given as adjuvant chemotherapy. Patient is asymptomatic without any evidence of tumor recurrence after six months of postoperative followup. Imatinib as such is recommended in metastatic, residual or recurrent cases of GISTs or which are surgically not removable; however, recent recommendations suggests the use of imatinib mesylate after radical surgery in high-risk cases, because it has shown a significant decrease in the recurrence rate, and the Food and Drug Administration (FDA) has also approved the use of imatinib as adjuvant therapy after complete resection of localized, primary GIST.

Clinical evaluation of two antiemetic combinations palonosetron dexamethasone versus ondansetron dexamethasone in chemotherapy of head and neck cancer.

INTRODUCTION: Palonosetron and ondansetron are two selective 5-hydroxytryptamine (5-HT3) receptor antagonists that have shown remarkable efficacy in controlling nausea and vomiting following administration of moderately emetic anticancer chemotherapy. Their efficacy is enhanced by the concurrent administration of dexamethasone. In the present study, we aimed to compare the antiemetic efficacy of a palonosetron plus dexamethasone (PD) schedule versus an ondansetron plus dexamethasone (OD) schedule. METHODS: A randomised, crossover trial was conducted in 30 patients with head and neck cancer who were receiving moderately emetogenic chemotherapy. The patients were divided into two groups. In the first cycle, one group was given a PD schedule and the other, an OD schedule. For the subsequent cycle, crossover of the antiemetic schedules was done. The antiemetic effects were evaluated by recording the intensity of nausea and the frequency of vomiting in the acute and delayed phases. RESULTS: Complete response in the acute phase was observed in 83.3 percent of the patients on the PD schedule and in 80 percent of those on the OD schedule. In the delayed phase, complete response was observed in 76.7 percent and 66.7 percent of the patients on the PD schedule and OD schedule, respectively. The overall rate of complete response was 66.7 percent in the PD group and 46.7 percent in the OD group. In the PD group, there were 73.3 percent of nausea-free patients as opposed to 66.7 percent in the OD group. CONCLUSION: The results suggest that the PD schedule was superior to the OD schedule in controlling emesis in cancer chemotherapy, although this difference was not statistically significant.

Primary retroperitoneal teratomas in children: a single institution experience.

OBJECTIVE: This study aims to highlight the clinical features, investigations and treatment outcome of retroperitoneal teratomas (RPT) in children. MATERIALS AND METHODS: A total of eight patients (six males and two females, age range between 6 months-10 years) of RPT admitted in the department of Paediatric Surgery, PGIMS, Rohtak, between 1996-2008, were studied. The patients were investigated with hematology, x-ray, ultrasound, and computerised tomography (CT) of abdomen and serum alpha-fetoprotein levels in pre and postoperative period. All patients underwent complete surgical resection. In one patient, the tumour had malignant component (yolk sac) and was given postoperative chemotherapy. Postoperative follow-up included serum alpha-fetoprotein in addition to clinical examination and radiological assessment to detect recurrences. RESULTS: The tumours were located on both sides in almost equal proportion (four on right, three on left, and one bilateral]. All tumours could be excised completely preserving the kidneys in all patients. But in one patient injury to inferior vena cava (IVC) occurred which was repaired successfully. Majority (7 out of 8) were histological benign, and in one yolk sac tumour was malignant component which needed chemotherapy. All children were on follow-up and one patient with malignancy lost to follow-up after three cycles of chemotherapy. In rest there was no tumour recurrence. CONCLUSION: RPT are rare paediatric neoplasms. As majority are benign, a complete excision preserving the kidneys, is usually curative. Serum alpha-fetoprotein is a reliable method of assessing recurrence. Malignancy in the tumour may warrant further chemotherapy.

Cytological diagnosis of pulmonary nocardiosis in an immunocompromised patient.

We report a case of pulmonary nocardiosis in an immunosuppressed patient having vasculitis who presented with fever, cough and chest pain. A suspicion of nocardiosis was made on auramine O staining of material procured by CT guided fine needle aspiration cytology right lung. Modified Ziehl-Neelsen staining was useful in confirming the diagnosis. The patient showed remarkable recovery after treatment with co-trimoxazole. Quick identification of this uncommon pathogen in the cytological material using special stains helped in timely diagnosis and successful treatment of the patient.

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.

Acanthamoeba encephalitis.

Central nervous system infection with free-living amoebae is rare. We present a fatal case of Acanthamoeba encephalitis in a 63-year-old female from India where acanthamoebae were demonstrated and cultured from CSF. In spite of treatment with amphotericin B, fluconazole and rifampicin the patient did not survive. Amoebic infection should be suspected in a patient of encephalitis of unexplained aetiology as timely diagnosis can lead to a favourable outcome.

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.

Pansinusitis due to Sporothrix schenckii.

Summary A case of mucocutaneous sporotrichosis presenting as mycotic pansinusitis with polyposis with intracranial and intraorbital extension in a patient from Punjab, India is described. The patient had nasal discharge, sneezing and nasal obstruction for 12 years, had undergone repeated surgeries (for endoscopic clearance) but had recurrence. Computerized tomography (CT) and magnetic resonance imaging (MRI) findings revealed pansinusitis. A definitive diagnosis of sporotrichosis was established by culture of Sporothrix schenckii, verification of its dimorphic character and a positive pathogenicity test. The patient was successfully treated with potassium iodide and itraconazole.