CADASIL in Arabs: clinical and genetic findings

Background  

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is increasingly recognized as an inherited arterial disease leading to a step-wise decline and eventually to dementia. CADASIL is caused by mutations in NOTCH3 epidermal growth factor-like repeat that maps to chromosome 19. CADASIL cases have been identified in most countries of Western and Central Europe, the Americas, Japan, Australia, the Caribbean, South America, Tanzania, Turkey, South Africa and Southeast Asia, but not in Arabs.     

Modification of rat brain Kv1.4 channel gating by association with accessory Kvβ1.1 and β2.1 subunits

 We have examined the effects of co-expression of Kvβ1.1 and Kvβ2.1 subunits on the gating of rat brain Kv1.4 channels, expressed in Xenopus oocytes. Expression of Kv1.4 subunits alone produced a rapidly inactivating ”A” type current, which activated at potentials beyond –60 mV in a solution containing high levels of rubidium. Current activation curves obtained from tail current measurements were fitted with a Boltzmann function, with V _1/2 = –47 mV and k = 10 mV. Neither the Kvβ1.1 nor Kvβ2.1 subunits altered the voltage dependence of activation. Both subunits accelerated the activation time constant of Kv1.4, without affecting its voltage dependence. Surprisingly, the Kvβ2.1 subunit, which lacks an N-terminal inactivation domain, was almost as effective as the Kvβ1.1 subunit in speeding up Kv1.4. Steady-state inactivation of Kv1.4 was unchanged upon co-expression with either Kvβ1.1 or Kvβ2.1 subunits. Kv1.4 recovered from inactivation with two time constants; apart from an ≈ 50% lengthening of the slow time constant with a high Kvβ2.1 injection ratio, neither time constant was altered by either the Kvβ1.1 or Kvβ2.1 subunits, suggesting little interaction with recovery from C-type inactivation. Clearly, β subunits have the potential to modify the gating of Kv1.4 channels in the brain more subtly than has been suggested previously. Received: 17 March 1997 / Accepted: 30 June 1997     

Aspiration cytology of chromophobe cell carcinoma of the kidney

Fine-needle aspiration biopsy findings in three cases of chromophobe cell carcinoma are described and correlated with histologic and ultrastructural observations. In addition, comparisons are made with three cases each of oncocytoma and granular cell carcinoma. The cells in aspiration smears from chromophobe cell carcinoma closely correlated with histologic pattern of three cell types which were not present in oncocytomas and granular cell carcinomas. These cells had prominent cell borders, and their cytoplasm was either opaque and granular (type I) or variably translucent and reticular (type II and III). Ultrastructurally, the translucent areas within the cytoplasm contained large numbers of microvesicles which were unique to chromophobe cell carcinoma and were not seen in other neoplasms. Fine-needle aspiration may be used to diagnose chromophobe cell carcinoma and distinguish it from other related renal neoplasms. © 1995 Wiley-Liss, Inc.     

Relationship between the expression of various markers and prognostic factors in breast cancer

The immunohistochemical detection of six markers of breast cancer has been compared in the present study with known prognostic factors of the disease to establish locally a standard panel of markers for the management of breast cancer. Sections of tissue of 114 consecutive breast cancer cases were studied immunohistochemically, using antibodies against oestrogen receptor (ER), progesterone receptor (PR), androgen receptor, c-erbB2, cathepsin D, and cyclin D. Marker labelling was graded as recommended in the literature. Using the chi(2)-test, relationships were determined between marker labelling and histological type of cancer, tumour grade, tumour size, axillary lymph node status and age of patient. A p value below 0.05 was considered significant. A positive relationship was found between ER and PR and lower grades of cancer, and a negative relationship was found with medullary and atypical medullary carcinoma. The four other markers showed no relationship with grade or type of cancer. All markers showed no significant relationship with size of tumour, presence of axillary node metastasis or age of patient. There was positive correlation between c-erbB2 and cathepsin D. Our study confirms the association between ER and PR and histological type and grade of breast cancer, both known parameters of good prognosis. We found no consistent relationship between the other four markers and prognostic factors studied, other than the suggestion that c-erbB2 and cathepsin D may be useful markers for poor prognosis and can be usefully applied locally, especially in the light of the current availability of trastuzumab (Herceptin) for management of c-erbB2-positive cases. We found no relationship between the markers and tumour size, axillary lymph node status or age.     

Modulation of the cellular immune response during Plasmodium falciparum infections in sickle cell trait individuals.

Plasma and peripheral blood mononuclear cells (PBMC) were obtained from P. falciparum-infected individuals with and without the sickle cell trait at diagnosis and 7 days after treatment. HbAA and HbAS patients were compared for levels of plasma soluble IL-2 receptors (IL-2R) and the in vitro cellular reactivity to affinity-purified soluble P. falciparum antigens (SPAg), PPD and phytohaemagglutinin (PHA). At diagnosis, HbAS patients with clinical disease had lower plasma-soluble IL-2R levels and parasite counts than the corresponding HbAA patients, whereas HbAS and HbAA patients with asymptomatic infections had comparable soluble IL-2R levels and parasite counts. PBMC from HbAS patients had higher proliferation and IFN-gamma production in response to SPAg than PBMC from HbAA patients. The difference in the lymphoproliferative responses to SPAg between the two groups was evident in patients with asymptomatic infections. In all patients, the clinical severity, the soluble IL-2R levels and the parasite counts were directly related. The former two were inversely related to the proliferative responses to SPAg. After treatment, all the studied parameters were comparable in the two groups. The study indicates that during P. falciparum infection, HbAS compared with HbAA patients had lower in vivo cellular activation and higher in vitro cellular reactivity in response to soluble malaria antigens.     

A novel frame shift mutation in the HMG box of the SRY gene in a patient with complete 46,XY pure gonadal dysgenesis.

Pure gonadal dysgenesis or Swyer syndrome is a sex-reversal disorder resulting from embryonic testicular regression sequences especially during the first few weeks of fetal life and is induced by mutations in the SRY gene. In the present report, we describe a nonmosaic XY sex-reversed female with pure gonadal dysgenesis. Molecular analysis using sequential PCR to detect Y chromosomal microdeletions showed the presence of SRY, ZFY and AZFa, b and c regions. Automated sequencing of the SRY region revealed a new mutation (deletion of A (adenine) in codon 82 at position +244), leading to a frame shift mutation within the helix I of the HMG-box domain. This mutation generates a truncated protein and is very likely to produce an impairment of SRY DNA binding activity. The present findings further support the functional importance of the putative DNA binding activity of the SRY HMG-box domain.     

Linking: a dynamic electrophysiologic phenomenon in macroreentry circuits

The term "linking" has been used specifically to describe the mechanism for perpetuation of functional anterograde bundle branch block: namely, repetitive transseptal retrograde concealed penetration by impulses propagating along the contralateral bundle. We present selected examples that demonstrate tht linking-type phenomena actually have a wide spectrum of expression in human macroreentry circuits, particularly those incorporating either the bundle branches and His bundle or the normal pathway and Kent bundle. The examples presented are as follows: (1) persistent retrograde functional conduction delays in the His-Purkinje system during right ventricular pacing, (2) anterograde Kent bundle condution at rapid rates, dependent on prior block in the normal pathway, (3) persistent anterograde functional infra-His block of atrial impulses during rapid ventricular pacing in the presence of a retrogradely conducting accessory pathway, and (4) transient advancement of His activation with ventricular fusion complexes during overdrive ventricular pacing of bundle branch reentrant tachycardia. Based on these examples, we characterize linking as a generalized electrophysiologic phenomenon in which each successive impulse entering a macroreentry circuit propagates preferentially along one limb because of functional block in the contralateral limb resulting from the effects of the prior impulse. It is proposed that such functional block may be dynamically maintained either by repetitive impulse interference, which perpetuates local refractoriness (examples No. 1 to 3), or by repetitive impulse collision (example No. 4). The general conceptual scheme outlined can be applied to specific electrophysiologic phenomena associated with a wide variety of reentry circuits in man.     

Pakistan’s Response to COVID-19: Overcoming National and International Hypes to Fight the Pandemic

The COVID-19 outbreak started as pneumonia in December 2019 in Wuhan, China. The subsequent pandemic was declared as the sixth public health emergency of international concern on January 30, 2020, by the World Health Organization. Pakistan could be a potential hotspot for COVID-19 owing to its high population of 204.65 million and its struggling health care and economic systems. Pakistan was able to tackle the challenge with relatively mild repercussions. The present analysis has been conducted to highlight the situation of the disease in Pakistan in 2020 and the measures taken by various stakeholders coupled with support from the community to abate the risk of catastrophic spread of the virus.     

An Overview of the Treatment Options Used for the Management of COVID-19 in Pakistan: Retrospective Observational Study

BackgroundSince the first reports of COVID-19 infection, the foremost requirement has been to identify a treatment regimen that not only fights the causative agent but also controls the associated complications of the infection. Due to the time-consuming process of drug discovery, physicians have used readily available drugs and therapies for treatment of infections to minimize the death toll.ObjectiveThe aim of this study is to provide a snapshot analysis of the major drugs used in a cohort of 1562 Pakistani patients during the period from May to July 2020, when the first wave of COVID-19 peaked in Pakistan.MethodsA retrospective observational study was performed to provide an overview of the major drugs used in a cohort of 1562 patients with COVID-19 admitted to the four major tertiary-care hospitals in the Rawalpindi-Islamabad region of Pakistan during the peak of the first wave of COVID-19 in the country (May-July 2020).ResultsAntibiotics were the most common choice out of all the therapies employed, and they were used as first line of treatment for COVID-19. Azithromycin was the most prescribed drug for treatment. No monthly trend was observed in the choice of antibiotics, and these drugs appeared to be a random but favored choice throughout the months of the study. It was also noted that even antibiotics used for multidrug resistant infections were prescribed irrespective of the severity or progression of the infection. The results of the analysis are alarming, as this approach may lead to antibiotic resistance and complications in immunocompromised patients with COVID-19. A total of 1562 patients (1064 male, 68.1%, and 498 female, 31.9%) with a mean age of 47.35 years (SD 17.03) were included in the study. The highest frequency of patient hospitalizations occurred in June (846/1562, 54.2%).ConclusionsGuidelines for a targeted treatment regime are needed to control related complications and to limit the misuse of antibiotics in the management of COVID-19.